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

Neuro Endocriene Tumoren

Wim Wynendaele, MD, PhDImeldaziekenhuis, Bonheiden

Steve Jobs Death Certificate Reveals Cause of Death to be Respiratory Arrest Due to Metastatic Pancreatic Tumor10/10/2011

NET

IntroductionGastroenteropancreatic (GEP)

Carcinoid tumor – Carcinoid syndroomPancreatic NET

gastrinomainsulinoma

Diagnosis & Stagingimagingpathology

Therapysurgeryloco regionaltransplantationsystemic treatment

Merckel Cell Carcinoma

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

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: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 symptoms4–6

1. Buchanan KD Gastroenterol Today 2003; 13: 2–32. Anderson RJ et al. Curr Opin Oncol 1997; 9: 45–543. Calendar A et al. Ann Oncol 2001; 12 (Suppl 2): S3–11

4. Edney JA et al. Am J Surg 1990; 160: 625–6295. Neuman HPH et al. Sem Nephrol 2002; 22: 89–996. Soga J et al. J Exp Clin Cancer Res 1998; 17: 389–400

Credits: 1BSIP, Estiot; 2Pasieka; 3BSIP, Vero/Carlo; Science Photo Library

1

2

3

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

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

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)

RA

RE,

BU

T C

HA

LLEN

GIN

G

Van Hootegem Ph, Acta Gastro Belgica 2009

Aetiology of NETs

Majority of NETs are sporadic:• Assumed to be sporadic mutations

NETs may also be familial: • Autosomal dominant inherited syndromes1–4

o Multiple endocrine neoplasia I (MEN I)o MEN II o von Hippel Lindau (VHL) diseaseo Carney complex

• Associated with other familial conditions4–5

o Neurofibromatosis type Io Tuberous sclerosis

1. Buchanan KD Gastroenterol Today 2003; 13: 2–32. Neuman HPH et al. Sem Nephrol 2002; 22: 89–993. Kaltsas GA et al. Endocr Rev 2004; 25: 458–5114. Calendar A et al. Ann Oncol 2001; 12 (Suppl 2): S3–115. Robbins SL et al. In Pocket Companion to Robbins Pathologic Basis of Disease (5th ed). WB Saunders Co, 1994. pp:

538

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

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 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)

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

NETs1

NET Terminology

Incidence of NETs

1. Modlin IM et al. Lancet Oncol 2008; 9: 61–722. Modlin IM et al. Cancer 2003; 97: 934–9593. Öberg K and Jelic S Annals Oncol 2009; 20 (Suppl 4): 147–

149

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

o Racial differences exist2

o 4.5 per 100,000/year in black populationo 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

4. Öberg K and Jelic S Annals Oncol 2009; 20 (Suppl 4): 150–1535. Alexakis N et al. Best Pract Res Clin Gastroenterol 2008; 22: 183–2056. Öberg K and Eriksson B Best Pract Res Clin Gastroenterol 2005; 19:

753–781

Introduction

Yao J, et al. J Clin Oncol, 2008; Van Hootegem Ph, Acta Gastro Belgica 2009

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

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

20

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20

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19

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19

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19

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81

19

79

19

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1.20

1.00

0.80

0.60

0.40

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0

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er 1

00,0

00LungAppendixStomachColonSmall intestineRectumCaecumPancreas

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,

20043. Rindi G et al. Virchows Arch 2006; 449: 395‒4014. Rindi G et al. Virchows Arch 2007: 451: 757–762

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.

TNM?

