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Neuro Endocriene Tumoren

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1 Neuro Endocriene Tumoren
Wim Wynendaele, MD, PhD Imeldaziekenhuis, Bonheiden


3 Steve Jobs Death Certificate Reveals Cause of Death to be Respiratory Arrest Due to Metastatic Pancreatic Tumor 10/10/2011

4 NET Introduction Gastroenteropancreatic (GEP)
Carcinoid tumor – Carcinoid syndroom Pancreatic NET gastrinoma insulinoma Diagnosis & Staging imaging pathology Therapy surgery loco regional transplantation systemic treatment Merckel Cell Carcinoma

5 Introduction DEFINITION
A subgroup of endocrine tumors formed by cells of epithelial origin, presenting with structural and functional characteristics similar to those of the normal endocrine cells specialised in the production of peptide hormones and amines Capacity to express specific markers such as chromogranin A, synaptophysin, neuron-specific enolase and Neural Cel Adhesion Molecule Scoazec J-Y, 2009; Van Hootegem Ph, Acta Gastro Belgica 2009

6 What are Neuroendocrine Tumours?
Neuroendocrine Tumours (NETs) Rare, heterogeneous, slow-growing tumours1 Mainly sporadic, can be familial2,3 Arise from cells with neuroendocrine origin1 Can arise from most organs, commonly1: GI tract and pancreas Endocrine organs Lung NETs may synthesise and secrete peptides/amines Secreted peptides/amines can be used as tumour markers, and may lead to clinical symptoms4–6 1 3 2 Credits: 1BSIP, Estiot; 2Pasieka; 3BSIP, Vero/Carlo; Science Photo Library Buchanan KD Gastroenterol Today 2003; 13: 2–3 Anderson RJ et al. Curr Opin Oncol 1997; 9: 45–54 Calendar A et al. Ann Oncol 2001; 12 (Suppl 2): S3–11 Edney JA et al. Am J Surg 1990; 160: 625–629 Neuman HPH et al. Sem Nephrol 2002; 22: 89–99 Soga J et al. J Exp Clin Cancer Res 1998; 17: 389–400

7 Introduction Neuroendocrine cells are distributed widely throughout the body, and neoplasms of these dispersed cells can arise at many sites. Broad spectrum: carcinoid tumors, pancreatic neuroendocrine tumors, medullary thyroid cancers, pheochromocytomas,…: characterized by slow growth and frequent secretion of hormones or vasoactive substances small cell carcinoma of the lung, Merckel cell tumor, poorly differentiated neuroendocrine carcinoma,… are highly aggressive neoplasms, and are usually advanced when diagnosed.

8 Indolent vs. Aggressive Biology
Well differentiated neuroendocrine tumor (carcinoid, atypical carcinoid, many primary sites) Medullary carcinoma of the thyroid Well differentiated pancreatic neuroendocrine tumor (islet cell tumor) Paraganglioma Pheochromocytoma Poorly differentiated  neuroendocrine carcinoma (many primary sites) (Extra)pulmonary small cell carcinoma Merkel cell tumor of the skin skin Neuroblastoma, adrenal Small cell lung cancer

9 Introduction RARE, BUT CHALLENGING All NETs have a malignant potential
In general, they grow slower than adenocarcinomas of the GI tract Most NETs are functionally inactive Some NETs never develop metastases Biological behaviour is different and can change over time NETs can arise solitarily or part of a genetic syndrome (e.g. MEN1) RARE, BUT CHALLENGING Van Hootegem Ph, Acta Gastro Belgica 2009

10 Aetiology of NETs Majority of NETs are sporadic:
Assumed to be sporadic mutations NETs may also be familial: Autosomal dominant inherited syndromes1–4 Multiple endocrine neoplasia I (MEN I) MEN II von Hippel Lindau (VHL) disease Carney complex Associated with other familial conditions4–5 Neurofibromatosis type I Tuberous sclerosis Buchanan KD Gastroenterol Today 2003; 13: 2–3 Neuman HPH et al. Sem Nephrol 2002; 22: 89–99 Kaltsas GA et al. Endocr Rev 2004; 25: 458–511 Calendar A et al. Ann Oncol 2001; 12 (Suppl 2): S3–11 Robbins SL et al. In Pocket Companion to Robbins Pathologic Basis of Disease (5th ed). WB Saunders Co, pp: 538


