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, /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
Because these tumors derive from neuroendocrine
cell compartments, their frequency of occurrence
correlates with the site-density of neuroendocrine
cells. Thus, nearly 60% of carcinoid tumors arise
along the largest endocrine organ of man,

4. Gastroenteropancreatic NETs (GEPNETs)

5. Classifications WHO classification: TNM classification tumour site
degree of differentiation and grading
functionality
TNM classification
Well-differentiated versus poorly differentiated
Grading: G1, G2, G3
Mitotic count
Ki-67 proliferation index
Functional versus non-functional

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% Non-specific
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
CgA: first indicator for recurrence (ahead of 5-HIAA/ imaging)

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
Multidisciplinary involvement is important

24. Proven benefit for local and hormonal symptom control
Palliative surgery in metastatic disease:
Debulking
Resection of primary tumour
Proven benefit for local and hormonal symptom control
Curative surgery only possible in ~30% patients

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
S/E mainly attributed by IFN – fever/ anorexia/ depression/ confusion/ arthralgia

31. Radionuclide therapy: Radiolabelled SST analogs
SST analogs, IFN, chemotherapies, and external irradiation all have poor response in advanced or rapidly progressing GEPNETs
A gentleman with pancreatic NET with liver mets

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
Good vascularization -> important condition for proper diffusion of radiolabelled peptides into tumour mass
Yttrium-90
Indium-111
Lutetium-177

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:
Paganelli G et al. Biopolymers 2008; 66:
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
Ablation reserved for unresectable metastases smaller than 5 to 7 cm

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
Inconvenient to measure: 24 hour urine sampling/ serotonin-rich food abstinence

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
- Only <1% of patients with SST-induced choledolithiasis develop acute symptoms requiring 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:
Paganelli G et al. Biopolymers 2002; 66:
De Jong M et al. Int J Cancer 2001 Jun 1; 92(5):
Ebrahim S et al. Cancer biotherapy and radiopharmaceuticals Vol 23, No. 3, 2008
Coinfusion of amino acids is proposed for renal protection

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

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