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 NETs1

Staging of NETs1

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 NETsStage Description T N M

Stage 0 In situ tumour/dysplasia [for stomach only] Tis N0 M0

Stage I NETs with limited growth T1 N0 M0

Stage IIA

NETs that are larger in size or more invasiveT2 N0 M0

B T3 N0 M0

Stage IIIA NETs that have invaded surrounding tissues

or have regional node metastases

T4 N0 M0

B Any T N1 M0

Stage IV NETs with distant metastases always present

Any T Any N M1

Grading

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

Chro

mog

ran

in A

, C

gA

- 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

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

Serotonin & 5-HIAA

Sero

tonin

, 5

-hydro

xy-i

ndolic

aci

d (

5-H

IAA

)

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

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

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

o Risk of reduced survival in patients with NETs classified as

TNM stage III–IV, or grade 2–34

o Tumour grading, mitotic rates and Ki67 index are inversely

associated with survival for metastatic tumours5

1. Soga J J Exp Clin Cancer Res 2003; 22: 517–5302. 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

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

NET







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

Carcinoid tumoren:

Distribution

Modlin IM et al. Gastroenterol, 2005

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: 1Dr M.A. Ansary; 2GCA; 3Living Art Enterprises; Science Photo Library

1

2

3

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

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 ?

Carcinoid syndroom

* Trypthophaan wordt 70% omgezet tot serotonine (ipv nl +/-1 %)

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:

o Profound flushingo Bronchospasmo Tachycardiao Hypotensiono Confusiono Coma

• Precipitated by: o Anaesthetic inductiono Surgical stress o Embolisationo Chemotherapyo Insufficient somatostatin

analogue cover

1. Ramage JK et al. Gut 2005; 54 (Suppl IV): 1–16

Pancreatic NeuroEndocrineTumors

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 peptidePP : pancreatic polypeptide

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

Gast

rin

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 test Gastric pH probe

Positive ≤ 4.0 > 4.0 - STOP

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

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

Insulinoma

NET





TherapysurgeryTransplantationloco regionalsystemic treatment


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!

- 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

- 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


- 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


•gallium-68 is a positron emitter

• DOTATOC has 10 times more affinity for subtype 2 receptor

• PET/CT evaluation is possible

• 17% addtional information

- 68Ga-labelled DOTATOC PET/CT

(18-F-dihydroxy-phenyl-alanine [18F-DOPA] and 11-C-5-hydroxytryptophan [11-C-5-HTP])


- 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


- A correct histological diagnosis, but also

- A correct histological staging

HE-staining

Ki67-staining

Behaviour Invasion of m. propria

Differentiation Size (cm) AngioInvasion KI-67

• Benign - Well ≤ 1 - < 2%

• Benign or Low-Grade

- Well ≤ 2 -/+ < 2%

• Low-Grade + Well > 2 + > 2%

• High-Grade + Poorly Any + > 30%

Kloppel et al. Ann NY Acad Sci, 2004; Rindi et al. Neuroendocrinology,

2004

Diagnosis & Staging: Pathology

Suspected NET or Symptoms

Biochemical/Pathological Diagnosis

Imaging incl. DOTATOC PET CT

LocalizedMetastatic

Inherited disorder?

Diagnosis & Staging: Algoritm

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

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

- 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

Localized

Roeyen G et al. Acta Gastro Belgica 2009

Therapy : surgery

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

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?

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

Met HCC de enige indicatie voor levertx in maligne ziekte

Uiteraard enkel leveraantasting

5 jaars overleving van 36%

(laaggradige NET’s, jonge patienten,…)

Levertransplantatie?

Mazzaferro V et al. J Hepatol, 2007

No S

tan

dard

of

Care

! INCLUSION EXCLUSION

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?

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 Yttrium90

No randomized trials!

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 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

1. O’Toole D et al. Endocr Rel Cancer 2003; 10: 463–4682. Dominguez S et al. Eur J Gastroenterol Hepatol 2000; 12: 151–1573. Fiorentini G et al. J Chemother 2004; 16: 293–2974. 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

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

NET





Therapysurgerytransplantation loco regionalsystemic treatment


Verslype C et al. Acta Gastro Belgica 2009

Som

ato

stati

n a

nalo

gs

(SSA

s)

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

Som

ato

stati

n a

nalo

gs

(SSA

s)

Novartis Pharma Beaufour 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

SSTR2-5(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’

