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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.

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.

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

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

• 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

• 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

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

PTPᶯ

Caspase 8

Wt P53 ↑

Bax ↑

pHi ↓

Endonuclease ↑

Apoptosis ↑

ERK1/2 ↑ ERK1/2 ↓

P27Kip1 ↑

Cell growth ↓Hormone

Secretion ↑

(infrequently)

Ca2+ ↑

channelPLCβ/IP3

+Gαααα

GβGƔ

channel

Voltage

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)

Serotonin

hormonal syndromeflushing, diarrhoea.....

Tryptophan-Hydroxylase

NET-Cell5-HIAA

Telotristatetiprate

5-HIAA: 5-hydroxyindole acetic acid

SSA somatostatin analogue

SSTR somatostatin receptor

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

Evaluation of primary endpoint:

Reduction in number of daily BMs from baseline (averaged over 12-week double-blind

treatment phase)

Run in:

Evaluation of

movement (BM)

frequency

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

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