NEN-related functional syndromes
Dr. Christos G. Toumpanakis MD PhD FRCPConsultant in Gastroenterology/Neuroendocrine Tumours
Hon. Senior Lecturer University College of London
Neuroendocrine Tumour Unit - ENETS Centre of Excellence
ROYAL FREE HOSPITAL, London,UK
IPSENHonoraria for lectures
Educational Grants for RFH NET Unit Advisory Board
AAAHonoraria for lectures
Educational Grants for RFH NET Unit
NOVARTISHonoraria for lectures
Educational Grants for RFH NET UnitAdvisory Board
LEXICONAdvisory Board
Diagnosis of NENs
History and clinical examination
Biochemical tests (Biomarkers)
Imaging studies
( for localization of primary and metastatic lesions)
Histology - “ gold standard”
In 20-30% of METASTATIC small bowel
NENs &(in 5% of bronchial and 1% of pancreatic NENs)
a. “ Carcinoid syndrome”Flushing, diarrhoea,
bronchospasm, Carcinoid heart disease
• 20 – 30 % of patients with liver metastases • 5% of patients with carcinoid syndrome do not have liver metastases
b. “Carcinoid crisis”Severe symptoms of carcinoid syndrome + hypotension during
procedures that involve GA, as well as in TAE, and when the
patient is on inotropes
24hour urinary 5-HIAA
Please note that : certain foods like bananas, avocados, aubergine,
pinepapple, plums, walnuts and some drugs like paracetamol,
fluorouracil, methysergide, naproxen and caffeine , may cause
false positive results, whilst other drugs like levodopa or
phenothiazines may cause false negative results.
.
Plasma fasting 5-HIAA levels
seem to correlate with 24h urine levels
Adaway et al, Ann Clin Biochemistry 2015
5-hydroxyindoleacetic acid (5-HIAA) : a
biomarker for Carcinoid Syndrome
Development and progression of CHD were linked to 5-HIAA levels.
5-HIAA > 300 µmol/L is independent predictor for development and progression of CHD (2-3 fold increase in risk). Multivariate model, in a prospective study of 252 patients..
Bhattacharyya et al, Am J cardiol 2011
Carcinoid Heart Disease• It represents the development of
fibrotic plaques on the heart
valves.
• It DOES NOT mean development of
myocardial metastases.
Reported in the past in 40-50% of
patients with carcinoid syndrome,,
recent prevalence : about 20%, (midgut NETs with hepatic or retro-
peritoneal metastases, ovarian NETs
and bronchial NETs).
• Its development is associated with
• 30 – 50% reduction in the
expected survival of those
patients.
The median survival improved from
1.5 years in the 1980s to 4.4 years in
the late 1990s.Davar J et al, JACC 2017
Davar J et al, JACC 2017
“Carcinoid Heart Disease”• May develop in 20-50% of patients, with
carcinoid syndrome.
• Main cause of death in 40-50% of
patients with carcinoid syndrome.
• Involves mainly the right valves of the
heart.
• NT pro BNP can serve as a screening
biomarker.
• May be present even in asymptomatic
patients.
• Valve replacement in a selected group
of patients.
Endocardial deposits of fibrous tissue
• Occur primarily on the downstream side of the valve leaflets (on the ventricular aspect of the tricuspid valve and the pulmonary arterial side of the pulmonary valve) - preferentially right-sided lesions.
– the lungs filter the vasoactive peptides, inactivating them in the pulmonary circulation before they reach the left atrium
Left-sided valvular pathology (5-10%) - seen only in patients with bronchial carcinoid or patent foramen ovale or in those with poorly controlled, severe carcinoid syndrome that overwhelms the pulmonary degradative capacity.
Palaniswamy C et al., Cardiol Rev 2012;20:167-76.Gustafsson BI et al., Int J Cardiol 2008;129(3):318-24.
Usefulness of N-terminal pro-brain natriuretic peptide (NT pro BNP as a biomarker of the presence of carcinoid heart disease.Bhattacharyya S, Toumpanakis C, Caplin ME, Davar J.Am J Cardiol. 2008 Oct 1;102(7):938-42
200 patients µε with midgut NETs underwent cardiac ECHO and estimation of N-
terminal pro-brain natriuretic peptide.