Som

ato

stati

n a

nalo

gs

(SSA

s)

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


For metastatic NET patients SEER* registry

*Surveillance, Epidemiology and End ResultsYao J.C. et al. J Clin Oncol 2008;26:3063-3072

Improved survivalPatients 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”

Som

ato

stati

n a

nalo

gs

(SSA

s)

Authors Primary NET n° SD (%) OR (%)

Saltz Mixed 34 50 0

Maton Pancreatic 107 39 7.5

Arnold Mixed 52 36.5 0

Di Bartolomeo Mixed 58 47 3

Erikson Mixed 13 70 5

Faiss Mixed 30 36 6.7

Aparicio Mixed 35 57 3

Shojamanesh Gastrinoma 15 47 6

Arnold Mixed 52 15.2 5.7

Verslype C et al. Acta Gastro Belgica 2009


Month

-1 0 3 6 9 12 15 18Screening

Informed

consent

Randomization1:1

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


Sandostatine LAR (n=42)

Placebo(n=43)

• Complete response (n) 0 0

• Partial response (n) 1 1

• Stable disease (n) 28 16

• Progressive disease (n) 10 23

• Unknown (n) 3 3

- Histologically confirmed, locally inoperable or metastatic well-differentiated midgut NETs

- Functionally active or inactive midgut NETs


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)

Pro

port

ion

wit

hou

t p

rog

ressio

n

0

0.25

0.5

0.75

1

0 6 12 18 24 30 36 42 48 54 60 66 72 78

HR= 0.34 [95% CI: 0.20–0.59], p = 0.000072

Delaunoit T et al. Acta Gastro Belgica 2009

Well-differentiated pancreatic endocrine tumors

media

n O

S u

ntr

eate

d o

f 4

0 m

on

ths

Authors Regimen n° ORR (%) mOS (mths)

Moertel S/S+5-FU 42/42 36/63 16.5/26

Moertel 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 D+S 16 6 NR

Kouvaraki 5-FU+D+S 83 39 37

Bajetta DTIC+E+5-FU 28 28 /

Rougier D+CDDP+5-FU 24 15 27

Rivera D+S+5-FU 12 54 21

Therapy : systemic therapy

Inte

rfero

n

- 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 3.0x109/l

• response : biochemical = 50%; tumour = 12-15%.

Therapy : immunotherapy

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

Therapy : targeted nuclear therapies

Hendlisz A et al. Acta Gastro Belgica 2009

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

Therapy – 177Lu-DOTA0, TYR3-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.

Type ResponseComplete Partial Stable

Pancreas 9 % 22 % 34 %

Midgut Carcinoid - 20 % 42 %

All tumour 2 % 26 % 35 %

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

Therapy – ‘targeted’ therapy

Vascular Endothelial Growth Factor andVascular Endothelial Growth Factor Receptor Inhibitors

Placebo, n 79 25 6 1 0Sunitinib, n 74 32 14 2 0

1.0

Surv

ival

pro

babi

lity

0 5 10 15 20

Efficacy endpoint variable value (mo)

SunitinibPlacebo

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 benefitUnplanned 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

Therapy – ‘targeted’ therapy

mTOR Inhibitors

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 riskEverolimus

Placebo207203

189177

153 98

126 59

114 52

8024

4916

36 7

28 4

21 3

10 2

61

21

01

Kaplan-Meier median PFSEverolimus: 11.0 monthsPlacebo: 4.6 months

HR = 0.35; 95% CI [0.27-0.45]P < .0001

01

00

Time (mo)

100

80

% E

vent

-fre

e

Censoring TimesEverolimus (n/N = 109/207)Placebo (n/N = 165/203)

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Yao J et al. 12th World Congress on Gastrointestinal Cancer; June 30-July 3, 2010; Barcelona, Spain. Poster # O-0028.

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

NET







Merckel cell carcinoma

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

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

Merckel Cell carcinoma: relative survival

Documents

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