neuroendocrine tumors - semmelweis egyetem |...
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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)
_____________________________________________________
gastrin Zollinger- pancreas, duodenum
Ellison
__________________________________________________________
Insulin hypoglycemia pancreas (duodenum)
___________________________________________________________
VIP Verner- pancreas
Morrison
___________________________________________________________
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