19.5% had ECHO findings consistent with CHD
NT pro-BNP levels were significantly higher (p<0.001) in patients µε carcinoid heart disease.
Sensitivity and specificity for “cut-off” level of 260pg/ml was 92% and 91%.
NT pro-BNP levels had positive correlation with CHD score (r:0.81, p<0.001) andNYHA scale (p<0.001)
Central role of c. ECHO for diagnosis of
Carcinoid Heart Disease
The ECHO spectrum is wide.
Patients with diffuse thickening of valve leaflets or isolated thickening of a single valve leaflet without significant reduction in leaflet mobility or the development of valvular regurgitation may represent the early stages of carcinoid heart disease.
Advanced techniques such as 3D TTE or 3D TEE are helpful in identifying and assessing valve pathology, particularly in the pulmonary and tricuspid valves, because all leaflets may not be visualized on 2D echocardiography.
S. Bhattacharyya et al. Circ Cardiovasc Imaging. 2010
Mesenteric fibrosis in midgut NENs
Episodes of sub-acute bowel obstruction
Hydronephrosis
Malnutrition
Small bowel bacterial overgrowth
Recurrent ascites & GI bleeding from ectopic varices
Abnormal metabolism of tryptophan
Niacin
Tryptophan 5-HTP
Serotonin
Carcinoid Syndrome flushing
� Dry
�Intermittent
�Provoked by exercise, alcohol,
and food-containing tyramines
(eg, blue cheese,chocolate etc)
� Involves the face
and upper trunk as far as the nipple line.
Differential Diagnosis - Flushing
Flushing related to other causes
+ Diarrhoea Other NETs : medullary
Thyroid carcinoma, pancreatic VIPoma
Wet flushing : Menopause
Constant flushing : alcoholism,
polycythemia, and mitral valve disease
+ headaches : phaeocromocytoma
or mastocytosis
+ rash features : rosacea, mastocytosis
Different causes of diarrhoea
in small bowel NENs
• Hormone production (carcinoid syndrome)
• Steatorrhoea
• Bacterial overgrowth
• Bile acid malabsorption
• Mesenteric ischaemia
Insulinomas
10% malignant – 10%
multiple.
6-7 % are associated with
MEN-1 syndrome.
Differential diagnosis:
Nesidioblastosis
Neuroglycopaenic symptoms
• Headache
• Lethargy
• Diplopia
• Blurred vision
• Seizures
Catecholaminergic symptoms
• Tremor
• Palpitations
• Sweating
• Anxiety
Kaltsas & Grossman in : Caplin & Yao, Handbook of GEP and bronchial NETs, 2011
Ιnsulin & Insulinoma
Blood glucose < 40 mg/dl
Insulin levels > 36 pmol /l
C-peptide > 200 pmol/l
Pro-insulin levels > 5 pmol/l
β- Hydroxybutyrate levels < 2.7 mmol/l
Absence of sulfonylurea metabolites in plasma and urine
72 h – Fast test
• When symptoms occur and if glucose is low: estimation of
insulin, pro-insulin and C-peptide
• Usually diagnosis is made within the first 48h
Tucker at al, Br J Surgery 2006De Herder et al, ΕΝΕΤ guidelines, Neuroendocrinology 2006
Gastrinomas & Zollinger-Ellison Syndrome
Up to 25% may be associated with MEN-1 syndrome.
40% of sporadic gastrinomas and up to 90% of MEN-1 associated gastrinomas are located within the duodenal submucosa.
Majority are malignant.
Symptoms: recurrent/resistant to
treatment peptic ulcers in unusual
locations, not related to H.pylori &
NSAIDs, oesophagitis, chronic
diarrhoea responding to PPIs.
Kaltsas & Grossman in : Caplin & Yao, Handbook of GEP and bronchial NETs, 2011
Gastrin & Gastrinoma
PPIs should be discontinued for at least 10 days
Fasting gastrin > 10-folds Fasting gastrin < 10-folds
p H stomach < 2 p H stomach > 2 p H stomach < 2
Consider other causes(atrophic gastritis,PPIs, Vagotomy)
Exclude other causes:DIAGNOSIS Pyloric stenosis , G cell hyperplasia,
Short bowel syndrome, H.Pylori gastritis etc
SECRETIN TEST(+, if increase of gastrin levels > 100ng/L above the baseline following IV secretin)
Jensen et l, Neuroendocrinology 2006
VIPomasVerner Morrison syndrome,
Watery Diarrhoea Hypolkalemia Achlorydria (WDHA) syndrome
Pancreatic Cholerae
VIPomas arise from the pancreas in 90% of cases, but they may also
be found in periganglionic tissue or at other sites (eg, colon, bronchus,
adrenal glands, and liver), especially in children.
