OVERVIEW OF THE DIAGNOSIS

AND TREATMENT OF GI NETS

Dr Christos G. Toumpanakis MD PhD FRCP FEBGH

Consultant in Gastroenterology/Neuroendocrine Tumours
Hon. Senior Lecturer University College of London
Neuroendocrine Tumour Unit - ENETS Centre of Excellence
ROYAL FREE HOSPITAL, London, UK
NEUROENDOCRINE CELLS
Peptide hormone-producing cells that share a
neural-endocrine phenotype

Cells that form glands Cells that are diffusely distributed

- Adenohypophysis - Skin
- Parathyroids - Thyroid
- Lung
- Paraganglia - Thymus
- Adrenal medulla - Genitourinary tract
- GI tract
Cell Type Localisation Products - Pancreas
D cells GI tract Somatostatin
Enterochromaffin GI tract Serotonin, Substance P
Enterochromaffin-like GI Tract Histamine
G cells Stomach and duodenum Gastrin
VIP cells GI Tract VIP
A cells Pancreas Glucagon
B cells Pancreas Insulin
Chromaffin Adrenals Catecholamines
C cells Thyroid Calcitonin
Image from: http://www.brown.edu/Courses/Digital_Path/systemic_path/index.html
 Rare

Usually
May secrete Slow
hormones NETs growing

Usually can
be treated
May have with more
somatostatin than one
receptors options
INCIDENCE OF NEUROENDOCRINE
TUMOURS (NETS) OVER TIME,
BY SITE AND BY DISEASE STAGE

Reproduced with permission from Dasari A, et al. JAMA Oncol 2017;3(10):1335–42. Copyright©2017 American Medical Association.
All rights reserved.
HISTOPATHOLOGICAL
ASSESSMENT OF NETS

 Cell morphology

 Immunohistochemistry
General markers
Chromogranin,
synaptophysin, cytokeratin
Peptide hormones (serotonin)
Receptors

 Ki67 (to assess tumour grading)

(marker of proliferation, showing
how many cells are in cycle)

Courtesy of the Royal Free Hospital, London, Histopathology Lab database.

Klöppel G. Best Pract Res Clin Endocr Metabol 2007;21:15–31.

HISTOPATHOLOGICAL
CLASSIFICATION OF NETS
WHO 2017 CLASSIFICATION

1. Well-differentiated neuroendocrine
tumours of G1 grade (Ki67 <2%)
2. Well-differentiated neuroendocrine
tumours of G2 grade (Ki67 3-20%)
3a. Neuroendocrine tumours of G3 grade
(Ki67 >20%): well differentiated
3b. Neuroendocrine carcinoma, NEC
(Ki67 >20%): poorly differentiated
(small or large cell)

+ TNM staging SilverScreen / Alamy Stock Photo

World Health Organization 2017.

 NET HETEROGENEITY

 Intra-tumoural phenotypic heterogeneity is

frequently observed in GEP-NETs
 Most primary small bowel NETs are G1
tumours (Ki67<2%)
 However, when these tumours metastasize
to the liver, they may become highly
proliferative
 More than two-thirds of the patients who
had G1 primary tumour developed G2 or
G3 liver metastases

Shi C, et al. Am J Clin Pathol 2015; 143(3): 398–404, by permission of the American Society for Clinical Pathology.
CLINICAL CLASSIFICATION
OF NETS

Pancreatic neuroendocrine tumours Functional

or
Gastrointestinal neuroendocrine Non-functional
tumours
“Carcinoids”
foregut
midgut
hindgut
Functional
Up to 10% associated with adenocarcinoma or
Non-functional

Solcia E, et al. WHO 2002.

TYPES OF GASTRIC NETS

Type I Type ΙΙ Type ΙΙΙ

Relative frequency 70 – 80% 5 – 6% 14 – 25%
Usually multiple Usually multiple Usually solitary
Features
(<10mm) (<10mm) (> 20mm)
Ass. diseases Atrophic gastritis ΜΕΝ-1/ Gastrinoma No
Histology G1 G1 G2 / G3
Serum Gastrin Raised Raised Normal
Gastric p H Alkaline Hyperacid Normal
Metastases <5% 10 – 30% 50 – 100%
Tumour related
- < 10% 25 – 30%
deaths
DUODENAL NEUROENDOCRINE
TUMOURS
 1–3 % of all duodenal neoplasms
 Five types:
 Non-functional d-NENs (positive
immunohistochemistry for serotonin and
calcitonin)
 Duodenal gastrinomas
 Somatostatinomas
 Duodenal gangliocytic paragangliomas
Copyright © Sato Y, et al. Published by
 High-grade poorly differentiated Baishideng Publishing Group Inc. All rights
reserved. Distributed under the terms of the
neuroendocrine carcinomas Creative Commons Attribution-Noncommercial
(CC BY-NC 4.0) License
(https://creativecommons.org/licenses/by-nc/4.0/)
 90% are located in D1 and D2
 >75% are measuring <2 cm
 Lymph nodal metastases are noted: 20–60%
 20% are located in peri-ampullary region (18% Image from Dermatology Oasis. Available at:
are associated with von-Reckinhausen’s disease) http://dermatologyoasis.net/. Accessed
February 2018

