1. Case Presentation: Neuroendocrine Tumor in the Midgut
Vasiliki Michalaki, MD, PhD
Consultant Medical Oncologist
Aretaieion Hospital University of Athens

2. Case presentation 46-year-old male, no relevant family history
May 2009: intermittent, generalized, dull and colicky abdominal
pain, weight loss and constipation during recent year
5 days prior to admission developed severe generalized colicky abdominal
pain.
Physical examination: Soft abdomen with mild tenderness in periumbilical, right lower quadrant
U/s: hypoechoic pelvic mass, without peristalsis was seen in abdomen and pelvic sonography.
Abdominal CT scan: 2.5 cm mass in terminal ileum plus two liver lesions suspicious for metastases

3. Case presentation-Additional investigations
Endoscopic biopsy of ileum mass
– Grade 2 neuroendocrine tumor
– Ki-67 4%; 3 mitoses per 10 high power fields
Somatostatin receptor scintigraphy (Octreoscan®)
– Uptake in liver lesions noted
5-HIAA levels and neuron-specific enolase (NSE): within normal range

4. Question1 What would be the preferred treatment approach?
Radical surgery of primary tumor and metastases
SSAs
Locoregional liver therapies

6. Parameters With an Impact on Therapeutic Decision Making
Histology
– Grading grade 1 / grade 2 (NET) vs grade 3 (NEC) (WHO 2010)
– Well / moderately or poorly differentiated NET / NEC (US)
Hormonal release
– Carcinoid syndrome, insulinoma, gastrinoma, VIPoma
Primary tumor site
– Pancreatic vs intestinal
Somatostatin receptor imaging
Tumor burden / extrahepatic disease

7. Locoregional Treatments in Metastatic Setting
Radical surgery of primary tumor and metastases is recommended when R0 can be achieved
•No data of adjuvant therapy are available in this setting
•Locoregional liver therapies (radiofrequency ablation,hepatic artery (chemo)embolization) could be a treatment option based on tumor size, anatomical location, number of metastases and presence of extrahepatic disease

8. Case presentation Patient underwent radical resection
–Full recovery and in complete remission
–Lost to follow-up in 2010
•In 2014, he presented with an abdominal ultrasound, showing multiple liver metastases
─Body CT scan identified bilobar liver metastases and lymph nodes
─Octreoscan: Uptake in liver and lymph nodes
─No carcinoid syndrome, asymptomatic
─Lab tests within normal range, including liver function,except for CgA 850 U/L (N<100 U/L)

9. Question 2 What would be the preferred treatment approach? SSAs
Chemotherapy
Peptide receptorradiotherapy (PRRT)
Molecular targeted therapy

11. Systemic Therapy: How Guidelines Could Help Us
Öberg K, et al. Ann Oncol. 2012;23 Suppl 7:vii

12. Chemotherapy: Limited Role in Enteric NETs
Treatment
Author
Histology No
ORR%
Median Survival
Doxorubicin
Engstrom
Carcinoid 81 21 12
Docetaxel
Kulke 24
Temozolomide
Ekeblad
Pancreatic NET 8 7
Pemetrexed
Chan
Pancreatic and carcinoid 17 6
12.1
Gemcitabine 18
11.5
Topotecan
Ansell 22

13. Chemotherapy: Limited Role in Enteric NETs
Streptozotocin-based Chemotherapy Is Effective in Pancreatic NET Grade 1 / Grade 2
Objective response rate: 40%-50 % ENETS: First-line therapy in progressive or advanced pNET Alternatively, oral regimen with temozolomid/capecitabine
Platinum-based Chemotherapy Is First-Line Therapy in Poorly Differentiated NEC Grade 3
Etoposide + cisplatin: •Objective response rate: 40% - 70% •Median survival: months

14. Peptide Receptor Targeted Radiotherapy (PRRT)
Option for patients with unresectable metastatic SSTR- positive NETs
• Usually second-line therapy(ENETS)
• Only retrospective data or phase II studies
Essen M, et al. Nat Rev Endocrinol. 2009;5(7): Kwekkeboom DJ, et al. J Clin Oncol. 2008;26(13): Modlin IM, et al. Lancet Oncol. 2008;9(1):61-72.

15. Molecular Targeted Therapies in Extrapancreatic NETs
Ongoing Phase III Clinical Trials in Extrapancreatic NETs
• RADIANT-4
–Nonfunctioning gastrointestinal and lung grade 1 / grade2 NETs
– Documented disease progression
–Everolimus vs placebo
• SWOG0518
•Octreotide + bevacizumab vs octreotide + IFNα
•Grade 2 small intestine NETs in prior disease progression
• NETTER-1 – Lutetium+octreotidevsoctreotide
– Grade1/grade2 small intestine in progression after somatostatin analog (SSA)

16. The PROMID Study: Octreotide LAR in Midgut NETs – What Did We Learn?
Lessons Octreotide LAR shows antitumor effect in : midgut tumors
Low hepatic tumor burden (<10%)
Grade 1 tumors
Limitations The efficacy of SSAs is uncertain in :
Non Midgut tumors
Higher liver tumor burden
Grade 2 tumors
Progressive disease

17. The CLARINET Study
A randomized double-blind placebo-Controlled phase III study ofLanreotide Antiproliferative Response In enteropancreatic NET
Lanreotide Prolong PFS in Enteropancreatic NET
CLARINET: Lanreotide Is Well Tolerated and Effective Without Compromising Quality of Life
CLARINET-OLE Study: Lanreotide Is Effective in Progressive Enteropancreatic NET

18. CLARINET / OLE•
Lanreotide substantially prolongs PFS in metastatic well / moderately differentiated enteropancreatic NETs
– Median PFS with lanreotide not reached vs 18 months with placebo (P = .0002)
– 53% risk reduction for progression / death
• Antiproliferative effect was observed In patients with grade 1 and grade 2 tumors (Ki67 <10%) – In patients with low and high hepatic tumor load – In patients with progressive disease (OLE study)
• Very good tolerability consistent with previous studies Data support simportant role of SSA in the treatment algorithm of GEP-NETs

19. Case Presentation Patient begins treatment with lanreotide
– Follow-up CT shows stable disease by RECIST with necrosis of some metastases
Benefit persisted for 17 months (last follow up)