CARCINOID SYNDROME - oncologypro.esmo.org · Differential Diagnosis -Flushing Carcinoid Syndrome...
Transcript of CARCINOID SYNDROME - oncologypro.esmo.org · Differential Diagnosis -Flushing Carcinoid Syndrome...
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
u5
-HIA
A C
ha
ng
e F
rom
B
as
elin
e, m
g/2
4 H
ou
rs
20
10
0
-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