Delle Fave G, et al. ENETS Consensus Guidelines for the management of patients with gastroduodenal neoplasms. Neuroendocrinology 2012;95(2):74–87.
Reproduced with permission from S. Karger AG, Basel.
Sato Y, et al. World J Gastroenterol 2016;22(30):6817-28.
DIAGNOSIS OF NETS

 History and clinical examination

 Biochemical tests

 Imaging studies (for localisation of primary and metastatic lesions)

 Histology - “ gold standard”

CLINICAL PRESENTATION (1)
SPECIFIC SYMPTOMS

MIDGUT NETs
(in 5% of bronchial NETs and 1% of pancreatic NETs)

“Carcinoid syndrome”
 Flushing, diarrhoea, bronchospasm, carcinoid heart disease
20–30 % of patients with liver metastases


Image courtesy of
Dr. Christos G. Toumpanakis 5% of patients with carcinoid syndrome do not have


liver metastases

“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
CARCINOID HEART DISEASE

 May develop in 20–50% of

patients, with carcinoid syndrome

 Main cause of death in 40–50%

of patients

 Involves mainly the right valves

of the heart

 May be present even in

asymptomatic patients

 Valve replacement in a selected

group of patients Image courtesy of Dr. Christos G. Toumpanakis

Battacharyya S, Toumpanakis CG, et al. Am J Cardiol 2008;101(3):378-81.

CLINICAL PRESENTATION (2)
NON-SPECIFIC SYMPTOMS

 Dyspepsia

 Chronic abdominal pain

 Weight loss

 Symptoms compatible with IBS

 Etc, etc.. So…

Tumours are diagnosed incidentally:

a. During surgery
b. During endoscopy
c. On imaging studies and guided biopsy
of tumour lesions
BIOCHEMICAL TESTS
(BIOMARKERS): NON-SPECIFIC -
CHROMOGRANIN-A (CGA)

 Sensitivity: 60-90%, Specificity: 68 – 100%

 Correlate with tumour burden
 Independent factor of survival in midgut NETs

Not raised in: May be raised in non-NETs situations:

 Rectal NETs  Chronic PPI use

 Poorly differentiated NECs  Atrophic gastritis
 IBD
 Renal failure
 Cirrhosis
 Other cancers

Modlin IM, et al. Ann Surg Oncol 2010.

BIOCHEMICAL TESTS
(BIOMARKERS): SPECIFIC

a) 24 hour urinary 5-HIAA (metastatic midgut NETs)

Please note that certain foods like banana, avocado, aubergine, pineapple, plum,
walnut 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.

b) Role of Gastrin in differentiation of types of Gastric NETs

USEFULNESS OF N-TERMINAL
PRO-BRAIN NATRIURETIC PEPTIDE AS A
BIOMARKER OF THE PRESENCE OF CARCINOID
HEART DISEASE
 200 patients 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 with
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)
Reprinted from Am J Cardiol, 102(7), Bhattacharyya S, et al. Usefulness of N-terminal Pro–Brain Natriuretic Peptide as a Biomarker of the Presence of Carcinoid
Heart Disease, 938-42. Copyright 2008, with permission from Elsevier.
NOVEL BIOMARKERS
CIRCULATING TUMOUR CELLS
(CTCS) AS PROGNOSTIC MARKERS
IN NEUROENDOCRINE TUMOURS

 Presence of CTCs was associated with

increased burden, increased tumour grade, and
elevated serum chromogranin A
 The presence of ≥ one CTC was associated
with worse PFS and overall survival
 Within tumour grades, presence of CTCs was
able to define a poor prognostic subgroup
 CTCs are a promising prognostic marker for
patients with NETs and should be assessed in
the context of clinical trials with defined tumour
subtypes and therapy

Different types of NETs (midgut, pancreatic) with same cut-off (one CTC) as predicting a
worse outcome applied, whilst evidence from other cancers suggested the correct cut-off
varied depending on tumour type.

Khan MS, et al. J Clin Oncol, 31(3), 2013:365–72. Reprinted with permission. © 2013 American Society of Clinical Oncology. All rights reserved.
EARLY CHANGES IN CIRCULATING
TUMOUR CELLS
Are associated with response and survival following treatment of
metastatic neuroendocrine neoplasms 138 patients with metastatic NENs (G1/G2)
commencing therapy were prospectively recruited

First post-treatment time point (PT1): 3–5 weeks

Group A: 0 CTCs at baseline and PT1
Group B: >50% reduction from baseline
Group C: <50% reduction or increase

0 CTCs at PT1: only 4% progressed

>8 CTCs at PT1: 65% progressed

CTCs No Median Survival mo

0 Not reached at 54
1-8 31.2
>8 10.8

Early post-treatment CTC change is associated with radiologic response and survival,
presenting an opportunity to explore biomarker-led sequencing studies in patients with NENs
Reprinted from Clin Cancer Research 2015, 22(1) 365-72, Khan MS, et al. Early Changes in Circulating Tumor Cells Are Associated with Response and Survival
Following Treatment of Metastatic Neuroendocrine Neoplasms. with permission from AACR.
MAAA PCR-BASED TEST (NETEST)

