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Management of Gastroenteropancreatic Neuroendocrine Tumour: an update Joint Hospital Surgical Grand Round Dr Chan Kwan Kit Caritas Medical Centre.

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Presentation on theme: "Management of Gastroenteropancreatic Neuroendocrine Tumour: an update Joint Hospital Surgical Grand Round Dr Chan Kwan Kit Caritas Medical Centre."— Presentation transcript:

1 Management of Gastroenteropancreatic Neuroendocrine Tumour: an update Joint Hospital Surgical Grand Round Dr Chan Kwan Kit Caritas Medical Centre

2 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

3 Distribution Gastrointestinal tract: ~65% Bronchopulmonary system: ~25% Other locations ~10%:  thymus  gonads  heart  kidneys  prostate

4 Gastroenteropancreatic NETs (GEPNETs)

5 Classifications WHO classification:  tumour site  degree of differentiation and grading  functionality TNM classification

6 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.


8 Investigation Biochemical markers Radiological imaging

9 Investigation: biochemical markers Specific markers depending on origin  Urinary 5-hydroxyindoleacetic acid (5-HIAA): main metabolite of serotonin  Gastrin  Insulin  Glucagon etc.

10 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

11 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

12 Investigation: radiology Computed tomography:  arterial enhancing lesions with washout in venous phase Magnetic resonance imaging:  more sensitive for liver and bone marrow metastases


14 Endoscopic ultrasound High sensitivity for tumours at esophagus, stomach, duodenum, and pancreas Allows image-guided biopsy


16 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


18 Positron Emission Tomography Ga-68 DOTATOC: high binding affinity for SST receptors 18-FDG: identifies clinically aggressive lesions with high metabolism

19 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

20 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

21 Cehic G et al. COSA. Nov 2010

22 Management Surgical Non-surgical

23 Management Surgery remains the only curative treatment Curative surgery should always be considered if feasible

24 Palliative surgery in metastatic disease:  Debulking  Resection of primary tumour Proven benefit for local and hormonal symptom control

25 Surgery Surgical plan dictated by:  Tumour’s site of origin  Degree of tumour burden  General health or debility of the patient

26 Operative consideration Perioperative somatostatin analogs  Prevents excessive hormone release during manipulation  Particularly important for intestinal carcinoids

27 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

28 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

29 SST analogs No conclusive evidence for survival benefit with use of SST analogs

30 Alpha-Interferon (IFN) Induces apoptosis Antiproliferative and anti-angiogenic effects Evidence suggested usage in low- proliferating NETs only

31 Radionuclide therapy: Radiolabelled SST analogs SST analogs, IFN, chemotherapies, and external irradiation all have poor response in advanced or rapidly progressing GEPNETs

32 Radiolabelled SST analogs GEPNETs: high level of SSTR expression and good vascularization Studied radionuclide agents:  90Y-DOTA-octreotide  111In-pentetreotide  177Lu-DOTA-Tyr-octreotide

33 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

34 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

35 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

36 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

37 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

38 Liver resection/ ablation Advocated if more than 90% of tumours can be successfully resected or ablated Symptom palliation and survival prolongation well reported

39 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


41 Conclusion GEPNETs represent a complex and heterogenous tumour entity with rising incidence and prevalence Diagnostic and therapeutic challenges due to its relative rarity

42 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


44 Pancreatic-NETs


46 Investigation: biochemical markers Urinary 5-hydroxyindoleacetic acid (5-HIAA) Main metabolite of serotonin  helps diagnosing carcinoid syndrome Not applicable for non-functional tumours

47 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

48 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

49 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

50 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


52 Hepatic artery embolization Contraindication:  Poor liver function  Moderate to severe ascites  Portal venous thrombosis

53 Liver-directed therapies Novel approaches:  Radioembolization  Liver transplantation

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