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

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Presentation on theme: "Neuro Endocriene Tumoren Wim Wynendaele, MD, PhD Imeldaziekenhuis, Bonheiden."— Presentation transcript:

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 tumours 1 Mainly sporadic, can be familial 2,3 Arise from cells with neuroendocrine origin 1 Can arise from most organs, commonly 1 : o GI tract and pancreas o Endocrine organs o Lung NETs may synthesise and secrete peptides/amines Secreted peptides/amines can be used as tumour markers, and may lead to clinical symptoms 4–6 1.Buchanan KD Gastroenterol Today 2003; 13: 2–3 2.Anderson RJ et al. Curr Opin Oncol 1997; 9: 45–54 3.Calendar A et al. Ann Oncol 2001; 12 (Suppl 2): S3–11 4.Edney JA et al. Am J Surg 1990; 160: 625–629 5.Neuman HPH et al. Sem Nephrol 2002; 22: 89–99 6.Soga J et al. J Exp Clin Cancer Res 1998; 17: 389–400 Credits : 1 BSIP, Estiot; 2 Pasieka; 3 BSIP, Vero/Carlo; Science Photo Library 1 2 3

7 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. Introduction

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 - 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 syndromes 1–4 o Multiple endocrine neoplasia I (MEN I) o MEN II o von Hippel Lindau (VHL) disease o Carney complex Associated with other familial conditions 4–5 o Neurofibromatosis type I o Tuberous sclerosis 1.Buchanan KD Gastroenterol Today 2003; 13: 2–3 2.Neuman HPH et al. Sem Nephrol 2002; 22: 89–99 3.Kaltsas GA et al. Endocr Rev 2004; 25: 458–511 4.Calendar A et al. Ann Oncol 2001; 12 (Suppl 2): S3–11 5.Robbins SL et al. In Pocket Companion to Robbins Pathologic Basis of Disease (5th ed). WB Saunders Co, 1994. pp: 538


12 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) NET Terminology

13 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) 1. SEER database 1973–2004 Carcinoid tumour distribution (%) based on 20,436 NETs 1 NET Terminology

14 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) 1.Solcia E et al. Pancreatic endocrine tumors: General concepts; Non-functioning tumors and tumors with uncommon function. 1991. CRC Press 2.Öberg K and Modlin IM S Annals Oncol 2009; 20 (Suppl 4): 147–149 Pancreatic NETs by type based on 1,639 pancreatic NETs 1 NET Terminology

15 Incidence of NETs 1.Modlin IM et al. Lancet Oncol 2008; 9: 61–72 2.Modlin IM et al. Cancer 2003; 97: 934–959 3.Ö berg K and Jelic S Annals Oncol 2009; 20 (Suppl 4): 147–149 All GEP-NETs: 2.5–5 cases/100,000/year 1–2 Carcinoid tumours Bronchial carcinoids: 0.6 per 100,000/year 3 Midgut carcinoids: 2.4 per 100,000/year (based on 5-decade analysis of 13,715 carcinoids) 2 o Racial differences exist 2 o 4.5 per 100,000/year in black population o 2.6 per 100,000/year in white population Pancreatic NETs 60% non-functional: 3.5–4 per million/year 4 Insulinomas: 2–4 per million/year 5,6 Gastrinomas: 0.5–4 new cases per million/year 5,6 4.Öberg K and Jelic S Annals Oncol 2009; 20 (Suppl 4): 150–153 5.Alexakis N et al. Best Pract Res Clin Gastroenterol 2008; 22: 183–205 6.Öberg K and Eriksson B Best Pract Res Clin Gastroenterol 2005; 19: 753–781

16 Introduction Yao J, et al. J Clin Oncol, 2008; Van Hootegem Ph, Acta Gastro Belgica 2009 GastroEnteropancreatic NETs (GEP)55-70 % Thoracic NETs25 – 30 % Other sites1-10 % - NETs are rare, yearly incidence of 2-4 (?) per 10 5 /year - < 2 % of all GI malignancies are NETs - 10% -13% without primary tumor

17 1.Yao JC et al. J Clin Oncol 2008; 26: 3063–3072 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