They are almost always solitary, with fewer than 5% being multi-centric.
Symptoms include : severe diarrhoea, dyhydration, hypokalaemia,
hypochlorydria, facial flushing (20%), and hypercalcaemia
Approximately 5% of VIPomas are associated with MEN-1 syndrome.l
GlucagonomasLarge tumours mainly located in
pancreatic tail.
Highly malignant.
Symptoms: weight loss, new
onset of diabetes mellitus,
diarrhoea, “migratory necrolytic
erythema”, cheilitis, glossitis.
Increase risk of thromboembolic
events.
5-17% are associated with MEN-1
syndrome.
Kaltsas & Grossman in : Caplin & Yao, Handbook of GEP and bronchial NETs, 2011
Very rare functioning p NENs
Somatostatinomas
Located in pancreas or duodenum (ampulla)
Symptoms : hyperglycaemia, cholelithiasis, steatorrhoea, hypochlorydria.
ACTHomas : Cushing’s syndrome
PTHrp – secreting p NENs: intractable hypercalcaemia
Serotonin-secreting p NENs : carcinoid syndrome
Kaltsas & Grossman in : Caplin & Yao, Handbook of GEP and bronchial NETs, 2011
Diagnosis of NENs
History and clinical examination
Biochemical tests (Biomarkers)
Imaging studies
( for localization of primary and metastatic lesions)
Histology - “ gold standard”
Glucagon-like peptide-1 receptor imaging for the localisation of insulinomas: a prospective multicentre imaging study
Emanuel Christ, MD, Damian Wild, MD, Susanne Ederer, MD, Martin Béhé, PhD, Guillaume Nicolas, MD, Martyn E Caplin, MD, Michael Brändle, MD, Thomas Clerici, MD, Stefan Fischli, MD, Christoph Stettler, MD, Peter J Ell, MD, Jochen Seufert, MD, Beat
Gloor, MD, Aurel Perren, MD, Jean Claude Reubi, MD and Flavio Forrer, MD
The Lancet Diabetes & Endocrinology, 2013
• 25 patients
• 111In-DTPA-exendin-4 SPECT/CT revealed
19 benign insulinomas [positive predictive
value of 83% (95% CI 62—94)].
• 7 patients (23%) underwent surgery only on
the basis 111In-DTPA-exendin-4 results
• 111In-DTPA-exendin-4 SPECT/CT had higher
sensitivity (95% [95% CI 74—100]) than
CT/MRI (47%)
Treatment of NETs
A) Medical control of
patient’s symptoms.
B) Resection of tumor
primary and if
possible, metastatic
lesions.
C) Control of tumor
growth in cases of
advanced disease.
D) Improvement and
maintenance of
patient’s quality of life.
Somatostatin Analogues
Lanreotide Autogel
Octreotide LAR
Somatostatin analogues in “carcinoid syndrome”
First & best choice medications
Reduce flushing > 70%
Reduce diarrhoea > 60%
Biochemical response ~ 50%
Shah T & Caplin M, Best Pract Res Clin Gastroenterol. 2005
Plockinger U & Wiedenmann B, Best Pract Res Clin End Metab 2007
Inhibition
of hormone
secretion
by the tumour
SST
SST
• Prospective cross over
analysis of 33 patients
• No differences between
octreotide and lanreotide in
symptom control or
biochemical response
O’Toole et al, Cancer 2000
Gastrointestinal neuroendocrine tumors treated with high dose octreotide-LAR: A systematic literature review
Michael S Broder, David Beenhouwer, Jonathan R Strosberg, Maureen P Neary, Dasha Cherepanov, World J Gastroenterol 2015 Feb
Octreotide LAR dose Results
Valle et all (2001) Dose escalation Improvement of symptoms
Woltering et all (2006) 20mg/30mg/60mg Flushing not controlled in 0% (20 mg), 11.1% (30 mg), vs7.1% (60 mg), diarrhea not controlled in 0% of pts. (20 mg), 27.8% (30 mg), vs 30.8% (60 mg) groups
Ferolla et all (2012) 30mg every 3 weeks Complete normalization 40%Partial symptom control in 60%
Strosberg at all (2013) 30mg every 3 weeks40mg / 60 mg
62% improvement of diarrhoea56% improvement of flushing
Wolin at all (2013)(phase III study with pasireotide)
40mg 27% symptoms’ improvementin month 6
Interferon – Alpha for carcinoid syndrome
symptoms’ control
• Of the 19 patients given alpha-interferon
in combination with octreotide, 72%
showed significant reduction in urinary 5-
HIAA for a median of 10 months.
