Neuroendocrine tumors

Dr. Attila Patocs

2nd Department of Medicine,

Department of Laboratory Medicine

Semmelweis University

Clinical features

• increasing incidence

• at the time of diagnosis: metastasis in 50% of cases

liver 60-80%

bone 5-20%

lung 5-15%

• tumors produce hormones

endocrine syndromes

• unique treatment options

• variable clinical course

personalized treatment strategy

• few clinical trials

expert opinion

consensus guidelines (ESMO, ENETS)

Incidence of neuroendocrine tumors

(USA, 1970-2005) (Modlin et al., Lancet Oncol, 2008 9:61-72)

Biologic features

ability to produce hormones – 40 different hormones

relatively benign, but heterogenous course – histopathologic features: grade I, II, III (Ki67)

– organ from which originate

– pathomechanism

WHO classification (2000)

• Well-differentiated neuroendocrine tumor

(carcinoid) G1 Ki-67 <2%,

• Well differentiated neuroendocrine

carcinoma (malignant carcinoid) G2 Ki-67

3-20 %,

• Poorly-differentiated neuroendocrine

carcinoma G3>20%

• Mixed endocrine/exocrine carcinoma

Hormones Syndrome Organ

_____________________________________________________

serotonin (histamin, Carcinoid ileum (pancreas, lung,

bradykinin) stomach)

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gastrin Zollinger- pancreas, duodenum

Ellison

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Insulin hypoglycemia pancreas (duodenum)

___________________________________________________________

VIP Verner- pancreas

Morrison

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glucagon glucagonoma pancreas

___________________________________________________________

somatostatin somatostatinoma pancreas,

duodenum

_________________________________________________________

Hormone overproduction syndromes

Carcinoid syndrome

typical ”flush”

dry, warm skin

palpitation

diarrhea

CARCINOID HEART DISEASE

pellagra

asthma bronchiale

myopathy

CARCINOID CRISIS

Right side

endocardium

thickening, fibrosis

Valvular fibrosis

– pulmonal stenosis

– tricuspidal

regurgitation

Carcinoid heart disease

Carcinoid heart disease: 5-year survival (200 patients, 20 years follow-up)

Moller JE et al., Circulation 2005; 112:3320.

Incidence of carcinoid heart disease decreased from 40% to 5%

Rare neuroendocrine tumors

Insulinoma 1-4/1 million/y

Gastrinoma 1-2/1 million/y

VIPoma 1/10 million/y

Glucagonoma 1/20 million/y

Somatostatinoma 1/40 million/y

Clinically non-functioning neuroendocrine

tumors

Autopsy findings

Mayo Clinic, Malmö 0.65-1.2%

Clinical symptoms and laboratory findings associated

with hormonal overproduction in patients with

neuroendocrine tumors

Clinical symptom Laboratory finding

____________________________________________

Diarrhoe Hypokalemia

”Flush” Hyponatremia

Dyspnoe (asthma bronch) Dehydration

Body weight change Hypoglycemia

Peptic ulcer Hyperglycemia

Steatorrhea Achlorhydria

Anemia Hyperacidity

Skin symptoms Malabsorbtion

Mucosal symptoms

Cushing’s syndrome, acromegaly

Classification of neuroendocrine tumors: according

to the origin of the organ

Foregut Midgut Hindgut

trachea, bronchus, lung, small intestine, appendix, rectum

stomach, pancreas, . right colon, testis, ovarium

___________________________________________________________

Chromogranin A Chromogranin A Chromogranin A

Histamin serotonin

Gastrin Prostaglandin

ACTH (cortisol)

GH (IGF-I)

_____________________________________________________

Serum chromogranin A ENETS consensus guidelines: Biochemical markers.

Neuroendocrinology 2009; 90: 194-202.

