Management of Gastroenteropancreatic Neuroendocrine Tumour:an update

Joint Hospital Surgical Grand RoundDr 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 gonadsheart kidneysprostate

Gastroenteropancreatic NETs (GEPNETs)

Classifications

WHO classification: tumour sitedegree 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 serotoninGastrin InsulinGlucagon 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 originDegree of tumour burdenGeneral health or debility of the patient

Operative consideration

Perioperative somatostatin analogsPrevents excessive hormone release during

manipulationParticularly 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

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/ ablationHepatic 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 cholecystectomyRationale: somatostatin analogs treatment

leads to development of gallstonesHowever most of these stones are

asymptomaticNo 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 functionModerate to severe ascitesPortal venous thrombosis

Liver-directed therapies

Novel approaches:RadioembolizationLiver transplantation