 Multianalyte with Algorithm Analysis Assay

 Using gene microarray-based approaches of both malignant NET
tissue and blood, a PCR-based 51 marker signature (multigene
test) was developed
 High sensitivity (85–98%) and specificity (93–97%) for the detection
of intestinal and p NETs in circulating blood
 Not affected by age, gender, ethnicity, fasting or PPIs
 A NET score (0–8) is derived from the PCR data
 Values ranged from 0 to 8; a value of >2 is a positive tumour score

Reprinted by permission from Springer Customer Service Centre GmbH: Springer Nature, Am J Gastroenterol, The Clinical Utility of a Novel Blood-Based Multi-
Transcriptome Assay for the Diagnosis of Neuroendocrine Tumors of the Gastrointestinal Tract, Modlin IM, et al. Copyright 2015.
NETEST – POTENTIAL CLINICAL
APPLICATIONS
Can it define the effectiveness of operative resection
and loco-regional [TA(C)E, RFA] treatments?
 35 patients with GEP-NET (mainly G1 & G2) were
included
 Surgery was performed in 27 (1) to remove primary
tumour, including loco-regional lymph nodes (n = 21);
(2) for debulking (n = 4); and (3) for suspicion of NET
 8 subjects had loco-regional treatments (TAE = 3,
TACE: 3, RFA = 3) for hepatic metastases
 The NETest was scaled as minimal activity risk <14%,
low activity risk 14–47%, and high activity risk >47%.
 Surgery significantly reduced scores in each of these
groups
 4 (27%) developed disease recurrence loco-
regionally at 6 months identified by imaging (68Ga-
somatostatin receptor-based PET). At 1 month after
surgery, all 4 patients exhibited increased NETest
scores (median, 30%; range 13-87%)
 For group III, the pre-ablation NETest scores were
elevated (76.2 ± 4.4%) and reduced after treatment

Reprinted from Surgery 159(1), Modlin IM, et al. Blood measurement of neuroendocrine gene transcripts defines the effectiveness of operative resection and ablation
strategies, 336–47. Copyright 2016, with permission from Elsevier.
CONVENTIONAL IMAGING IN NETS

Images courtesy of Dr Christos G.Toumpanakis Image from Paulsen RD, et al.

 Spiral CT and MRI: can reveal the primary site in ~30–70% and distal metastases
in 90% of patients
 CT enterography: can detect the primary small bowel NET with sensitivity 85%
and specificity 97%

Ricke J, et al. European J Radiol 2001;37(1):8-17.

Paulsen SR, et al. Radiographics 2006;26(3):641–57. Copyright © 2006 Radiological Society of North America
ENDOSCOPIC ULTRASOUND &
WIRELESS SMALL BOWEL
CAPSULE ENDOSCOPY

Endoscopic ultrasound
Can assess depth of invasion of
stomach, duodenal, rectal wall

Wireless small bowel capsule

endoscopy
May have a role for detection of
occult small bowel NETs

Jensen RT, Neuroendocrinology 2004;80 Suppl 1:23–7;

Tucker ON, et al. Br J Surg 2006;93(3):264–75
Rondonotti E, et al. Endoscopy 2008;40(6):488–9
 SOMATOSTATIN RECEPTORS
IN NETS

 Carcinoid tumours:
sst2>sst5>sst1>sst3&4
 Gastrinomas: sst2>sst5=sst1>sst3>sst4
 Insulinomas: sst5>sst3>sst2>sst4>sst1
 NFPETS: sst2>sst3>sst1>sst5>sst4
 Glucagonomas/MCT/phaeo:
sst2>sst1>sst5=sst4>ssst3

From N Engl J Med, Lamberts SW, et al. Octreotide, 334:246–54. Copyright © 1996 Massachusetts Medical Society. Reprinted with permission from Massachusetts
Medical Society.
ΟCTREOSCAN

 Reveals the primary in 50-80% and

the metastases 95% of patients
 Can predict the response with
somatostatin analogues
 Low sensitivity in poorly-differentiated
NETs, small duodenal gastrinomas
and insulinomas

Ant Post
Images courtesy of Dr. Christos G. Toumpanakis

Warner RR. Gastroenterology 2005;128(6):1668–84

THE ROLE OF 18F-FDG-PET
IN NETS

18F-FDG – PET is useful for evaluation

of extent of disease:

a) In poorly –differentiated G3 tumours

b) In tumours with high Ki67 ≥10% ,and no

Octreoscan uptake

It seems that intense 18F- FDG uptake by

tumour lesions predicts survival (one study)

Image courtesy of Dr. Christos G. Toumpanakis

Eriksson B, et al. Ann N Y Acad Sci 2002;970:159–69

Binderup T, et al. Clin Cancer Res 2010;16(3):978–85
Abgral R, et al. J Clin Endocrinol Metab 2011;96(3):665–71
PET SCANS SPECIFIC FOR NETS

PET with 68Ga-somatostatin analogues

68GaDOTATATE
68Ga DOTATOC
68Ga DOTANOC

Better sensitivity than OCTREOSCAN, CT

More expertise is needed in interpretation of its results, in view of its
physiological uptake
18F-DOPA PET