12 NET Terminology Clinicians often use ‘carcinoid’ to define non-pancreatic NETs arising from the GI tract (i.e. foregut, midgut, hindgut NETs) Clinicians use ‘carcinoid syndrome’ to describe symptomatic NETs with flushing of the skin, secretory diarrhoea, abdominal cramps and bronchoconstriction Pathologists often use ‘carcinoid’ to describe tumours with endocrine function (derived from enterochromaffin cells)

13 Carcinoid tumour distribution (%) based on 20,436 NETs1
NET Terminology Carcinoids (~67% of NETS) Carcinoids secrete numerous peptides, including serotonin (5-HT) and tachykinins ~10% carcinoids metastasise to liver and release 5-HT into the blood resulting in ‘carcinoid syndrome’ (cutaneous flushing, diarrhoea, abdominal pain) Carcinoid tumour distribution (%) based on 20,436 NETs1 1. SEER database 1973–2004

14 Pancreatic NETs by type based on 1,639 pancreatic NETs1
NET Terminology Pancreatic NETs (non-carcinoid): Functional (~40%) or non-functional (~60%) Functional pancreatic NETs usually defined by the predominant, clinically relevant hormone they secrete (eg insulin, gastrin, glucagon, VIP) Pancreatic NETs by type based on 1,639 pancreatic NETs1 Solcia E et al. Pancreatic endocrine tumors: General concepts; Non-functioning tumors and tumors with uncommon function CRC Press Öberg K and Modlin IM S Annals Oncol 2009; 20 (Suppl 4): 147–149

15 Incidence of NETs All GEP-NETs: 2.5–5 cases/100,000/year1–2
Carcinoid tumours Bronchial carcinoids: 0.6 per 100,000/year3 Midgut carcinoids: 2.4 per 100,000/year (based on 5-decade analysis of 13,715 carcinoids)2 Racial differences exist2 4.5 per 100,000/year in black population 2.6 per 100,000/year in white population Pancreatic NETs 60% non-functional: 3.5–4 per million/year4 Insulinomas: 2–4 per million/year5,6 Gastrinomas: 0.5–4 new cases per million/year5,6 Modlin IM et al. Lancet Oncol 2008; 9: 61–72 Modlin IM et al. Cancer 2003; 97: 934–959 Öberg K and Jelic S Annals Oncol 2009; 20 (Suppl 4): 147–149 Öberg K and Jelic S Annals Oncol 2009; 20 (Suppl 4): 150–153 Alexakis N et al. Best Pract Res Clin Gastroenterol 2008; 22: 183–205 Öberg K and Eriksson B Best Pract Res Clin Gastroenterol 2005; 19: 753–781

16 Introduction GastroEnteropancreatic NETs (GEP) 55-70 % Thoracic NETs
25 – 30 % Other sites 1-10 % NETs are rare, yearly incidence of 2-4 (?) per 105/year < 2 % of all GI malignancies are NETs 10% -13% without primary tumor Yao J, et al. J Clin Oncol, 2008; Van Hootegem Ph, Acta Gastro Belgica 2009

17 Improved diagnosis may underlie rising incidence of NETs
Increasing Incidence of NETs Based on 35,618 patients with carcinoids in the US (SEER database, 1973–2004)1 Improved diagnosis may underlie rising incidence of NETs Yao JC et al. J Clin Oncol 2008; 26: 3063–3072

18 Classification of NETs
Tumour-node-metastasis (TNM) classification system3,4 Staging based on anatomical features Applied to gastroenteric tumours (foregut NETs3, midgut and hindgut NETs4) Major prognostic factor for survival Complementary to pathological WHO classification Helps clinicians to characterise tumours more precisely and to define most appropriate therapeutic strategy WHO classification systems1,2 Based on macroscopic and histopathological features Introduced for common NETs (digestive NETs, 20001; thoracic NETs , 20042) No specific classification for rare NETs Classification does not drive therapeutic strategy Solcia E et al. (Eds) In WHO International histological classification of tumors, Edition 2. New York, Springer, 2000. De Lellis RA et al. (Eds) In WHO Classification of tumours. Pathology and genetics: Tumours of endocrine organs. IARC, Lyon, 2004 Rindi G et al. Virchows Arch 2006; 449: 395‒401 Rindi G et al. Virchows Arch 2007: 451: 757–762

19 TNM? The most recent 7th edition of the AJCC staging manual, which reflects a modification of proposal by ENETS , includes separate TNM staging systems for NETs of the appendix , pancreas ,stomach ,small bowel/ampulla of Vater and colorectal primary sites Although functionality may impact prognosis (eg, insulinomas are generally indolent tumors), the biologic behavior of most functioning NETs is defined by the grade and stage of the tumor.

