CARCINOID SYNDROME

Dr. Christos G. Toumpanakis MD PhD FRCP AGAF

Consultant in Gastroenterology/Neuroendocrine Tumours

Honorary Associate Professor, University College of London

Neuroendocrine Tumour Unit - ENETS Centre of Excellence

ROYAL FREE HOSPITAL, London,UK

DISCLOSURE OF INTEREST

NOVARTIS: advisory board, research grants, educational grants, honoraria for lectures

IPSEN: advisory board, research grants, educational grants, honoraria for lectures

AAA: research grants, educational grants, honoraria for lectures

Lexicon: advisory board

PFIZER: advisory board, educational grants

CONTENTS

• In Which Neuroendocrine Neoplasms

• Pathophysiology

• Diagnostic approach

- Symptoms and signs

- Differential diagnosis

- Biomarkers and imaging studies

• Principles of treatment

- Initial approach for symptoms’ control

- Options for refractory symptoms

- Control of tumour growth

• Management algorithms

• Mainly in SMALL BOWEL NENs

• In 20 – 30 % of them with liver metastases

• 5% of patients with carcinoid syndrome do not have liver metastases

• In 5% - 10% of bronchial NENs

• In 1% of pancreatic NENs

ENETS Consensus Guidelines, Neuroendocrinology 2016

CARCINOID SYNDROME : IN WHICH TUMOURS ?

Serotonin

Tryptophan

5-Hydroxytryptophan (5-HTP)

Serotonin (5-HT)

Tryptophan-

Hydroxylase

5-HIAANET-Cell

Urine

The carcinoid syndrome: role of serotonin

5-HIAA: 5-hydroxyindole acetic acid

Other important hormones/peptides

Tachykinins

Prostaglandins

Kallikrein

Bradykinins

Abnormal metabolism of tryptophan

Niacin

Tryptophan 5-HTP

Serotonin

DIAGNOSTIC APPROACH

• History and clinical examination

• Biochemical tests (“Biomarkers”)

• Imaging studies

( for localization of primary and metastatic lesions)

• Histology - “ gold standard”

a.“ Carcinoid syndrome”• Flushing (90%)

• Diarrhoea (70%) • Abdominal pain (40%) • Carcinoid heart disease(20%)• Telangiectasias (25%)

• Bronchospasm (15%)• Pellagra (5%)

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

Differential Diagnosis - Flushing

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.

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

• 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.

• Surgical replacement of heart valves is the treatment of

choice in severe cases

Battacharyya S , et al, AJC 2008

Davar et al, JACC 2017

CARCINOID HEART DISEASE

Leading to the development of “Carcinoid Plaque” - composed of

smooth muscle cells & myofibroblasts , lining on the endocardial surface

of cardiac valves, superficial to normal valve

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.

ENDOCARDIAL DEPOSITS OF FIBROUS TISSUE

Bhattacharyya S et al. Circ Cardiovasc Imaging. 2010;3:103-111Palaniswamy C et al., Cardiol Rev 2012;20:167-76.

Gustafsson BI et al., Int J Cardiol 2008;129(3):318-24.

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.

Non-specific - Chromogranin-A (CgA)

Sensitivity : 60-90%

• Correlate with tumour burden

• Early decrease of its levels may predict PFS and OS

• Independent factor of survival in midgut NETs

May be raised in non-NETs situations:

• Chronic PPI use

• Atrophic gastritis

• IBD

• Renal failure

• Cirrhosis

• Other cancers

Specificity: 10 – 35 %

Biochemical tests (Biomarkers)

SPECIFIC

24hour urinary 5-Hydroxy-Indol-Acetic-Acid

(5-HIAA)

Plasma fasting 5-HIAA levelsseem to correlate with 24h urine levels

Adaway et al, 10th UKI-NETS conference, 2012

Tellez et al, Pancreas 2013

5-HIAA levels for prediction

of development and / or progression of Carcinoid Heart Disease

� 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.

� No significant value was noted for Chromogranin-A.

