Ching-Yao Yang, Yu-Wen Tien

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1 Ching-Yao Yang, Yu-Wen Tien Division of General Surgery, Department of Surgery, National Taiwan University Hospital Oct

2

3 Pancreatic NET have poorer prognosis when presence of liver metastases at diagnosis

4 Liver metastasis in Digestive NET Up to 75% of patients who present with mid- or hindgut tumors also have liver metastases. In particular, patients with nonfunctioning tumors often already present with liver involvement. The site of the primary tumor is also of prognostic value, with pancreatic tumors exhibiting a much worse prognosis than tumors of the gastrointestinal tract.

5 Management for NET liver mets Multidisciplinary approaches 1. Surgical 2. Medical 3. Radiological 4. Nucleomedical

6

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8 Treatment approach to liver metastases without extrahepatic spread

9 Treatment approach to liver metastases with extrahepatic spread

10 Results of surgical resection therapy in NET liver metastases

11 Minimal Consensus Statements Surgery Surgical resection remains the gold standard in the treatment of liver metastases, achieving a survival rate of 60 80% at 5 years with low mortality (0 5%). The minimal requirements for resection with curative intent are the following: (1) Resectable well-differentiated liver disease with acceptable morbidity and < 5% mortality (2) absence of right heart insufficiency, (3) absence of extraabdominal metastases (4) absence of diffuse peritoneal carcinomatosis. In both synchronous and metachronous tumors, one- and two-step procedures may be undertaken, depending upon whether the liver disease is unilobar or complex. Debulking resections can exceptionally be justified in palliative situations; however, removal of at least 90% of the tumor volume is necessary. If the primary tumor is still present, it should be removed at this time as well.

12 Liver Transplantation for NET In patients with diffuse unresectable liver metastases or who suffer from life-threatening hormonal disturbances refractory to medical therapy. NETs remain one of the few indications for liver transplantation in metastatic disease, particularly if livingrelated donation is feasible. Patients less than 50 years old who are free of extrahepatic tumor and have low expression of Ki-67 and E-cadherin are those who are most likely to benefit from liver transplantation. A long-term cure from the disease by transplantation will be an exceptional event even in this highly selected subgroup.

13 Liver transplantation for metastatic neuroendocrine tumors

14 Medical Treatment Goals Symptom relief Anti-proliferative therapy Biotherapy- Somatostatin analogues Systemic Chemotherapy

15 Consensus Statements Symptomatic Treatment Symptoms from hormonal hypersecretion are frequent in functional tumors with liver metastases. Control of these symptoms is urgent and somatostatin analogues (with or without interferon) are often effective. Locoregional therapies may be required to achieve symptomatic relief. Prophylaxis against carcinoid crisis should be performed prior to surgical or locoregional interventions using adequate doses of somatostatin analogues.

16 Antiproliferative Therapy Somatostatin analogues and/or interferon have weak antiproliferative effects. Systemic chemotherapy using combinations of streptozotocin and doxorubicin and 5-fluorouracil should be considered in patients with inoperable welldifferentiated progressive foregut NET with liver metastases. Cytotoxics are not efficacious for liver metastases of midgut tumors. Combinations of etoposide and cisplatin are indicated in advanced/ metastatic poorly-differentiated NET regardless of the origin of the primary.

17 Octreotide Mechanism of Action Octreotide Targets sstr subtypes 2 and 5 to inhibit cell growth and enhance apoptosis Susini C, Buscail L. Ann Oncol. 2006;17: Grozinsky-Glasberg S et al. Neuroendocrinology. 2008;87: Theodoropoulou M et al. Cancer Res. 2006;66: Florio T. Front Biosci. 2008;13:

18 Octreotide LAR May Prolong Survival Retrospective database analysis compared patients with advanced NET receiving octreotide LAR (n=24) with those who did not (n=25) Median overall survival (OS) was significantly longer with octreotide LAR treatment (112 months vs 53 months; HR, 2.46; P=.021) 10-yr survival was 40% with octreotide LAR vs 22% without Survival Probability Octreotide LAR No Yes Months Townsend A et al. J Clin Gastroenterol. 2010;44:

19 Somatostatin analogue (SSA) In nonfunctioning pancreatic NETs somatostatin analogue (SSA) therapy aims at the stabilization of tumor growth. Partial and complete remission can be observed in fewer than 10% of the patients, while stabilization of tumor growth occurs in 24 57% of patients. SSA therapy should be initiated as first-line medical therapy, whenever tumor progress is documented and surgical or ablative treatment is no option.

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21 Octreotide LAR vs long-acting Lanreotide Biochemical response rates (partial plus complete responses) for chromogranin A and urinary 5-hydroxyindoleacetic acid for octreotide LAR were 51% (range, 31.5% 100%), and for longacting lanreotide were 39% (range, 18% 58%). The overall response (stable plus partial response) was 57% to 70% for octreotide and octreotide LAR and about 48% for lanreotide and 65% for long-acting lanreotide. Aliment Pharmacol Ther 2010;31:

22 Interferon-alpha in patients with nonfunctioning pancreatic neuroendocrine tumors

23 Minimal Consensus Statement on Chemotherapy Chemotherapy is indicated as medical therapy in progressive tumors after biotherapy has failed. Streptozotocin and 5-FU or doxorubicin are used in tumors with a low proliferation index (Ki67 <20%), while cisplatin and etoposide are indicated in fast growing tumors. Stabilization of the disease may occur in about 30 50% of the patients. No data exist to support the use of adjuvant therapy in pancreatic nonfunctioning NETs.

24 Peptide Receptor Radionuclide Therapy PRRT is a new therapeutic option in tumors with high somatostatin receptor density. [ 90 Y-DOTA 0, Tyr 3 ] octreotide or [ 177 Lu-DOTA 0, Tyr 3 ] octreotate can be used. However, PRRT is still experimental, as randomized comparison to various treatments is lacking.

25 Conclusion Management of well-differentiated pancreatic NET with liver metastasis need multi-disciplinary treatment through surgical, medical, radiological, and nucleomedical treatment.

26 Thanks a lot!

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