20 Tumour-Node-Metastasis Classification of NETs1
Tumour (T): Size and location of primary tumour TX Primary tumour cannot be assessed Tis In situ tumour/dysplasia (<0.5 mm) (only defined for stomach) T0 No evidence of primary tumour T1‒T4 Dependent on specific Node (N): Has the tumour spread to regional lymph nodes? NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Regional lymph node metastases Metastases (M): Has the cancer metastasised to other parts of the body? MX Distant metastases cannot be assessed M0 No distant metastases M1 Distant metastases Rindi G et al. Virchows Arch 2006; 449: 395‒401

21 TNM classification used to define stage of specific NETs
Staging of NETs1 TNM classification used to define stage of specific NETs Stage Description T N M Stage 0 In situ tumour/dysplasia [for stomach only] Tis N0 M0 Stage I NETs with limited growth T1 Stage II A NETs that are larger in size or more invasive T2 B T3 Stage III NETs that have invaded surrounding tissues or have regional node metastases T4 Any T N1 Stage IV NETs with distant metastases always present Any N M1 Staging has been developed with some specificities for each digestive NET location Staging helps clinicians to characterise tumours and to define most appropriate therapeutic strategy Rindi G et al. Virchows Arch 2007: 451: 757‒762

22 Grading

23 Grading + IHC G1 en G2: goed gedifferentieerde NET, intense expressie van synaptophysin en Chromogranine A, Lokale necrose duidt meestal op G2 G3: hooggradig met necrotische zones, meestal minder chromogranine A expressie maar behoudt de intense synaptophysine kleuring

24 Chromogranine A Chromogranin A, CgA
a glycoprotein, stored in secretory granules ‘first-line’ marker of NETs sensitivity 84% and specificity 85-96% Borbath I et al. Acta Gastro Belgica 2009

25 Chromogranine A For non-serotonin producing carcinoids and pancreatic neuroendocrine tumors, serum chromogranin A (CGA): more sensitive than 5-HIAA serum levels of CGA can also be elevated in non-neuroendocrine related conditions!

26 Serotonin, 5-hydroxy-indolic acid (5-HIAA)
Serotonin & 5-HIAA - Serotonin (5-hydroxytryptamin) midgut (foregut) NETs dosage in blood is unreliable - 5-HIAA Serotonin, 5-hydroxy-indolic acid (5-HIAA) main metabolite of serotonin at least once with midgut tumors 24 h urinary collection is the gold standard collection on chlorydric acid AVOID: bananas, avocados, plums, eggplant, tomatoes, plantain, pineapples, walnuts Borbath I et al. Acta Gastro Belgica 2009

27 Endocrine Tumours, WHO classification
Well-differentiated Endocrine Tumours Benign Behaviour Uncertain Behaviour In general, slow-growing malignancies with low mitotic and proliferation indices Cells retain antigenic assets of their normal DES cell counterparts Well-differentiated Endocrine Carcinoma Poorly differentiated Endocrine Carcinoma Elevated proliferating and metastatic capacity. Cells of an abortive/incomplete endocrine phenotype. Mixed Endocrine Exocrine Tumour Tumour-Like Lesions Solcia et al. WHO international Histological Classification ot Tumours, Berlin 2000

28 NET Features Associated With Poor Prognosis
Poorer prognosis associated with: Presence of metastases1 *Poor differentiation2 * ≥ 3 cm primary tumour size2 *Non-functioning tumours2 High proliferative (Ki67) index3 Specific TNM classifications and grades Risk of reduced survival in patients with NETs classified as TNM stage III–IV, or grade 2–34 Tumour grading, mitotic rates and Ki67 index are inversely associated with survival for metastatic tumours5 * Evidence based on duodenopancreatic tumours Soga J J Exp Clin Cancer Res 2003; 22: 517–530 Madeira I et al. Gut 1998; 43: 422–427 Rindi G et al. Gastroenterology 1999; 116: 532–542 Pape UF et al. Cancer 2008; 113: 256‒265 Strosberg J et al. Hum Pathol [Epub ahead of print]

29 Survival rate depends on site of tumour origin and tumour spread
5 Year Survival Rate Decreases with Degree of Tumour Spread in Patients with Gastroenteric NETs Survival rate depends on site of tumour origin and tumour spread Janson ET et al. Ann Oncol 1997; 8: 685–690

30 NET Introduction Gastroenteropancreatic (GEP)
Carcinoid tumor – Carcinoid syndroom Pancreatic NET gastrinoma insulinoma Diagnosis & Staging imaging pathology Therapy surgery loco regional transplantation systemic treatment Merckel Cell Carcinoma

31 Carcinoid tumoren: Carcinoid tumors have traditionally been classified based upon their origin from the embryonic divisions of the alimentary tract.