18 Tumour-node-metastasis (TNM) classification system 3,4  Staging based on anatomical features  Applied to gastroenteric tumours (foregut NETs 3, midgut and hindgut NETs 4 )  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 systems 1,2  Based on macroscopic and histopathological features  Introduced for common NETs (digestive NETs, 2000 1 ; thoracic NETs, 2004 2 )  No specific classification for rare NETs  Classification does not drive therapeutic strategy Classification of NETs 1.Solcia E et al. (Eds) In WHO International histological classification of tumors, Edition 2. New York, Springer, 2000. 2.De Lellis RA et al. (Eds) In WHO Classification of tumours. Pathology and genetics: Tumours of endocrine organs. IARC, Lyon, 2004 3.Rindi G et al. Virchows Arch 2006; 449: 395 ‒ 401 4.Rindi G et al. Virchows Arch 2007: 451: 757–762

19 The most recent 7 th 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. TNM?

20 1.Rindi G et al. Virchows Arch 2006; 449: 395 ‒ 401 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 Tumour-Node-Metastasis Classification of NETs 1

21 Staging of NETs 1 1.Rindi G et al. Virchows Arch 2007: 451: 757 ‒ 762 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 TNM classification used to define stage of specific NETs StageDescriptionTNM Stage 0 In situ tumour/dysplasia [for stomach only]TisN0M0 Stage I NETs with limited growthT1N0M0 Stage II A NETs that are larger in size or more invasive T2N0M0 BT3N0M0 Stage III A NETs that have invaded surrounding tissues or have regional node metastases T4N0M0 BAny TN1M0 Stage IV NETs with distant metastases always presentAny TAny NM1

22 Grading

23  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 Grading + IHC

24 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 Chromogranine A

25 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! Chromogranine A

26 Serotonin & 5-HIAA Serotonin, 5-hydroxy-indolic acid (5- HIAA) Borbath I et al. Acta Gastro Belgica 2009 - Serotonin (5-hydroxytryptamin) - 5-HIAA midgut (foregut) NETs dosage in blood is unreliable 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

27 WHO Classification 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 Poorer prognosis associated with: Presence of metastases 1 *Poor differentiation 2 * ≥ 3 cm primary tumour size 2 *Non-functioning tumours 2 High proliferative (Ki67) index 3 Specific TNM classifications and grades o Risk of reduced survival in patients with NETs classified as TNM stage III–IV, or grade 2–3 4 o Tumour grading, mitotic rates and Ki67 index are inversely associated with survival for metastatic tumours 5 1.Soga J J Exp Clin Cancer Res 2003; 22: 517–530 2.Madeira I et al. Gut 1998; 43: 422–427 3.Rindi G et al. Gastroenterology 1999; 116: 532–542 4.Pape UF et al. Cancer 2008; 113: 256 ‒ 265 5.Strosberg J et al. Hum Pathol 2009 [Epub ahead of print] NET Features Associated With Poor Prognosis * Evidence based on duodenopancreatic tumours

29 5 Year Survival Rate Decreases with Degree of Tumour Spread in Patients with Gastroenteric NETs 1.Janson ET et al. Ann Oncol 1997; 8: 685–690 Survival rate depends on site of tumour origin and tumour spread

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

32 Distribution Modlin IM et al. Gastroenterol, 2005

33 Clinical Features: Carcinoid Tumours 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 Liver metastases Obstructive Jaundice 1.Kaltsas G and Grossman A In: Handbook of Neuroendocrine Tumours: Their Current and Future Management. BioScientifica, 2006, p. 98 Credits : 1 Dr M.A. Ansary; 2 GCA; 3 Living Art Enterprises; Science Photo Library 1 2 3

34  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 Carcinoid Syndroom

35 OrgaanSymptoomFrekwentieOorzaak HuidFlushing85Kinines Telengiectasasien25 Cyanose18 Pellagra7Tryptophaan * GIDiarree/krampen75-85Serotonine HartRe hartklep40? RespiratoirBronchospasmen19? Carcinoid syndroom * Trypthophaan wordt 70% omgezet tot serotonine (ipv nl +/-1 %)


37 Development of Carcinoid Syndrome and Crisis 1 Carcinoid DiseaseCarcinoid SyndromeCarcinoid 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: o Profound flushing o Bronchospasm o Tachycardia o Hypotension o Confusion o Coma Precipitated by: o Anaesthetic induction o Surgical stress o Embolisation o Chemotherapy o Insufficient somatostatin analogue cover 1.Ramage JK et al. Gut 2005; 54 (Suppl IV): 1–16

