Management of Gastroenteropancreatic Neuroendocrine T umour: a n update
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Management of Gastroenteropancreatic Neuroendocrine Tumour:an update
Joint Hospital Surgical Grand RoundDr Chan Kwan Kit
Caritas Medical Centre
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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
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Distribution
Gastrointestinal tract: ~65% Bronchopulmonary system: ~25% Other locations ~10%:
thymus gonadsheart kidneysprostate
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Gastroenteropancreatic NETs (GEPNETs)
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Classifications
WHO classification: tumour sitedegree of differentiation and grading functionality
TNM classification
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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.
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Investigation
Biochemical markers Radiological imaging
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Investigation: biochemical markers
Specific markers depending on origin Urinary 5-hydroxyindoleacetic acid (5-HIAA):
main metabolite of serotoninGastrin InsulinGlucagon etc.
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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
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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
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Investigation: radiology
Computed tomography: arterial enhancing lesions with washout in
venous phase Magnetic resonance imaging:
more sensitive for liver and bone marrow metastases
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Endoscopic ultrasound
High sensitivity for tumours at esophagus, stomach, duodenum, and pancreas
Allows image-guided biopsy
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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
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Positron Emission Tomography
Ga-68 DOTATOC: high binding affinity for SST receptors
18-FDG: identifies clinically aggressive lesions with high metabolism
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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
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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
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Cehic G et al. COSA. Nov 2010
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Management
Surgical Non-surgical
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Management
Surgery remains the only curative treatment
Curative surgery should always be considered if feasible
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Palliative surgery in metastatic disease:Debulking Resection of primary tumour
Proven benefit for local and hormonal symptom control
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Surgery
Surgical plan dictated by:Tumour’s site of originDegree of tumour burdenGeneral health or debility of the patient
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Operative consideration
Perioperative somatostatin analogsPrevents excessive hormone release during
manipulationParticularly important for intestinal carcinoids
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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
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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
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SST analogs
No conclusive evidence for survival benefit with use of SST analogs
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Alpha-Interferon (IFN)
Induces apoptosis Antiproliferative and anti-angiogenic
effects Evidence suggested usage in low-
proliferating NETs only
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Radionuclide therapy:Radiolabelled SST analogs SST analogs, IFN,
chemotherapies, and external irradiation all have poor response in advanced or rapidly progressing GEPNETs
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Radiolabelled SST analogs GEPNETs: high level of SSTR expression and good
vascularization Studied radionuclide agents:
90Y-DOTA-octreotide 111In-pentetreotide 177Lu-DOTA-Tyr-octreotide
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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; 32:133-140Paganelli G et al. Biopolymers 2008; 66: 393-398
No long term result available yet
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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
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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
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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
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Liver-directed therapies
Liver is the predominant site of metastases for GEPNETs
Metastatic liver disease gives more carcinoid syndrome
Treatment options:Liver resection/ ablationHepatic artery embolization
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Liver resection/ ablation
Advocated if more than 90% of tumours can be successfully resected or ablated
Symptom palliation and survival prolongation well reported
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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
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Conclusion
GEPNETs represent a complex and heterogenous tumour entity with rising incidence and prevalence
Diagnostic and therapeutic challenges due to its relative rarity
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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
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Pancreatic-NETs
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Investigation: biochemical markers
Urinary 5-hydroxyindoleacetic acid (5-HIAA) Main metabolite of serotonin
helps diagnosing carcinoid syndrome
Not applicable for non-functional tumours
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Operative consideration (2)
Role of prophylactic cholecystectomyRationale: somatostatin analogs treatment
leads to development of gallstonesHowever most of these stones are
asymptomaticNo conclusive evidence to recommend
prophylactic cholecystectomy
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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
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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
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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; 32:133-140Paganelli G et al. Biopolymers 2002; 66: 393-398
De Jong M et al. Int J Cancer 2001 Jun 1; 92(5): 628-33Ebrahim S et al. Cancer biotherapy and radiopharmaceuticals Vol 23, No. 3, 2008
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Hepatic artery embolization
Contraindication:Poor liver functionModerate to severe ascitesPortal venous thrombosis
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Liver-directed therapies
Novel approaches:RadioembolizationLiver transplantation