32 Distribution Modlin IM et al. Gastroenterol, 2005

33 Abdominal obstruction
Clinical Features: Carcinoid Tumours Obstructive Jaundice 1 Non-functional (~90%)1 Represent majority of carcinoid tumours Incidental finding − e.g. liver ultrasound Abdominal pain/obstruction GI bleeding Obstructive jaundice Weight loss Functional (~10%) Symptoms due to excess hormone production − e.g. flushing, diarrhoea, wheezing Abdominal obstruction 3 2 Credits: 1Dr M.A. Ansary; 2GCA; 3Living Art Enterprises; Science Photo Library Liver metastases Kaltsas G and Grossman A In: Handbook of Neuroendocrine Tumours: Their Current and Future Management. BioScientifica, 2006, p. 98

34 Carcinoid Syndroom Symptomen veroorzaakt door het vrijzetten van een aantal polypeptiden, aminozuren en prostaglandines. Aminozuren: Serotonin, 5-Hydroxytryptophan, Norepinephrine, Dopamine, Histamine Polypeptides: Kallikrein, Pancreatic polypeptide, Bradykinin, Motilin, Somatostatin, Vasoactive intestinal peptide, Neuropeptide K, Substance P, Neurokinin A Prostaglandins

35 Carcinoid syndroom Orgaan Symptoom Frekwentie Oorzaak Huid Flushing 85
Kinines Telengiectasasien 25 Cyanose 18 Pellagra 7 Tryptophaan * GI Diarree/krampen 75-85 Serotonine Hart Re hartklep 40 ? Respiratoir Bronchospasmen 19 * Trypthophaan wordt 70% omgezet tot serotonine (ipv nl +/-1 %)


37 Development of Carcinoid Syndrome and Crisis1
Carcinoid Disease Carcinoid Syndrome Carcinoid Crisis Primary NETs usually asymptomatic for hormonal effects May present with obstructive symptoms (pain, nausea, and vomiting) despite normal radiology Usually result of liver metastases exacerbating clinical symptoms Hormone levels increase as tumour mass increases and liver function is compromised Associated with advanced disease Rare sequel to carcinoid syndrome Characterised by: Profound flushing Bronchospasm Tachycardia Hypotension Confusion Coma Precipitated by: Anaesthetic induction Surgical stress Embolisation Chemotherapy Insufficient somatostatin analogue cover Ramage JK et al. Gut 2005; 54 (Suppl IV): 1–16

38 Pancreatic NeuroEndocrine
Tumors SubType Distribution 5-year Survival Insulinoma 20 – 30 % 80 – 95 % Gastrinoma 15 – 20 % 50 – 70 % Glucagonoma 1 – 3 % 50 – 60 % VIPoma 2 – 4 % 40 – 50 % Somatostatinoma 0 – 1 % 20 – 40 % Non-Functioning and PPoma 10 – 50 % 30 – 50 % VIP: vasoactive intestinal peptide PP : pancreatic polypeptide

39 GASTRINOMA : duodenaal/pancreatisch
Extreem zz: 0.5-3/millioen/jaar Meest frekwente functionele NET van pancreas… MEN 1 syndroom (hyperparathyroidie) Variabele agressiviteit Diagnose: uitstuiten HP, geen PPI gebruik tijdens test, pH meting samen met Gastrine serum bij nuchter patient

40 Gastrin Suspected ZES (gastrinoma) Serum Gastrin off PPI (1 week)
multiple peptic ulcers personal or family history of hypercalcemia or pituitary tumor post bulbar ulcer recurrent PUD after surgery PUD + diarrhea PUD refractory to conventional dose of PPI unexplained refractory diarrhea large gastric fold Gastrin Serum Gastrin off PPI (1 week) < 1000 pg/ml ≥ 1000 pg/ml Secretin stimulation test Gastric pH probe Negative, but reassess Positive ≤ 4.0 > STOP Kaltas G, 2009

41 Insulinoma ZZ Vaak multipel, meestal benigne
1. Symptomen van hypoglycemie 2. Glucose <40mg/dL 3. verhoogd insuline 72 uur vastentest met meten van glucose, C-pepetide en insuline: diagnose van autonoom functionerend en sereterend insulinoma

42 Insulinoma a homogeneous enhancing lesion (black arrow) in the uncinate process of the pancreas, just posterior to the superior mesenteric vein (white arrow).