38 Pancreatic NeuroEndocrine Tumors SubTypeDistribution5-year Survival Insulinoma20 – 30 %80 – 95 % Gastrinoma15 – 20 %50 – 70 % Glucagonoma1 – 3 %50 – 60 % VIPoma2 – 4 %40 – 50 % Somatostatinoma0 – 1 %20 – 40 % Non-Functioning and PPoma10 – 50 %30 – 50 % VIP: vasoactive intestinal peptide PP : pancreatic polypeptide

39  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 GASTRINOMA : duodenaal/pancreatisch

40 Gastrin Kaltas G, 2009 Suspected ZES (gastrinoma) Serum Gastrin off PPI (1 week) Negative, but reassess < 1000 pg/ml 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 ≥ 1000 pg/ml Secretin stimulation testGastric pH probe Positive≤ 4.0> 4.0 - STOP

41  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 Insulinoma

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

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 - 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 Diagnosis & Staging: Imaging

46 - 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 Diagnosis & Staging: Imaging

47 - S omatostatin R eceptor S cintigraphy - ‘Octreoscan’ 111 Indium-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 Diagnosis & Staging: Imaging

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

49 - 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 Diagnosis & Staging: Imaging

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

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

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

53 Therapy : surgery Surgery is the sole option to cure a patient with GEP but,… - R 0 -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 - 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 - non-Functioning aggressive surgery for lesions more than 3 cm only if patients develop symptoms Localized Roeyen G et al. Acta Gastro Belgica 2009 Therapy : surgery

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

56  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) Levermetastasen: heelkunde?

57  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, … Levermetastasen: RFA

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

59 Mazzaferro V et al. J Hepatol, 2007 No Standard of Care! INCLUSIONEXCLUSION 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 Levertransplantatie?

60 Therapy : locoregional therapy Hendlisz A et al. Acta Gastro Belgica 2009 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) b) Hepatic arterial chemoembolization (HACE) c) Hepatic arterial radioembolization with Yttrium 90 No randomized trials!

61 Hepatic Artery Embolisation/Chemoembolisation 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 block 1 In carcinoid syndrome, somatostatin analogues are co-administered to avoid carcinoid crisis 1 Outcomes Tumour shrinkage observed in 50% patients and expected to reduce overall tumour mass Effective procedure 2,3 but significant side effects (e.g. fever, nausea, pain, abnormal liver function) 4 1.O’Toole D et al. Endocr Rel Cancer 2003; 10: 463–468 2.Dominguez S et al. Eur J Gastroenterol Hepatol 2000; 12: 151–157 3.Fiorentini G et al. J Chemother 2004; 16: 293–297 4.Moertel CG et al. Ann Intern Med 1994; 120: 302–309 Angiogram of the hepatic artery in a patient with carcinoid liver metastases Used to target hepatic metastases by interrupting tumour blood supply Courtesy of Dr J. Ramage, North Hampshire Hospital, UK

62 before after - 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. Therapy : locoregional therapy

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 Verslype C et al. Acta Gastro Belgica 2009 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

65 Somatostatin analogs (SSAs) Novartis PharmaBeaufour Ipsen Octreotide SC, 2-3x100-500µg/d Lanreotide IM, 30 mg/14 d Octreotide LAR IM, 20-30 mg/28 d Lanreotide autogel SC, 60-120 mg/28 d SSTR 2-5(3) - ‘cornerstone’ in the management of patients with NET - symptom control, anti-proliferative (?) - efficacy is dependent on tumor receptor expression (e.g. low in gastrinomas) Therapy – ‘Somatostanine analogs’

66 Somatostatin analogs (SSAs) EFFICACYTOXICITY 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 Therapy – ‘Somatostanine analogs’

67 For metastatic NET patients SEER* registry *Surveillance, Epidemiology and End Results Yao J.C. et al. J Clin Oncol 2008;26:3063-3072 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”