11C 5-HTP PET

 For GI-NETs, 18F-DOPA PET was found to be more
sensitive than 11C-5-HTP PET (98% vs. 89%), whilst just
the opposite was noted in patients with pNETs
 A cyclotron is required
 Sensitivity seems to be inferior to 68Ga PET studies
Image from: Toumpanakis CG, et al. Neuroendocrinology
2014;99:63–74. Copyright © 2014, Karger Publishers,
Basel, Switzerland

Sundin A, et al. Neuroendocrinology 2007; Gabriel M, et al. J Nucl Medicine 2007; Frilling A, et al. Ann Surg 2010.
HEPATIC METASTASES IN THE
SAME PATIENT
Hepatic metastases from NET Colorectal cancer (FDG-PET, right)
(68Ga-octreotate PET, left) in the same patient

Image courtesy of
Dr. Christos G. Toumpanakis

Use of molecular imaging to differentiate liver

metastasis of colorectal cancer metastasis from
neuroendocrine tumour origin

Desai AP, et al. J Clin Gastroenterol. 2011;45(1):e8-11.

COMBINATION OF PETS FOR NET
HETEROGENEITY

Ga68 Ga68

FDG FDG

Images courtesy of Dr. Christos G. Toumpanakis

NOVEL MOLECULAR IMAGING
 IMAGING WITH SOMATOSTATIN
RECEPTOR ANTAGONISTS

Comparison of 111In-DTPA-octreotide scintigraphy (SSTR2 agonist), 111In-DOTA-BASS

scintigraphy (SSTR2 antagonist), and 111In-DOTA-JR11 scintigraphy (SSTR2 antagonist)
in a patient with NET of unknown origin (G2).

Reprinted from Best Pract Res Clin Endocrinol Metab, 30(1), Baumann T, et al. Gastroenteropancreatic neuroendocrine tumours (GEP-NET) – Imaging and staging, 45–57.
Copyright 2016, with permission from Elsevier.
 Image courtesy of Dr. Christos G. Toumpanakis

Image courtesy of Dr. Christos G. Toumpanakis with consent

“AS REQUIRED” IMAGING
MODALITIES

Parathyroid scan

MRI spine, most sensitive technique

for demonstrating bone metastases

MRI pituitary

Images courtesy of Dr. Christos G. Toumpanakis.

Kos-Kudla B, et al. Neuroendocrinology 2010;91(4):341–50.
DIAGNOSTIC ALGORITHM

History – clinical
examination

Chromogranin-A
5-HIAA
NT-pro BNP Cardiac ECHO

Triple phase CT c/a/p  MRI liver

FDG-PET scan Or MRI  MRI spine
 High-grade tumours
 Suspected tumour  CT/MRI
heterogeneity Somatostatin Receptor Scintigraphy enterography
 Suspected second (Ga-68 PET OctreoScan)  S.B capsule
malignancy endoscopy
 EUS
Tissue diagnosis

Commencement of treatment
Clinical, biochemical and radiological
follow-up
TREATMENT OF NETS

A. Medical control of patient’s

symptoms
B. Resection of tumour primary and if
possible, metastatic lesions
C. Control of tumour growth in cases of
advanced disease
D. Improvement and maintenance of
patient’s quality of life.
SOMATOSTATIN ANALOGUES

Octreotide LAR

https://www.hcp.novartis.com/products/sandostatin-lar-depot/carcinoid-syndrome/dosing-administration/. Accessed May 2018

Lanreotide autogel
SOMATOSTATIN ANALOGUES IN
“CARCINOID SYNDROME”

 First and best choice medications1,2  Prospective cross over analysis of

 Reduce flushing >70%1,2
 Reduce diarrhoea
 Biochemical response ~50%1,2
33 patients3
 No differences between octreotide
>60%1,2 and lanreotide in symptom control
or biochemical response3

Inhibition
of hormone
SST secretion
by the tumour

SST
1. Shah T & Caplin M, Best Pract Res Clin Gastroenterol. 2005; 2. Plockinger U & Wiedenmann B, Best Pract Res Clin End Metab 2007;
3. O’Toole D, et al. Cancer 2000.
INTERFERON-ALPHA FOR
CARCINOID SYNDROME
SYMPTOMS’ CONTROL
RFH Interferon Data2
 24 pts, in combination with SSTA
 Diarrhoea improved 45%
 Flushing improved in 54%
 No statistically significant decrease of
5-HIAA levels
 Of the 19 patients given alpha-interferon  27% of patients discontinued treatment
in combination with octreotide, 72% at 3 months, due to AE
showed significant reduction in urinary
5-HIAA for a median of 10 months1
 A symptomatic improvement was seen
in 49%1
 The combination was well tolerated1
1. Janson ET & Oberg K, Acta Oncol 1993; 2. Mirvis E, et al. Anticancer Research 2015.
PASIREOTIDE (SOM230)

K+
K+
K+ Somatostatin

Pasireotide is a novel
Voltage

 SSTR

multireceptor-targeted
K+
Ca2+ channel
Ca2+
Ca2+ channel + +
Ca2+
G
somatostatin analogue with -
-