43 NET Introduction Gastroenteropancreatic (GEP)
Carcinoid tumor – Carcinoid syndroom Pancreatic NET gastrinoma insulinoma Diagnosis & Staging imaging pathology Therapy surgery Transplantation loco regional systemic treatment Merckel Cell Carcinoma

44 Diagnosis & Staging ‘The majority of patients doesn’t present with flushing, hypertension and/or secretory diarrhea’ ‘Most of them are asymptomatic or have vague and misleading symptoms’ Need for performant diagnostic tools fo find the needle in the haystack!

45 Diagnosis & Staging: Imaging
CT-scan and MRI pancreatic NETs : CTscan is performant - sensitivity 87%, specificity 83%, detection limit 1cm - hypovascular, large tumors with calcifications: malignant intestinal NETs : CTenteroclysis is a possible option Diffusion MRI and CT perfusion small, benign and well-differentiated tumors = Highly vascularised, high blood flow and short mean transit time malignant and high metastatic potential = Low blood flow and long mean transit time Vullerme M-P, 2009

46 Diagnosis & Staging: Imaging
Endoscopic Ultrasound (EUS) pancreatic NETs : detection and localisation of small lesions - sensitivity > 90% for insulinomas - sensitivity ± 80% for gastrinomas intestinal NETs : detection, localisation, staging and guidance of therapy (rectal) EUS and Fine Needle Aspiration (FNA) cytology, but also histology and Ki-67 determination O’Toole D, 2009

47 Diagnosis & Staging: Imaging
- Somatostatin Receptor Scintigraphy - ‘Octreoscan’ 111Indium-pentetreotide imaging technique for detection & staging Cave: insulinoma & poorly differentiated NETs Cave: spatial resolution Cave: lymphoma, meningioma, paraganglioma, pheochromocytoma, sarcoidosis, rheumatoid arthritis Cave: > 4 weeks after last long acting analogue Borbath I et al. Acta Gastro Belgica 2009; Hoersch et al. ASCO 2009

48 Diagnosis & Staging: Imaging
- 68Ga-labelled DOTATOC PET/CT gallium-68 is a positron emitter DOTATOC has 10 times more affinity for subtype 2 receptor PET/CT evaluation is possible 17% addtional information (18-F-dihydroxy-phenyl-alanine [18F-DOPA] and 11-C-5-hydroxytryptophan [11-C-5-HTP])

49 Diagnosis & Staging: Imaging
At diagnosis to identify the site of the primary tumour to evaluate the extent of local invasion search for metastatic dissemination assess the surgical resectability of the lesion(s) During follow-up to evaluate the rate of progression assess the response to treatment(s) detect recurrences or late metastases

50 Diagnosis & Staging: Pathology
A correct histological diagnosis, but also A correct histological staging HE-staining Behaviour Invasion of m. propria Differentiation Size (cm) AngioInvasion KI-67 Benign - Well ≤ 1 < 2% Benign or Low-Grade ≤ 2 -/+ Low-Grade + > 2 > 2% High-Grade Poorly Any > 30% Ki67-staining Kloppel et al. Ann NY Acad Sci, 2004; Rindi et al. Neuroendocrinology, 2004

51 Diagnosis & Staging: Algoritm
Suspected NET or Symptoms Inherited disorder? Biochemical/Pathological Diagnosis Imaging incl. DOTATOC PET CT Metastatic Localized

52 Therapy multidisciplinary +++
Surgery functioning vs. non-functioning tumours resection, radiofrequency ablation (RFA) transplantation Locoregional and radioisotopic targeted treatment Systemic treatment chemotherapy somatostatin analogs interferon molecular therapy

53 Therapy : surgery Surgery is the sole option to cure a patient with GEP but,… R0-resection is mandatory (median survival 110 vs. 34 months) a small minority (± 20%) of patients present with a potentially resectable primary GEP resection of the primary might give a survival benefit even in metastatic patients (median survival 7.4 years vs. 4.0 years) Surgery is an option to control symptoms of patients with GEP bleeding bowel obstruction, especially in ileal NETs functioning tumours Roeyen G et al. Acta Gastro Belgica 2009

54 Therapy : surgery Functioning
minimal invasive (enucleation) for pancreatic NET with a lower malignant potential such as insulinoma more aggressive for pancreatic gastrinoma resection of primary and/or metastais to control symptoms Localized non-Functioning aggressive surgery for lesions more than 3 cm only if patients develop symptoms Localized Roeyen G et al. Acta Gastro Belgica 2009