Best neuroendocrine marker – usually better than NSE

Useful in non-functioning (clinically silent) neuroendcrine tumors

High sensitivity – Gastrinoma: 100%

– Large tumor volume

– Patients with metastasis

Prognostic use

Effectiveness of treatment

Simple measurement

Cost-effective

Fals positivity of CgA measurement due to proton-pump

inhibitor treatment

CGA

Gastrin

Pregun et al. Digestion 2011;84:22–28

Serum CGA and gastrin levels after discontinuation of PPI

treatment

CGA Gastrin

Pregun et al. Digestion 2011;84:22–28

Campana, D. et al. J Clin Oncol; 25:1967-1973 2007

Serum Chromogranin A levels in 238 patients with neuroendocrine tumors (NET), in 42 patients with chronic

atrophic gastritis (CAG) and 48 healthy controls

DF: No disease

LD: Loocal disease

HD: Liver metastasis

DD: Diffuse diseases

NH: No hyperplasia

H: hyperplasia

HP: Healthy

Sensitivity of serum CgA is influenced by the type

of neuroendocrine tumor

0

200

400

600

800

1000

1200

1400

1600

1800

2000

carcinoid

Car

ney ko

mplex

Cus

hing

beteg

ség

Mellékv

esek

éreg

cc.

MEN1

MEN1-

GEP-e

l

NF1

MEN2

VHL

SDHD

Spo

radiku

s PGL

Spo

radiku

s Phe

o

Serum CgA in our patients

CgA ug/L

ZES-MEN1 Pheochromocyto

ma

Serum CgA in patients without metastatic disease and

(M-) and in patients with various stages of (A, B, C) GEP

neuroendocrine tumors

Nehar D és mtsai, Clin Endocrinol 60: 644-652, 2004)

Serum CgA in patients with non-functioning (S-) and functioning (S+),

without metastatic (M-), with metastatic (M+) GEP tumors

Nehar D és mtsai, Clin Endocrinol 60: 644-652, 2004)

Study: 39 patients with carcinoid syndrome , mean survival was 48 months,

treatment with octreotid LAR

Serum CgA useful in therapy monitoring

CM. Korse et al. Neuroendocrinology 2009;89:296–301

0

100

200

300

400

500

600

700

800

CgA

month su

rger

y

48 24 12

Conservative therapy

(octreotid + DOTATOC)

Serum CgA in one patient with malignant PGL

AFP

Ki-67 (MIB-1) βHCG CgA Survival

(month)

Correlation coefficient 0.381 (**) 0.558 (**) 0.451 (**) -0.419 (**)

P-value 0.007 0.000 0.000 0.001

Serum AFP and βHCG concentrations as prognostic

markers in neuroendocrine tumors

Ki-67 (MIB-1) AFP CgA Survival

(month)

Correlation coefficient 0.012 0.634 (**) 0.291 (*) -0.229

P-value 0.931 0.000 0.019 0.074

** A szignifikancia < 0.01; * A szignifikancia < 0.05

T Shah, et. Al Br J Cancer. 2008 Jul 8;99(1):72-7.

βHCG

Both markers mean BAD prognosis!

Predisposing conditions

Hereditary endocrine tumor syndromes

– MEN1 (pancreas neuroendocrine tumor)

– vonHippel Lindau disease (insulinoma)

– neurofibromatosis type 1 (duod carcinoid)

Other

– type 1 atrophic gastritis

– diabetes mellitus (women)

– Family history of neoplasias

Treatment of neuroendocrine tumors

Surgical resection

debulking

Treatment of liver metastases

surgical

tumor-ablation: ethanol,

embolization, chemoembolization,

thermoablation,

radiofrequency ablation

Drug treatment

somatostatin analogues

diazoxid

proton-pump inhibitors

interferon-α

chemotherapy

novel drugs

Endoradiotherapy

131I-MIBG

90Y-DOTATOC

177Lu-DOTATOC

Well-differentiated

neuroendocrine

tumor

(Ki-67<2%)

Well-differentiated

neuroendocrine

carcinoma

(Ki-67 3-20%)

Poorly-differentiated

neuroendocrine

carcinoma

(Ki-67 >20%)

Surgery, interventional radiology

somatostatin-analog

interferon

sunitinib

everolimus

+ their combinations

doxorubicin +

streptozotocin

temozolamide +

capecitabin

bevacizumab

Somatostatin-analogue

cisplatin + etopozid

temozolamid +

capecitabin

bevacizumab

Endoradiotherapy:

somatostatin peptid radionuclid therapy (90Y-

DOTATOC, 177Lu-DOTATATE); 131I-MIBG

Treatment options of metastatic NET

Somatostatin-analogues currently

used in clinical practice

Octreotide (sc, infusion)

Sandostatin LAR (im, monthly)

Lanreotide PR (sc, 7, 10, 14 days)

Lanreotide Autogel (sc, monthly)

Pasireotide (SOM230)