Gβ
GƔ
+ Ca2+
high binding affinity for -

+ PLCβ/IP3
channel
Ca2+ ↓
somatostatin receptor Adenyl cyclase
SHP-1 ER

subtypes 1, 2, 3 and 51 cAMP ↓

PTPase SHP-2
PTPᶯ

 Preclinical models have Hormone Caspase 8

Ca2+ ↑

shown that pasireotide can Secretion ↓

Wt P53 ↑
Bax ↑
ERK1/2 ↑ ERK1/2 ↓
P27Kip1 ↑ Secretion ↑
pHi ↓ (infrequently)
influence tumour cell growth (frequently) Endonuclease ↑
+ -

via effects on apoptosis and Apoptosis ↑

Cell growth ↓
Hormone
angiogenesis1

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

PHASE III STUDY OF PASIREOTIDE
LAR VS. OCTREOTIDE LAR IN
PATIENTS WITH METASTATIC
MIDGUT NET
Blinded treatment period of 6 months

NET patients with Pasireotide LAR 60 mg IM every 28 days x 6 months

carcinoid syndrome with dose ↓ to 40 mg for tolerability (n=53)
symptoms inadequately 1:1
controlled by maximum randomisation
doses of currently Octreotide LAR 40 mg IM every 28 days x 6 months
available SSAs with dose ↓ to 30 mg for tolerability (n=57)

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)

Wolin EM, et al. J Clin Oncol 2013;31:(suppl; abstr 4031); http://clinicaltrials.gov identifier NCT00690430.
ΙN ADDITION TO SSA, TELOTRISTAT
ETIPRATE INHIBITS SEROTONIN
PRODUCTION AND ALLEVIATES SYMPTOMS

Serotonin
Hormonal syndrome
flushing, diarrhoea.....

5-HIAA NET-Cell
Tryptophan
Urine
Tryptophan- Telotristat
Hydroxylase etiprate
Serotonin
5-Hydroxytryptophan (5-HTP)
SSTR
Serotonin (5-HT)
5-HIAA: 5-hydroxyindole acetic acid
SSA somatostatin analogue
SSA
SSTR somatostatin receptor
 TELESTAR
PHASE 3 STUDY DESIGN

1:1:1
3- to 4-week
run-in R Placebo TID (n=45)
(n=135)
Telotristat
Telotristat etiprate 250 mg TID
etiprate
Run in: Evaluation (n=45)
of bowel movement
500 mg TID
(BM) frequency Telotristat etiprate 500 mg TID*
(n=45)
Evaluation of primary endpoint:
Reduction in number of daily BMs from baseline
(averaged over 12-week double-blind treatment phase)

All patients required to be on SSA at enrollment and continue SSA therapy

throughout study period

Kulke M, et al. J Clin Oncol 2017;35(1):14–23

 TELESTAR RESULTS: REDUCTION
IN MEAN DAILY BOWEL MOVEMENT
FREQUENCY AT BASELINE AND WEEK 12

–28%
–36%
–17%

Mild nausea: 15%

Mild depression: 15–20%

Kulke M, et al. J Clin Oncol 35(1), 2017:14–23. Reprinted with permission © 2017, American Society of Clinical Oncology. All rights reserved.
 SURVIVAL OF PATIENTS

With bowel bypass (12) versus failed resection (17) versus no resection
(80) versus resection (210)
Study supported by UKI-NETS
 5 UKI NET centres
 360 patients

Median survival
RP 9.92 years
NR 4.68 years
ByP 5.61 years
FR 6.74 years

Deaths due to fibrosis-

related cachexia
RP 4.78%
NR,ByP, FR 12.72%

Republished with permission of Society for Endocrinology from Endocr Relat Cancer, Ahmed A, et al. 16(7), 2009; permission conveyed through Copyright Clearance Center, Inc
 MESENTERIC FIBROSIS IN
MIDGUT NETS

 Episodes of sub-acute bowel

obstruction
 Diet modification
 Hydronephrosis
 Ureteric stents
 Malnutrition
 Nutritional supplements,
enteral feeding, TPN?
 Small bowel bacterial overgrowth
 Antibiotics
 Recurrent ascites, ectopic varices
 SMV stenting?
Images courtesy of Dr. Christos G. Toumpanakis

Toumpanakis CG, et al. BSG 2006; Naik et al. ENETS 2014.

