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 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,

Gastroenteropancreatic NETs (GEPNETs)

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

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% 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)

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 Multidisciplinary involvement is important

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

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 low-proliferating NETs only S/E mainly attributed by IFN – fever/ anorexia/ depression/ confusion/ arthralgia

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

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

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 Ablation reserved for unresectable metastases smaller than 5 to 7 cm

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

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

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 Coinfusion of amino acids is proposed for renal protection

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

Liver-directed therapies Novel approaches: Radioembolization Liver transplantation