Clinical features of octreotide and

lanreotide

Longer lasting effect compared to somatostatin

Selectivity for sst2 és sst5 receptors

Inhibition of hormone production

Anti-proliferative effect (sst2)

Inhibition of angiogenesis

Apoptosis induction (sst3)

Mild side-effects

Easy to use

Clinical use of somatostatin-analogues

Most effective treatment in carcinoid syndrome (VIPoma, glucagonoma) – Normalize clinical symptoms and hormone

overproduction in 60-70% of cases

– Inhibit tumor growth

• Tumor regression: 3-8% of cases

• Inhibition of tumor progression: 50% of cases

Good clinical response in several patients with insulinoma – Inhibition of insulin-secretion in >80% of cases

Few side-effects – diarrhoea (usually temporal)

– Bile stone, sludge (often symptomfree)

Non-functioning neuroendocrine tumors

30-40% of pancreas

Absence of characteristic clinical

syndrome

somatostatin analogues may be used

for treatment of somatostatin-receptor

positive cases

PROMID Study Grup (multicenter study,

Germany)

Novel somatostatin analogue:

PASIREOTIDE (SOM230)

N H

O

N H

O

N

O

O

N H

N H

N H

N H

N H

O

O

O O

N H 2

O

N H 2

2-aminoethyl-

carbamoyl-oxy-Pro

Pug

Tyr(Bzl)

D- tryptophan

sst1 sst2 sst3 sst4 sst5 t½ (h)

Somatostatin 0.9 0.2 0.6 1.5 0.3 0.05

Octreotide

280.0 0.4 7.1 >1000 6.3 2

Pasireotide 9.3 1.0 1.5 >1000 0.2 11.5

IC50

octreotide/

pasireotide

30 0.4 5 – 40

Binding of pasireotide to SST receptors

(IC50 nM)

Bruns C et al. Eur J Endo 2002;146:707–716

Effectiveness of pasireotide in patients with

carcinoid syndrome who were resistant to

Sandostatin LAR

Kvols L et al. Presented at ASCO-GI 2006

BM = Bowel movements

Interferon

Interferon – 14 studies, 348 patients

– biochemical response: 40% of cases

– tumor regression: 12% of cases

Human leukocyta interferon – 4 studies, 66 patients

– biochemical response: 40% of cases

– tumor regression: 12% of cases

Interferon and octreotid – 3 studies, 52 patients

– biochemical response: 72-75% os cases

– tumor regression: 0%

Disadvantage: toxic side-effects

Chemotherapy

Single agent – actinomycin D, carboplatin, cisplatin, cyclophosphamid,

dacarbazin, docetaxel, doxorubicin, etoposid, fluorouracil, melphelan, streptozocin, gemcitibin, paclitaxel

– poor response

Two (or more) agents – 5-FU plus streptozocin; streptozocin + cyclophosphamid;

cyclophoshphamid + doxorubicin; doxorubicin + cisplatin; dacarbazin + epirubicin, dacarbazin + leukovorin

– Poor response in G1 neuroendocrine tumors

– First-line treatment in G3 neuroendocrine tumors

Chemotherapy plus interferon – streptozocin + doxorubicin + interferon

Novel treatment options

(phase II and III studies)

Temozolomid

Thalidomid

Everolimus

Imatinib (TKI)

Sunitinib (TKI)

Bevacuzimab (VEGF-R Ab)

Endoradiotherapy

Endoradiotherapy:

radioligands

131I-MIBG (γ-emission)

111In-DTPA-octreotide (γ-emission)

90Y-DOTA-Tyr3-octreotide: DOTATOC (β-

emission)

90Y- DOTA-lanreotide: DOTALAN

90Y- DOTA-Tyr3-octreotat: DOTATATE

177Lu -DOTA-Tyr3-octreotat

177Lu ~ 131I (DOTA-NOC)

DOTA: = Tetra-aza-cyclo-dodecan-tetraecetsav

90Y-DOTATOC therapy

-emitting 90Yttrium molecule, complex-

forming (DOTA) plus octreotide aggregate

University Hospital, Basel: 116 patients

with metastatic neuroendocrine tumors

– 8-12 weeks following treatment

• total remission: 4% of cases

• partial remission: 23% of cases

• stabilization: 62% of cases

• progression: 11% of cases

• Improvement of clinical symptoms: 83% of cases

• side effects: hematologic, kidney damage