CONTROL OF TUMOUR GROWTH
FOR ADVANCED INOPERABLE
GASTRO-INTESTINAL NETS
Medical therapy
Somatostatin analogues (SSAs)
 Interferon-α
 Molecular targeted therapies
 mTOR inhibitors
 Systemic chemotherapy
Loco-regional therapy
 Radiofrequency ablation (RFA)
 Embolization/chemoembolization/
radioembolization
Nuclear medicine and radiation
 Tumour-targeted, radioactive therapy:
PRRT using:

177Lu –DOTATATE
 External radiation (for bone/brain
metastases)
OCTREOTIDE LAR IN PATIENTS
WITH METASTATIC NEUROENDOCRINE
MIDGUT TUMOURS
PROMID placebo-controlled, double-blind, randomized study

 Median time to progression:

14.3 months in LAR group vs. 6 months
in placebo

 After 6 m of treatment:
Stable disease in 66.7% of LAR vs.
37.2% of placebo

 Most favorable effect in patients with

low-hepatic tumour load and resected
primary tumour

Rinke A, et al. J Clin Oncol 27, 2009:4656–63. Reprinted with permission. © 2009 American Society of Clinical Oncology. All rights reserved.
PRIMARY ENDPOINT: PFS
PFS and tumour growth with Lanreotide Autogel in
patients with enteropancreatic NETs: Results from CLARINET,
a randomised, double-blind, placebo-controlled study

62%

22%

Time (months)

(ITT, N=204)
P-value derived from stratified log-rank test; HR derived from Cox proportional hazard model.
HR, hazard ratio; ITT, intention-to-treat.
From N Engl J Med, Caplin ME, et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors, 371(3):224–33. Copyright © 2014 Massachusetts Medical
Society. Reprinted with permission from Massachusetts Medical Society.
RESULTS OF PHASE III STUDY OF
PASIREOTIDE LAR VS. OCTREOTIDE LAR
In patients with metastatic midgut NET

 There was no difference in symptoms’

control between the two arms
 Overall there was no difference in
disease control (CR+PR+SD) between
the two arms
 Pasireotide LAR demonstrated a benefit
in tumour shrinkage
 Prolongation of PFS by 5 months
was observed in patients treated with
pasireotide LAR (11.8 vs. 6.8 months)

Wolin EM, et al. Drug Des Dev Ther 2015;9:5075–86. Licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) available at
http://creativecommons.org/licenses/by-nc/3.0/.
COMBINATION OF SOMATOSTATIN
ANALOGUES WITH INTERFERON

No
Study of Primary Combination SD % PR / CR %
pts
Frank M, et al. 21 Pancreatic / midgut OCT + INF-α 62 5
Fjällskog ML,
16 pancreatic OCT + INF-α >80
et al.
 Reduced risk in tumour
Kölby L, et al. 68 Midgut OCT + INF-α progression
 No benefit in survival
LAN or No benefit of the
Foregut/ midgut /


Faiss S, et al. 80 INF-α or combination

hindgut
LAN+ INF-α  More adverse effects
No superior to
OCT or
Arnold R, et al. 105 Pancreatic Midgut monotherapy
OCT + INF-α
In PFS & OS

Frank M, et al. Am J Gastroenterol 1999; Fjällskog ML, et al. Med Oncol 2002; Kölby L, et al. Br J Surg 2003; Faiss S, et al. J Clin Oncol 2003;
Arnold R, et al. Clin Gastroenterol Hepatol 2005
SYSTEMIC CHEMOTHERAPY

 Platinum-based chemotherapy is the

treatment of first choice in GEP-NECs
with good RR but short PFS
 A 55% cut-off level of Ki67 seems promising
predictive factor of response in NECs
 Streptozocin-based regimens induce
responses ONLY in 15% of small bowel
NETs
 Ki67 by itself cannot predict response in
well-diff NETs
 Chemotherapy could be an option to be the
preferred option in type III gastric NETs with
rapid symptomatic and radiological
progression; however, prospective studies
are needed

Kouvaraki MA, et al. J Clin Oncol 22(23), 2004:4762–71. Reprinted with permission © 2004. American Society of Clinical Oncology. All rights reserved.
Toumpanakis CG, et al. Best Pract Res Clin End Metab 2007; Sorbye et al. the NORDIC NEC study, Ann Oncol 2013.
 Sunitinib

Everolimus

Reprinted from Gastroenterology, 135(5), Metz D, Jensen R. Gastrointestinal Neuroendocrine Tumors: Pancreatic Endocrine Tumors, 1469–92. Copyright 2008,
with permission from Elsevier.
RADIANT-4 STUDY DESIGN

Patients with well-differentiated

(G1/G2), advanced, progressive, R
nonfunctional NET of lung or GI A Everolimus 10 mg/day
origin (N = 302) N N = 205
Absence of active or any history D

O
Treated until PD,
of carcinoid syndrome 2:1 intolerable AE, or
M
 Pathologically confirmed I consent withdrawal
advanced disease S Placebo
E
 Enrolled within 6 months from N = 97
radiologic progression

Endpoints: Stratified by:

 Primary: PFS (central)  Prior SSA treatment (yes vs. no)
 Key Secondary: OS  Tumour origin (stratum A vs. B)*
 Secondary: ORR, DCR, safety, HRQoL (FACT-G),  WHO PS (0 vs. 1)
WHO PS, NSE/CgA, PK

*Based on prognostic level, grouped as: Stratum A (better prognosis)  appendix, caecum, jejunum, ileum, duodenum, and
NET of unknown primary. Stratum B (worse prognosis)  lung, stomach, rectum, and colon except caecum.
Crossover to open label everolimus after progression in the placebo arm was not allowed prior to the primary analysis.