55 Aanpak van Levermetastasen
Belangrijke –negatief- prognostische factor Frekwent bij presentatie (tot 50%) Pancreas: 5 jaars overleving van 30-60% GI: 60-90% Primary unknown in 5-10%

56 Levermetastasen: heelkunde?
Bij alle operabele goed gedifferentieerde NET’s Duidelijk beter OS (in vergelijking met historische controles) Afwezigheid van extra abdominale metastasering of diffuse peritoneale carcinomatose Eventueel meerdere ingrepen Onvolledige debulking heelkunde? (meer dan 90% van tumor load)

57 Levermetastasen: RFA RFA: effectief, maar moeilijk zo M groter dan 3 cm, problemen met localisatie (bloedvaten, nabijgelegen organen) Eventueel in combinatie met heelkunde Laser induced thermotherapy, cryotherapy, ethanol injectie, brachytherapy, …

58 Levertransplantatie? Met HCC de enige indicatie voor levertx in maligne ziekte Uiteraard enkel leveraantasting 5 jaars overleving van 36% (laaggradige NET’s, jonge patienten,…)

59 Levertransplantatie? INCLUSION EXCLUSION No Standard of Care!
a low-grade NET small cell carcinoma and high-grade NET a primary NET drained by the portal system that was curatively resected conditions contraindicating liver transplantation metastatic liver involvement < 50% non-gastrointestinal NETs or tumors not drained by the portal system stable disease for at least 6 months age below 55 years No Standard of Care! Mazzaferro V et al. J Hepatol, 2007

60 Locoregional Approach
Therapy : locoregional therapy well differentiated Ki-67 < 2% absence of angio- and/or perineural invasion no p53 overexpression < 2 mitoses/10 high power fields Locoregional Approach Liver only metastatic a) Hepatic artery embolization (HAE) No randomized trials! b) Hepatic arterial chemoembolization (HACE) c) Hepatic arterial radioembolization with Yttrium90 Hendlisz A et al. Acta Gastro Belgica 2009

61 Hepatic Artery Embolisation/Chemoembolisation
Used to target hepatic metastases by interrupting tumour blood supply Technique Catheter passed into hepatic artery Arteriogram performed to identify artery supplying tumour Embolising particles or gelfoam injected to block blood supply to tumour In chemoembolisation, emulsion containing cytotoxic drug (e.g. streptozocin) precedes arterial block1 In carcinoid syndrome, somatostatin analogues are co-administered to avoid carcinoid crisis1 Outcomes Tumour shrinkage observed in 50% patients and expected to reduce overall tumour mass Effective procedure2,3 but significant side effects (e.g. fever, nausea, pain, abnormal liver function)4 Angiogram of the hepatic artery in a patient with carcinoid liver metastases Courtesy of Dr J. Ramage, North Hampshire Hospital, UK O’Toole D et al. Endocr Rel Cancer 2003; 10: 463–468 Dominguez S et al. Eur J Gastroenterol Hepatol 2000; 12: 151–157 Fiorentini G et al. J Chemother 2004; 16: 293–297 Moertel CG et al. Ann Intern Med 1994; 120: 302–309

62 Therapy : locoregional therapy
Indications progressive and/or symptomatic midgut tumours after failure of systemic chemotherapy to control hormone-related symptoms Contra-Indications complete portal vein thrombosis hepatic insufficiency previous Whipple procedure Results objective response : 33 – 86% response duration : 10 – 21 mths. before after

63 NET Introduction Gastroenteropancreatic (GEP)
Carcinoid tumor – Carcinoid syndroom Pancreatic NET gastrinoma insulinoma Diagnosis & Staging imaging pathology Therapy surgery transplantation loco regional systemic treatment Merckel Cell Carcinoma

64 Somatostatin analogs (SSAs)
Somatostatins = a family of peptide hormones (SST-14 & SST-28) SSTR-1-5 inhibition of growth hormone and all GI hormones gut motility splachnic flow absorption cell proliferation cell survival angiogenesis Somatostatin analogs (SSAs) Verslype C et al. Acta Gastro Belgica 2009

