Transcript Management of Gastroenteropancreatic Neuroendocrine tumour

Management of
Gastroenteropancreatic
Neuroendocrine Tumour:
an update
Joint Hospital Surgical Grand Round
Dr Chan Kwan Kit
Caritas Medical Centre
Neuroendocrine Tumours (NETs)
Epithelial neoplasms with predominant
neuroendocrine differentiation
 Considered rare traditionally, comprising
~0.5% of all malignancies
 Increasing incidence and prevalence, 2.5 5/100,000 people per year

 Increasing
awareness
 Improvement in diagnostic modalities
Distribution
Gastrointestinal tract: ~65%
 Bronchopulmonary system: ~25%
 Other locations ~10%:

 thymus
 gonads
 heart
 kidneys
 prostate
Gastroenteropancreatic NETs
(GEPNETs)
Classifications

WHO classification:
 tumour
site
 degree of differentiation and grading
 functionality

TNM classification
Presentation


Asymptomatic
Non-functional: non-specific symptoms
 abdominal
pain, small bowel obstruction,
gastrointestinal bleeding, anorexia, weight loss

Functional: hormone/ peptides-related
 Serotonin:
carcinoid syndrome
 Insulin: Whipple’s triad
 Gastrin
 Vasoactive intestinal peptide etc.
Investigation
Biochemical markers
 Radiological imaging

Investigation: biochemical markers

Specific markers depending on origin
 Urinary
5-hydroxyindoleacetic acid (5-HIAA):
main metabolite of serotonin
 Gastrin
 Insulin
 Glucagon etc.
Investigation: biochemical markers
Chromogranin A
 Co-secreted by different neuroendocrine cell
types
 Correlates with tumour burden and stage
 Established roles in literatures:
 Diagnosis
 Treatment
response monitoring
 Relapse detection
Chromogranin A

Relatively high sensitivity 53-85%
Ben L. Endocrinol Metab Clin N Am 40 (2011) 111–134


Non-specific
Elevated in non-NETs condition:
 Non-neoplastic:
chronic atrophic gastritis; renal failure;
liver cirrhosis
 Neoplastic: HCC; colon cancers
 Drugs: proton pump inhibitors
Investigation: radiology

Computed tomography:
 arterial
enhancing lesions with washout in
venous phase

Magnetic resonance imaging:
 more
sensitive for liver and bone marrow
metastases
Endoscopic ultrasound
High sensitivity for tumours at esophagus,
stomach, duodenum, and pancreas
 Allows image-guided biopsy

Octreoscan
Somatostatin (SST) receptor scintigraphy
 Principle: 80-90% of NETs express SST
receptors


Inflammatory lesions and some non-NET
malignancies may give false positive
results
Positron Emission Tomography


Ga-68 DOTATOC: high binding affinity
for SST receptors
18-FDG: identifies clinically aggressive
lesions with high metabolism
PET: pros and cons

Better spatial and contrast resolution
giving higher sensitivity
Specific radioisotopes not widely available
 Hasn’t been fully validated with strong
evidence yet

Principle of imaging for GEPNETs
CT or MRI combining with functional
imaging to obtain maximal information
 Currently Octreoscan is still the gold
standard for radionuclide imaging
 Will likely be replaced by PET scan with
specific radioisotopes

Cehic G et al. COSA. Nov 2010
Management
Surgical
 Non-surgical

Management
Surgery remains the only curative
treatment
 Curative surgery should always be
considered if feasible


Palliative surgery in metastatic disease:
 Debulking
 Resection
of primary tumour
Proven benefit for local and hormonal
symptom control
Surgery

Surgical plan dictated by:
 Tumour’s
site of origin
 Degree of tumour burden
 General health or debility of the patient
Operative consideration

Perioperative somatostatin analogs
 Prevents
excessive hormone release during
manipulation
 Particularly important for intestinal carcinoids
Somatostatin (SST) analogs


First line medication
Acts through SST receptors on NETs
 Inhibition
of cellular proliferation and hormonal
release

Available for clinical use: octreotide and
lanreotide
SST analogs
Reduction in tumour size: <10%
 Stabilization of tumour: 40-60%
 Biochemical response: 50-70%
 Symptomatic response: 70-90%

Evidence of tumour response AND
improvement of quality of life are well
established
SST analogs

No conclusive evidence for survival benefit
with use of SST analogs
Alpha-Interferon (IFN)
Induces apoptosis
 Antiproliferative and anti-angiogenic
effects
 Evidence suggested usage in lowproliferating NETs only