Yao JC, et al. Lancet 2016;387(10022):968–77

PRIMARY ENDPOINT: PFS BY
CENTRAL REVIEW
52% reduction in the relative risk of progression or death with everolimus vs. placebo
HR=0.48 (95% CI, 0.35-0.67); P<0.00001

P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model.
Reprinted from The Lancet, 387(10022), Yao JC, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or
gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study, 968–77. Copyright 2016, with permission from Elsevier.
TRANSARTERIAL HEPATIC
EMBOLIZATION AND
CHEMOEMBOLIZATION

 Symptomatic benefit (40–80%)1,2

 Partial response: ~50%1,2
 Survival benefit?1,2

 Morbidity (carcinoid crisis, fever, pain,

hepatic failure, intestinal ischaemia)2
 Mortality3
 IV octreotide infusion pre- and post-
therapy in midgut carcinoids3
Images courtesy of Dr. Christos G. Toumpanakis
 Careful selection of patients3

1. Brown KT, et al. J Vasc Interv Radiol 1999;10(4):397-403; 2. Chamberlain et al. J Am Coll Surg 2000;190:432-445;
3. Toumpanakis CG, et al. Best Pract Res Clin End Metab 2007.
OTHER ABLATION THERAPIES

• Radio-frequency ablation

• Laser-induced thermotherapy

• Cryotherapy
Reprinted from Gastroenterology, 134(6), El-Serag HB, et al. Diagnosis and Treatment of
Hepatocellular Carcinoma, 1752–1763. Copyright 2008 with permission from Elsevier

• Ethanol ablation

• Brachytherapy
SST ANALOGUE TARGETED
RADIOTHERAPY
Mechanism of action

Isotope + Sst
analogue
Somatostatin
receptor

Tumour
cell
Tumour
cell

The β-emitter labelled somatostatin

analogue delivers a lethal radiation dose
to the tumour cell
NETTER-1 STUDY OBJECTIVES
AND DESIGN

Evaluate the efficacy and safety of LUTATHERA® + SSAs (symptoms control) compared to
Aim Octreotide LAR 60mg (off-label use) in patients with inoperable, somatostatin receptor
positive, midgut NET, progressive under Octreotide LAR 30mg (label use)

Design International, multicentre, randomised, comparator-controlled, parallel-group

Treatment and assessments

Progression-free survival (RECIST criteria) every 12 weeks

4 administrations of 7.4 GBq of LUTATHERA® every

n = 116 8 weeks + SSAs (symptom control)
5 Years
follow up
n = 113 Octreotide LAR (high dose – 60mg every 4 weeks)

Baseline progression according to RECIST 1.1 criteria

The median time between the oldest pre-baseline and the baseline scans (used to determine the
progression at enrolment) was 11.4 months for patients in the LUTATHERA® arm and
11.7 months for the control arm
Strosberg J, et al. N Engl J Med 2017;376(2):125–35.
PFS, OS AND SUBGROUP
ANALYSIS IN NETTER-1

Adverse effects
 Nausea: 59%
 Vomiting: 47%
 Anaemia:14%
 Neutropenia: 6%
 Thrombocytopenia: 25%
 NO RENAL TOXICITY

From N Engl J Med, 376(2), Strosberg J, et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors, 125–35. Copyright © 2017 Massachusetts
Medical Society. Reprinted with permission from Massachusetts Medical Society.
OBJECTIVE RESPONSE IN
NETTER-1

Objective Tumor Response*

177Lu-dotatate group Control group
Response category (n=101) (n=100) P-value†
Complete response, n (%) 1 (1) 0

Partial response, n (%) 17 (17) 3 (3)

Objective response

No. with response 18 3

Rate, % (95% CI) 18 18 (10–25) 3 (0–6) <0.001

Learning point from NETTER-1 trial

PRRT with 177Lu-dotatate can control tumour growth in G1/G2 advanced and
progressive midgut NETs with quite good objective response rates

*The objective response rate was defined as the percentage of patients who had a response according to Response Evaluation Criteria in Solid Tumors
(RECIST) #(sum of partial responses and complete responses). Patients for whom no post-baseline computed tomography (CT) or magnetic resonance imaging
(MRI) scans or central response data were available (15 patients in the 177Lu-Dotatate group and 13 patients in the control group) were excluded from this
analysis (trial is still ongoing).
†P-value calculated using Fisher’s exact text.

Strosberg J, et al. NEJM 2017;376:125–35

LONG-TERM EFFICACY OF LU-177
DOTATATE IN GEP-NETS

Tumour CR PR SD ORR DoR (months)

N
type n % n % N % n % 95% CI Median 95% CI
All* 360 11 3% 151 42% 183 51% 162 45% 40% 50% 16.3 12.2 17.8
Bronchial 19 0 0% 7 37% 11 58% 7 37% 16% 62% 23.9 1.7 30.0
Pancreatic 133 7 5% 74 56% 47 35% 81 61% 52% 69% 16.3 12.1 21.8
Foregut** 12 1 8% 6 50% 4 33% 7 58% 28% 85% 22.3 0.0 38.0
Midgut 183 3 2% 58 32% 115 63% 61 33% 27% 41% 15.3 10.5 17.7
Hindgut 13 0 0% 6 46% 6 46% 6 46% 19% 75% 17.8 6.2 29.9