• A symptomatic improvement was seen in
49%.
• The combination was well tolerated.
Janson & Oberg, Acta Oncol 1993
RFH Interferon Data
• 24 pts, in combination with SSTA
- Diarrhoea improved 45%
- Flushing improved in 54%
- No statistically significant
decrease of 5-HIAA levels
- 27% of patients discontinued
treatment at 3 months, due to AE
Mirvis et al, Anticancer Research 2015
EVEROLIMUS FOR REFRACTORY CARCINOID SYNDROME
Control of carcinoid syndrome
with everolimus (CASE REPORT)
Capdevila J, Díez Miranda I, Obiols
G, Tabernero J. Ann Oncol. 2011
After a month of treatment, the
symptoms of carcinoid syndrome
improved with a reduction in the
flushing episodes to 1–2 per day, an
improvement in diarrhea and a
significant decrease in 5-HIAA levels
(up to 60%). Everolimus plus octreotide LAR resulted in greater reductions in serum chromogranin A (p treatment=0·0041) and urine 5-hydroxyindoleacetic acid (p treatment <0·0001) compared with placebo plus octreotide LAR.
RADIANT-2, Pavel et al, Lancet 2011
CgA
5-HIAA
Control of carcinoid syndrome symptoms
with PRRT
Percentages of patients who reported improvement in pain and diarrhoea score
after PRRT. Saima Khan et al. J Nucl Med 2011
RFH PRRT data• 35 patients
Koffas et al, ENETS & DDW 2016
No enough data for sunitinib or
systemic chemotherapy for
symptoms’ control in refractory
carcinoid syndrome
Transarterial Hepatic Embolization and Chemoembolization
Symptomatic benefit (40-80%)
Partial response : ~ 50%
? Survival benefit
Brown et al J Vasc Interv Radiol 1999;10(4):397-403
Chamberlain et al J Am Coll Surg 2000;190:432-445
Morbidity (carcinoid crisis, fever, pain, hepatic failure, intestinal ischaemia)
Mortality
i.v. octreotide infusion pre- and post therapy
Careful selection of patients
Toumpanakis et al, Best Pract Res Clin End Metab 2007
RFA + SIRT
Radio-Frequency-Ablation
•In the largest study to date, 17 patients
with carcinoid syndrome were included
• Symptom improvement was noted in
12 of 17 (70.6%)
• Reduction of 5-HIAA in 75% and CgA
by at least 50%.
Eriksson et al, Word J Surg 2008
Selective Internal Radiation Therapy
Only one prospective study (n = 34)
addresses syndrome control (55%
response).