Radionuclide therapy:
Radiolabelled SST analogs

SST analogs, IFN,
chemotherapies, and
external irradiation all
have poor response in
advanced or rapidly
progressing GEPNETs
Radiolabelled SST analogs


GEPNETs: high level of SSTR expression and
good vascularization
Studied radionuclide agents:

90Y-DOTA-octreotide
 111In-pentetreotide
 177Lu-DOTA-Tyr-octreotide
90Y-DOTA-octreotide

Encouraging short and intermediate term results:

23-28% objective response rate
 63-70% symptomatic response rate
 Longer progression free survival for pancreatic NETs
Waldherr et al. J Nucl Med. 2002; 32:133-140
Paganelli G et al. Biopolymers 2008; 66: 393-398

No long term result available yet
Cytotoxic chemotherapy

Sensitivity of NETs correlates with primary
tumour location and tumour grade
 low

grade carcinoid tumours typically resistant
First line therapy only for metastatic/
unresectable pancreatic NETs
 combination

of streptozotocin and 5-fluorouracil (5-FU)
Some evidence for use in high grade ileal NETs
Targeted therapy


Mammalian target of rapamycin (mTOR): serine
kinase regulating cell growth and proliferation
mTOR inhibitor: everolimus
 Two
recently completed phase III studies (RADIANT 2
and RADIANT 3) demonstrated statistically significant
improvement in progression-free survival (PFS) in
metastatic carcinoid tumours
Targeted therapy
NETs are highly vascular and frequently
overexpress VEGF ligand and receptor
 Bevacizumab and sunitinib: VEGF
inhibitors
 Phase II studies for both agents are
promising
 Multinational phase III study ongoing

Liver-directed therapies
Liver is the predominant site of metastases
for GEPNETs
 Metastatic liver disease gives more
carcinoid syndrome
 Treatment options:

 Liver
resection/ ablation
 Hepatic artery embolization
Liver resection/ ablation
Advocated if more than 90% of tumours
can be successfully resected or ablated
 Symptom palliation and survival
prolongation well reported

Hepatic artery embolization



Diffuse unresectable liver
metastases
Rationale: tumours derived
majority of their blood
supply from arterial
circulation
Bilobar metastases: staged
lobar embolization at 4-6
weeks interval
Conclusion
GEPNETs represent a complex and
heterogenous tumour entity with rising
incidence and prevalence
 Diagnostic and therapeutic challenges due
to its relative rarity

Conclusion
Diagnostic and treatment options for
GEPNETs are expanding
 Controversies exist for choice and
sequencing of treatments requiring
relevant expertise input
 Multidisciplinary approach warranted for
best outcome for patients

Pancreatic-NETs
Investigation: biochemical markers
Urinary 5-hydroxyindoleacetic acid (5-HIAA)
 Main metabolite of serotonin
 helps

diagnosing carcinoid syndrome
Not applicable for non-functional tumours
Operative consideration (2)

Role of prophylactic cholecystectomy
 Rationale:
somatostatin analogs treatment
leads to development of gallstones
 However most of these stones are
asymptomatic
 No conclusive evidence to recommend
prophylactic cholecystectomy
Side effects of SST analogs
Usually mild: flatulence; abdominal pain;
diarrhea in less than 10% patients
 Choledolithiasis: in 20-40% patients with
long term SST analogs; acute symptoms
rare

SST analogs + IFN



Combination therapy as upfront treatment in
therapy-naïve patients is not well established
Evidence for additive effect of tumour response:
 sequential use of the two drugs; and,
 combination after progression with single
agent
No proven survival benefit
Side effect profile (Radiolabelled
SST analogs)



Toxic effects are mild in most patients
Nausea and vomiting being the commonest
symptoms
Severe lymphopenia and renal toxicity have
been reported
Waldherr et al. J Nucl Med. 2002; 32:133-140
Paganelli G et al. Biopolymers 2002; 66: 393-398
De Jong M et al. Int J Cancer 2001 Jun 1; 92(5): 628-33
Ebrahim S et al. Cancer biotherapy and radiopharmaceuticals Vol 23, No. 3, 2008
Hepatic artery embolization

Contraindication:
 Poor
liver function
 Moderate to severe ascites
 Portal venous thrombosis
Liver-directed therapies

Novel approaches:
 Radioembolization
 Liver
transplantation