Case Presentation: Neuroendocrine Tumor

in the Midgut

Vasiliki Michalaki, MD, PhD

Consultant Medical Oncologist

Aretaieion Hospital University of Athens

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

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

Question1

What would be the preferred treatment approach?

1. Radical surgery of primary tumor and metastases

2. SSAs

3. Locoregional liver therapies

Parameters With an Impacton 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

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

Case presentationPatient 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)

Question 2

What would be the preferred treatment approach?

1. SSAs

2. Chemotherapy

3. Peptide receptorradiotherapy (PRRT)

Molecular targeted therapy

Systemic Therapy: How Guidelines Could Help Us

Öberg K, et al. Ann Oncol. 2012;23 Suppl 7:vii124-130

Chemotherapy: Limited Role in Enteric NETs

Treatment Author Histology No ORR%

Median Survival

Doxorubicin Engstrom Carcinoid 81 21 12

Docetaxel Kulke Carcinoid 21 0 24

Temozolomide

Ekeblad Pancreatic NET

12 8 7

Pemetrexed Chan Pancreatic and carcinoid

17 6 12.1

Gemcitabine Kulke Carcinoid 18 0 11.5

Topotecan Ansell Carcinoid 22 0 22

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: 12 - 18 months

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):382-393. Kwekkeboom DJ, et al. J Clin Oncol. 2008;26(13):2124-2130. Modlin IM, et al. Lancet Oncol. 2008;9(1):61-72.

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)

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

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

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

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)