PFS OS
Tumour Time (months) Time (months)
N CR: Complete Response
type
Median 95% CI Median 95% CI PR: Partial Response
All* 360 28.5 24.8 31.4 61.2 54.8 67.4 SD: Stable Disease
Bronchial 19 18.4 10.4 25.5 50.6 31.3 85.4 ORR: Overall Radiological Response
Pancreatic 133 30.3 24.3 36.3 66.4 57.2 80.9 PFS: Progression Free Survival
Foregut** 12 43.9 10.9 21.3 OS: Overall Survival
Midgut 183 28.5 23.9 33.3 54.9 47.5 63.2
Hindgut 13 29.4 18.9 35.0

Brabander T, et al. Clin Cancer Res. 2017

EARLY EFFICACY OF AND TOXICITY
FROM LU-177 DOTATATE TREATMENT
In patients with progressive metastatic GEP-NET

Kaplan-Meier chart of PFS for the whole cohort

Objective response: 13%
Disease stabilization: 64%

Estimated median PFS was 28 months, 95% CI: 23–33 months

Pencharz D, et al. Early efficacy of and toxicity from lutetium-177-DOTATATE treatment in patients with progressive metastatic NET Nucl Med Commun
2017;38(7):593–600. Available at: https://journals.lww.com/nuclearmedicinecomm/Abstract/2017/07000/Early_efficacy_of_and_toxicity_from.4.aspx.
 COMBINATION OF SOMATOSTATIN
ANALOGUES WITH OTHER AGENTS
IN MIDGUT NETS
No of SD PR/CR PFS %
CARCINOIDS pts % % (18 w)
Octreotide LAR
22 77 18 95
+ bevacizumab
Octreotide LAR
21 68 68
+ PEG - INF

CARCINOIDS PFS
Octreotide LAR + placebo 11.3 months
Octreotide LAR + everolimus 16.4 months

RADIANT-2 trial
No difference in partial response
No difference in disease stabilization
More adverse effects in combination group

Yao JC, et al. J Clin Oncol 2008;26(8):1316-23;

Reprinted from The Lancet, 378 (9808), Pavel ME, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours
associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study, 2005-12, Copyright 2011, with permission from Elsevier.
WHICH TREATMENT AND
FOR WHOM

 Patient’s clinical status, co-

morbidities and preferences
 Tumour histology
 Location of primary
 Positive uptake in Octreoscan or
Ga-68 PET
 Tumour burden
 Tumour status
 Presence of carcinoid heart
disease and/or mesenteric fibrosis
 Predictive molecular markers?
 Cost??
G3 GEP-NETS

Patient’s performance status 0-2

Systemic chemotherapy

Platinum-based chemotherapy
[Temozolomide-based
chemotherapy (if Ki67 < 55%)]
Well differentiated
G3 GEP-NETs
Disease progression
PRRT?
Molecular targeted?
2nd Line Systemic Chemotherapy
(FOLFOX, FOLFIRI)

Sorbye H, et al. Cancer 2014; ENETS Guidelines 2016.

 Biopsies of surrounding mucosa
Serum gastrin

No atrophic gastritis Atrophic gastritis No atrophic gastritis

Normal serum gastrin Hypergastrinaemia Hypergastrinaemia
ΤYPE III ΤYPE I ΤYPE II

In localised disease >2 cm 1-2 cm <1 cm >1 cm

Surgical resection
In advanced disease
Systemic treatment No vascular
Invasion beyond
invasion
Submucosa
No deep invasion
Lymph nodes?
Management algorithm G1 Resection, if
of gastric NETs symptomatic or
Somatostatin
Local resection analogues
Endoscopic
+/- antrectomy or resection
+/- somatostatin analogues

Annual endoscopic
surveillance
Delle Fave G, et al. Neuroendocrinology. 2016;103(2):119-24.
 ENETS 2016 CONSENSUS
GUIDELINES FOR DUODENAL NETS

Delle Fave G, et al. ENETS Consensus Guidelines Update for Gastroduodenal Neuroendocrine Neoplasms. Neuroendocrinology. 2016;103(2):119-24.
With permission from S. Karger AG, Basel.
ENETS 2016 CONSENSUS
GUIDELINES FOR INTESTINAL NETS

Pavel M, et al. ENETS Consensus Guidelines Update for the Management of Distant Metastatic Disease of Intestinal, Pancreatic, Bronchial Neuroendocrine
Neoplasms (NEN) and NEN of Unknown Primary Site. Neuroendocrinology 2016;103(2):172-85. With permission from S. Karger AG, Basel.
 Hepatobiliary
& GI surgery Specialist
NET Nurses
Dieticians

Pathology

Endocrinology
NET
patient Genetics

Cardiology

Oncology

Radiology &
Nuclear Medicine Palliative care
Gastroenterology & Pain control
MULTI-DISCIPLINARY TEAM (MDT)
APPROACH FOR NETS

 Accurate diagnosis & staging

 Evaluation of performance status &
quality of life
 Consensus agreement on treatment plan
 Continuous reassessment, discussion
and peer review of the individualised
treatment plan
THANK YOU!