23 patients, 8 had / developed CHD 71 patients

Denney et al, J Am Coll Cardiol 1998Moller et al, NEJM 2003

Bhattacharyya et al, Am J cardiol 2011

Usefulness of N-terminal pro-brain natriuretic peptide 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) and NYHA scale (p<0.001)

Central role of c. ECHO for diagnosis of CHD

� 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 arehelpful in identifying and assessing valve pathology, particularly in the pulmonary and tricuspid valves, because all leaflets may not be visualized on 2D echocardiography.

� 5 ECHO scores for CHD

S. Bhattacharyya et al. Circ Cardiovasc Imaging. 2010

� CMR can be a valuable adjunct

where echocardiographic windows are poor or

structures such as the pulmonary valve are difficult to visualize.

� Morphological features of severe carcinoid heartdisease can be delineated with assessment of valvular regurgitation, stenosis, and quantification of ventricular volumes.

� CMR enables measurement of size of cardiac metastases and is able to offer information regarding extension into extracardiac structures, which is not available on echocardiographictechniques.

Complementary role of cardiac MRI in CHD

S. Bhattacharyya et al. Circ Cardiovasc Imaging. 2010

• Medical control of patient’s

symptoms

• Resection of tumor primary and if

possible, metastatic lesions

• Control of tumor growth in cases of

advanced disease.

• Improvement and maintenance of

patient’s quality of life

TREATMENT GOALS IN CARCINOID SYNDROME

Somatostatin Analogues

Lanreotide Autogel

Octreotide LAR

Toumpanakis et al, AP&T 2009

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

Lanreotide : symptom control in carcinoid syndrome

(prospective ELECT and SYMNET studies)

� Phase 3 ELECT study : a 16-week, double-blind, placebo-

controlled phase and a 32-week open-label extension phase

� Subcutaneous lanreotide depot 120 mg every 4 weeks or placebo.

� Primary end point : mean percentage of days requiring rescue

medication (MPDR).

� MPDR was significantly lower in lanreotide depot vs placebo arms, at

34 vs 49 % (P = 0.017)

• SYMNET : large (n = 273), patient satisfaction with symptom

control during lanreotide depot treatment for carcinoid syndrome-related diarrhea.

• 79 % reported improved diarrhea control with lanreotide depot,and 76 % were completely or rather satisfied with this effect.

• The satisfaction regarding the control of flushing was similarlyhigh (73 %).

• Compared with baseline, a clinically significant decrease inmedian daily stool frequency (from 4 to 2) was observed.

Vinik et al, Endocr Pract 2016Ruszniewski P Dig Liver Dis 2016

Refractory Carcinoid syndrome : ongoing symptoms, despite

maximum licensed doses of somatostatin analogues (SSAs)

Are we really dealing with a “Refractory Carcinoid Syndrome” ?

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), vs 7.1% (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 weeks

40mg / 60 mg

62% improvement of diarrhoea

56% improvement of flushing

Wolin at all (2013)

(phase III study with pasireotide)

40mg 27% symptoms’ improvement in month 6

Interferon – Alpha injections

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)

Capdevilla J et al. 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

Symptomatic Control of Neuroendocrine Tumourswith Everolimus.

Bainbridge et al, Horm Cancer 2015

• 7/10 patients who were syndromic had improvements in symptoms, with a mean duration of symptom control 13.9

months.

• 6/10 had reduced stool frequency, 3/7 had a reduction of

asthenia, and 5/7 had reduced frequency and severity of flushing.

• Sixty percent of patients experienced any grade toxicities,

including the following: 40% grade 1/2 stomatitis, 7% grade 3/4 stomatitis, 20% grade 1/2 rash, 13% diarrhoea, and one case of

pneumonitis

No enough data for sunitinib or systemic

chemotherapy for symptoms’ control

in refractory carcinoid syndrome

for Refractory Carcinoid Syndrome

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; • Type I or II metastatic growth, assessable for R0 or R1 resection, with an anticipated liver remnant of at least 30%; • When there is no evidence of advanced carcinoid heart disease• When access to a hepatic surgery centre is possible

Frilling et al, Lancet Oncol 2014

Transarterial Hepatic Embolization and Chemoembolization

• Symptomatic benefit (40-80%)

• Partial response: ~ 50%

• ? Survival benefit

• Morbidity (carcinoid crisis, fever, pain,

hepatic failure, intestinal ischaemia)