65 Somatostatin analogs (SSAs)
Therapy – ‘Somatostanine analogs’ Novartis Pharma Beaufour Ipsen Octreotide SC, 2-3x µg/d Lanreotide IM, 30 mg/14 d Octreotide LAR IM, mg/28 d Lanreotide autogel SC, mg/28 d SSTR2-5(3) Somatostatin analogs (SSAs) ‘cornerstone’ in the management of patients with NET symptom control, anti-proliferative (?) efficacy is dependent on tumor receptor expression (e.g. low in gastrinomas)

66 Somatostatin analogs (SSAs)
Therapy – ‘Somatostanine analogs’ EFFICACY TOXICITY Flushing disappearance 60% improvement 85% Early abdominal discomfort bloating steatorrhea Diarrhea disappearance 30% improvement 75% Late gallstones persistent steatorrhea Biochemical (5-HIAA) improvement >50% Tachyphylaxis Somatostatin analogs (SSAs)

67 For metastatic NET patients SEER* registry
Improved survival Patients with metastic NETs diagnosed after 1988 showed a significant improvement in median survival duration “One possible explanation is that the introduction of octreotide in 1987 improved the control of carcinoid syndrome and changed the natural history of NETs” *Surveillance, Epidemiology and End Results Yao J.C. et al. J Clin Oncol 2008;26:

68 Somatostatin analogs (SSAs)
Therapy – ‘Somatostanine analogs’ Authors Primary NET SD (%) OR (%) Saltz Mixed 34 50 Maton Pancreatic 107 39 7.5 Arnold 52 36.5 Di Bartolomeo 58 47 3 Erikson 13 70 5 Faiss 30 36 6.7 Aparicio 35 57 Shojamanesh Gastrinoma 15 6 15.2 5.7 Somatostatin analogs (SSAs) Verslype C et al. Acta Gastro Belgica 2009

69 PROMID – randomized, multicentric, phaseIII
Octreotide LAR 30 mg i.m. every 4 weeks Placebo i.m. every 4 weeks Continuation of treatment if no progression Informed consent Randomization 1:1 Month -1 3 6 9 12 15 18 Screening Primary endpoint: time to tumor progression Treatment was continued until CT or MRI documented tumor progression Follow-up until death CT and/or MRI was evaluated by a blinded central reader

70 PROMID – randomized, multicentric, phaseIII
Histologically confirmed, locally inoperable or metastatic well-differentiated midgut NETs Functionally active or inactive midgut NETs Sandostatine LAR (n=42) Placebo (n=43) Complete response (n) Partial response (n) 1 Stable disease (n) 28 16 Progressive disease (n) 10 23 Unknown (n) 3

71 PROMID – randomized, multicentric, phaseIII
Sandostatine LAR: 42 patients / 26 events Median 14.3 months [95% CI: 11.0–28.8] Placebo: 43 patients / 40 events Median 6.0 months [95% CI: 3.7–9.4] Time (months) Proportion without progression 0.25 0.5 0.75 1 6 12 18 24 30 36 42 48 54 60 66 72 78 HR= 0.34 [95% CI: 0.20–0.59], p =

72 Therapy : systemic therapy
Well-differentiated pancreatic endocrine tumors Authors Regimen ORR (%) mOS (mths) Moertel S/S+5-FU 42/42 36/63 16.5/26 D+S/C/S+5-FU 38/33/34 69/30/45 26.5/18/16.8 Delaunoit D+S 45 36 22.4 Cheng 16 6 NR Kouvaraki 5-FU+D+S 83 39 37 Bajetta DTIC+E+5-FU 28 / Rougier D+CDDP+5-FU 24 15 27 Rivera D+S+5-FU 12 54 21 median OS untreated of 40 months Delaunoit T et al. Acta Gastro Belgica 2009

73 Therapy : immunotherapy
Interferon-α growth inhibition and/or attenuation of angiognesis dose : 3 – 9 MU SC, 3x/wk; (pegIFNα: µg SC, 1x/wk) Leucocyte count 3.0x109/l response : biochemical = 50%; tumour = 12-15%. Interferon

74 Therapy : systemic therapy
Poorly-differentiated GEPs very aggressive, median OS untreated of 6 months Etoposide/Cisplatin objective response: 42 – 67 % response duration : 9 mths. median survival : 15 – 19 mths. Delaunoit T et al. Acta Gastro Belgica 2009

75 Therapy : targeted nuclear therapies
Meta-IodoBenzylGuanidine (MIBG) Peptide receptor radionuclide therapy (PRRT) 131I-MIBG 111In-DTPA-, 90Y-DOTA0, TYR3-, 177Lu-DOTA0, TYR3-octreotide (-ate) rich catecholamine excretion SSTR-2 overexpression symptomatic carcinoids NET expressing receptor symptomatic response > 50% radiological response 30% bone marrow toxicity (thromboc.) haematological, renal or liver toxicity Prospective, randomized trials Hendlisz A et al. Acta Gastro Belgica 2009