68 Somatostatin analogs (SSAs) AuthorsPrimary NETn°SD (%)OR (%) SaltzMixed34500 MatonPancreatic107397.5 ArnoldMixed5236.50 Di BartolomeoMixed58473 EriksonMixed13705 FaissMixed30366.7 AparicioMixed35573 ShojamaneshGastrinoma15476 ArnoldMixed5215.25.7 Verslype C et al. Acta Gastro Belgica 2009 Therapy – ‘Somatostanine analogs’

69 Month 0369121518 Screening Informe d consent Randomization 1:1 Continuation of treatment if no progression Octreotide LAR 30 mg i.m. every 4 weeks Placebo i.m. every 4 weeks 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 PROMID – randomized, multicentric, phaseIII

70 Sandostatine LAR (n=42) Placebo (n=43) Complete response (n)00 Partial response (n)11 Stable disease (n)2816 Progressive disease (n)1023 Unknown (n)33 - Histologically confirmed, locally inoperable or metastatic well-differentiated midgut NETs - Functionally active or inactive midgut NETs

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 0.25 0.5 0.75 1 06121824303642485460667278 HR= 0.34 [95% CI: 0.20–0.59], p = 0.000072

72 Delaunoit T et al. Acta Gastro Belgica 2009 Well-differentiated pancreatic endocrine tumors median OS untreated of 40 months AuthorsRegimenn°ORR (%)mOS (mths) MoertelS/S+5-FU42/4236/6316.5/26 MoertelD+S/C/S+5-FU38/33/3469/30/4526.5/18/16.8 DelaunoitD+S453622.4 ChengD+S166NR Kouvaraki5-FU+D+S833937 BajettaDTIC+E+5-FU28 / RougierD+CDDP+5-FU241527 RiveraD+S+5-FU125421 Therapy : systemic therapy

73 Interferon - Interferon-α growth inhibition and/or attenuation of angiognesis dose: 3 – 9 MU SC, 3x/wk; (pegIFNα: 50-100 µg SC, 1x/wk) Leucocyte count 3.0x10 9 /l response: biochemical = 50%; tumour = 12-15%. Therapy : immunotherapy

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

75 Therapy : targeted nuclear therapies Hendlisz A et al. Acta Gastro Belgica 2009 Meta-IodoBenzylGuanidine (MIBG)Peptide receptor radionuclide therapy (PRRT) 131 I-MIBG 111 In-DTPA-, 90 Y-DOTA 0, TYR 3 -, 177 Lu-DOTA 0, TYR 3 -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

76 Therapy – 177 Lu-DOTA 0, TYR 3 -octreotate) Kwekkeboom DJ et al. J Clin Oncol, 2005 - Dose: 600 – 800 mCi - Indications high uptake on pretherapy SRSimaging limited number of liver metastases - Results stable or regression : TTP > 36 mths. TypeResponse CompletePartialStable Pancreas9 %22 %34 % Midgut Carcinoid-20 %42 % All tumour2 %26 %35 %

77 Figure 1 Intracellular signalling pathways in neuroendocrine tumours showing the PI3K/AKT/mTOR; RAS/RAF/MEK/ERK; PLC/PKC and JAK/STAT pathways. 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 Placebo, n7925610 Sunitinib, n74321420 1.0 Survival probability 05101520 Efficacy endpoint variable value (mo) Sunitinib Placebo Raymond E, et al. Presented at ESMO-GI 2009: Abstract 0013. Phase 3 Trial: Sunitinib vs Placebo in Advanced pNET Study halted prior to complete accrual due to treatment benefit Unplanned Kaplan-Meier PFS analysis Sunitinib: PFS 11.1 mo Placebo: PFS 5.5 mo P <.001; HR: 0.397 (95% CI: 0.243 to 0.649) 0.8 0.6 0.4 0.2 0

80 Therapy – ‘targeted’ therapy mTOR Inhibitors

81 RADIANT-3: PFS by Investigator Review P-value obtained from stratified one-sided log rank test Hazard ratio is obtained from stratified unadjusted Cox model 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 6161 2121 0101 Kaplan-Meier median PFS Everolimus: 11.0 months Placebo: 4.6 months HR = 0.35; 95% CI [0.27-0.45] P <.0001 0101 0000 Time (mo) 100 80 % Event-free Censoring Times Everolimus (n/N = 109/207) Placebo (n/N = 165/203) 60 40 20 0 024681012141618202224262830 Yao J et al. 12 th 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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