• Mortality

• IV octreotide infusion pre- and post-

therapy

• Careful selection of patients

Brown et al J Vasc Interv Radiol 1999;10(4):397-403Chamberlain et al J Am Coll Surg 2000;190:432-445

Toumpanakis et al, Best Pract Res Clin End Metab 2007

RFA + SIRT for Carcinoid Syndrome

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

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

Pasireotide (SOM230)

1. Feelders RA, et al. Drugs Today (Barc). 2013;49:89–103

Hormone

Ca2+ ↓

cAMP ↓

Adenyl cyclase

Secretion ↓(frequently)

PTPase

SHP-1SHP-2PTPᶯ

Caspase 8Wt 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 angiogenesis

Phase III study of pasireotide LAR vs octreotide LAR in patients

with metastatic small bowel NET and refractory carcinoid syndrome

Wolin et al, Drug Des Devel Ther. 2015

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=45)

Pasireotide LAR 60mg IM every 28 days x 6 months with dose ↓ to 40mg for tolerability (n=43)

1:1

randomisation

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)

Telotristat ethyl: A peripherally-acting serotonin synthesis inhibitor

�Telotristat etiprate is a novel, orally-delivered

inhibitor of tryptophan hydroxylase (TPH) that

reduces serotonin production:

� Absorbed into peripheral circulation

� Does not cross the blood-brain barrier

Lapuerta P, et al. Clinical Investigation (Lond.) 2015; 5(5): 447–456

Serotonin

Tryptophan

5-Hydroxytryptophan (5-HTP)

Serotonin (5-HT)

Urine

Serotonin

hormonal syndromeflushing, diarrhoea.....

Tryptophan-

Hydroxylase

NET-Cell5-HIAA

Telotristatethyl

5-HIAA: 5-hydroxyindole acetic acid

SSA somatostatin analogue

SSTR somatostatin receptor

SSA

SSTR

Ιn addition to SSA, telotristat ethyl inhibits serotonin production and alleviates symptoms

TELESTAR

Phase 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

Kulke et al, J Clin Oncol 2017

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%Kulke et al, J Clin Oncol 2017

Mean change in u5-HIAA (mg/24 hours) from baseline to week 121

• Wilcoxan rank-sum test showed significant differences for each telotristat ethyl dose vs placebo (P<0.001)

• Baseline 5-HIAA levels across treatment arms ranged from 80.96-92.65 mg/24 h

Phase III TELESTAR

Placebo

(n=29)

Telotristat ethyl 250mg

(n=32)Telotristat ethyl 500mg (n=31)

Me

an

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ng

e F

rom

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as

elin

e, m

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4 H

ou

rs

20

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-10

-40

-20

-30

-60

-50

11.47

-40.13 -57.73

All patients continued SSA therapy throughout the study period.

Data include only patients for whom both baseline and week 12 assessments were available.

• Somatostatin analogues (randomized trials)

• Peptide Receptor Radionuclide Treatment with Lu-177 DOTATATE (randomized trial)

• Everolimus (randomized trial) – no effect on symptoms

• Interferon-A (retrospective data)

• Loco-regional treatments (retrospective data)

• Systemic chemotherapy in Grade 3 NEN

CONTROL OF TUMOR GROWTH

IN PATIENTS WITH OF CARCINOID SYNDROME

AND ADVANCED DISEASE

ENETS 2016 Consensus Guidelines for intestinal NETs

Carcinoid syndrome Resistant to SSAs

No radiological progression

Exclude

other

causes

•Optimize dose of SSAs• Add Telotristat Ethyl (diarrhoea)

• Add interferon-A• Loco-Regional treatment options

• Debulking surgery

Radiological progression

• PRRT with Lu-177 PredominantlyLiver diseaseTAERFA? SIRT

MULTIDISCIPLINARY TEAM (MDT) APPROACH

FOR CARCINOID SYNDROME

• Accurate diagnosis & staging

• Evaluation of performance status & quality of life

• Consensus agreement on treatment plan

• Continuous reassessment, discussion and peer

review of the individualized treatment plan

Thank you very much