76 Therapy – 177Lu-DOTA0, TYR3-octreotate)
Dose: 600 – 800 mCi Indications high uptake on pretherapy SRSimaging limited number of liver metastases Results stable or regression : TTP > 36 mths. Type Response Complete Partial Stable Pancreas 9 % 22 % 34 % Midgut Carcinoid - 20 % 42 % All tumour 2 % 26 % 35 % Kwekkeboom DJ et al. J Clin Oncol, 2005

77 Figure 1 Intracellular signalling pathways in neuroendocrine tumours showing the PI3K/AKT/mTOR; RAS/RAF/MEK/ERK; PLC/PKC and JAK/STAT pathways. Intracellular signalling pathways in neuroendocrine tumours showing the PI3K/AKT/mTOR; RAS/RAF/MEK/ERK; PLC/PKC and JAK/STAT pathways. Adapted from Raymond et al. (2011a,b). VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet derived growth factor receptor; SSR, somatostatin receptor; IGF1R, insulin like growth factor 1 receptor; PI3K, phosphoinositide 3-kinase; RAS, rat sarcoma protein; PLC, phospholipase C; PKC, protein kinase C; JAK/STAT, Janus kinase signal transducer and activator of transcription. Karpathakis A et al. Endocr Relat Cancer 2012;19:R73-R92 © 2011 Society for Endocrinology

78 Therapy – ‘targeted’ therapy
Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor Inhibitors

79 Phase 3 Trial: Sunitinib vs Placebo in Advanced pNET
Study halted prior to complete accrual due to treatment benefit Unplanned Kaplan-Meier PFS analysis 1.0 P < .001; HR: (95% CI: to 0.649) 0.8 0.6 Sunitinib: PFS 11.1 mo Survival probability 0.4 Placebo: PFS 5.5 mo 0.2 Sunitinib Placebo Efficacy endpoint variable value (mo) Placebo, n Sunitinib, n Raymond E, et al. Presented at ESMO-GI 2009: Abstract 0013.

80 Therapy – ‘targeted’ therapy
mTOR Inhibitors

81 RADIANT-3: PFS by Investigator Review
Kaplan-Meier median PFS Everolimus: 11.0 months Placebo: 4.6 months HR = 0.35; 95% CI [ ] P < .0001 100 80 60 % Event-free 40 20 Censoring Times Everolimus (n/N = 109/207) Placebo (n/N = 165/203) 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (mo) No. of patients still at risk Everolimus Placebo 207 203 189 177 153 98 126 59 114 52 80 24 49 16 36 7 28 4 21 3 10 2 6 1 2 1 1 1 P-value obtained from stratified one-sided log rank test Hazard ratio is obtained from stratified unadjusted Cox model Yao J et al. 12th World Congress on Gastrointestinal Cancer; June 30-July 3, 2010; Barcelona, Spain. Poster # O-0028.

82 Flow diagram of therapies for localised and advanced gastroenteropancreatic neuroendocrine tumours.
Karpathakis A et al. Endocr Relat Cancer 2012;19:R73-R92 © 2011 Society for Endocrinology

83 NET Introduction Gastroenteropancreatic (GEP)
Carcinoid tumor – Carcinoid syndroom Pancreatic NET gastrinoma insulinoma Diagnosis & Staging imaging pathology Therapy surgery loco regional transplantation systemic treatment Merckel Cell Carcinoma

84 Merckel cell carcinoma
aggressive cutaneous malignancy that predominantly affects elderly Caucasians and has a propensity for local recurrence and regional lymph node metastases


86 Merckel Cell carcinoom
Casus: PM °09/06/1926 22/03/2012: excisie huidletsel onder been links: merckelcel tumor 17/04/2012: brede resectie Merkel-cel tumor pretibiaal links: Onvolledig verwijderd van 3 naar 12 uur en ter hoogte van 9 uur. Tekens van lymfevatinvasie. 03/05/2012: ziekteprogressie lokaal + inguinaal 15/05/2012 PET CT: + longmetastase: geen indicatie voor bijkomende lokale therapie 29/06/2012: 1x 8 Gy linker onderbeen 08/2012: 1x 8 Gy linker lies 15/01/2013: progressie lokaal + pleuraal vocht

87 Merckel Cell carcinoma: relative survival

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