King J, Cancer 2008
Pasireotide (SOM230)
1. Feelders RA, et al. Drugs Today (Barc). 2013;49:89–103
Hormone
Ca2+ ↓
cAMP ↓
Adenyl cyclase
Secretion ↓(frequently)
PTPase
SHP-1
SHP-2
PTPᶯ
Caspase 8
Wt P53 ↑
Bax ↑
pHi ↓
Endonuclease ↑
Apoptosis ↑
+
ERK1/2 ↑ ERK1/2 ↓
P27Kip1 ↑
+ -
Cell growth ↓Hormone
Secretion ↑
(infrequently)
Ca2+ ↑
+
+
Ca2+
channelPLCβ/IP3
ER
--
-
+Gαααα
GβGƔ
Ca2+
Ca2+
Ca2+
Ca2+
channel
K+
channel
Voltage
K+
K+
K+
SSTR
Somatostatin
• Pasireotide is a novel
multireceptor-targeted
somatostatin analogue with
high binding affinity for
somatostatin receptor
subtypes 1, 2, 3 and 51
• Preclinical models have
shown that pasireotide can
influence tumour cell growth
via effects on apoptosis and
angiogenesis1
Phase III study of pasireotide LAR vs octreotide LAR in
patients with metastatic midgut NET
Wolin EM, et al. J Clin Oncol. 2013;31:(suppl; abstr 4031); http://clinicaltrials.gov identifier NCT00690430
Blinded treatment period of 6 months
NET patients with
carcinoid
syndrome
symptoms
inadequately
controlled by
maximum doses of
currently available
SSAs Octreotide LAR 40mg IM every 28 days x 6 months
with dose ↓ to 30mg for tolerability (n=57)
Pasireotide LAR 60mg IM every 28 days x 6
months with dose ↓ to 40mg for tolerability (n=53)
1:1randomisation
Primary endpoint: symptom control (month 6)
Secondary endpoints: tumour response, PFS, safety
Trial was terminated early based on interim analysis demonstrating futility for
primary endpoint (symptom response at month 6)
Serotonin
Tryptophan
5-Hydroxytryptophan (5-HTP)
Serotonin (5-HT)
Urine
Serotonin
hormonal syndromeflushing, diarrhoea.....
Tryptophan-Hydroxylase
NET-Cell5-HIAA
Telotristatetiprate
5-HIAA: 5-hydroxyindole acetic acid
SSA somatostatin analogue
SSTR somatostatin receptor
SSA
SSTR
Ιn addition to SSA, telotristat etiprate inhibits serotonin production and alleviates symptoms
TELESTARPhase 3 Study Design
Telotristat etiprate 500 mg TID* (n=45)
Telotristat etiprate 250 mg TID (n=45)
Placebo TID (n=45)
All patients required to be on SSA at enrollment and continue SSA therapy throughout study period
1:1:13- to 4-
week run-
in (n=135)R
Telotristat
etiprate
500 mg
TID
Evaluation of primary endpoint:
Reduction in number of daily BMs from baseline (averaged over 12-week double-blind
treatment phase)
Run in:
Evaluation of
bowel
movement (BM)
frequency
38
TELESTAR results : Reduction in Mean Daily Bowel Movement Frequency
at Baseline and Week 12
–17%
–29% –35%
n=35 n=36 n=37
Mild nausea: 15%
Mild depression: 15-20%
Somatostatin analogues in functional pancreatic NETs
VIPomas Glucagonomas Insulinomas
Patients treated 31 32 55
SymptomaticImprovement %
87 75 36
Biochemical response %
87 78 45
4 weeks after first injection of Somatostatin analogues
Wermers, Fatourechi et al, Medicine (Baltimore) 1996
Nikou, Toumpanakis et al, Hepatogastroenterology 2005
Vezzosi, Bennet et al, Eur J Endocrinol 2005
Other medications for symptom control in pNETs
• IV octreotide or sc Octreotide pump in
severe VIPoma syndrome.
• High doses of Proton Pump Inhibitors
(PPIs) in Gastrinomas.
• Diazoxide, Everolimus, Verapamil,
Phenyntoin in Insulinomas.
• Aspirin to prevent thrombo-embolic events
in glucagonomas
• Topical or oral Zinc therapy for
glucagonoma-associated rash.
• Corticosteroids in life-threatening diarrhoea
in VIPomas and severe hypoglycaemia in
insulinomas.
UKI-NETS Guidelines for NETs, Gut 2011
DEBULKING SURGERY
• In NET associated with endocrine syndromes, debulking surgery is
attempted whenever feasible.
• Incomplete debulking surgery (R2) has limited indications, but it may
improve the quality of life in selected patients for whom medical treatment
has failed, especially in functioning tumors.
• Improvement of specific symptoms after surgery may be long-lasting with
a median duration of 19.3–45.5 months
ENETS Guidelines 2012
Candidates for hepatic resection include:
• grade 1 or 2 tumours;
• when no evidence of non-resectable extrahepatic disease exists;
• type I or II metastatic growth assessable for R0 or R1 resection with an
anticipated liver remnant of at least 30%;
• when no evidence of advanced carcinoid heart disease exists;
• and when access to a hepatic surgery centre is possible
Frilling et al, Lancet Oncol 2014
ENETS 2016 Consensus Guidelines for intestinal NETs
ENETS 2016 Consensus Guidelines for p NETs
Thank you
