Evaluation and Medical Management of

Neuroendocrine Tumors Encountered

During Endoscopy or Abdominal

Imaging

8th Annual Symposium on “Gastrointestinal Cancers: An update on

advances in diagnosis and management”

Session II: Commonly Encountered NETs of the Gut

Lowell Anthony, M.D., F.A.C.P.

Professor of Medicine

LSUHSC New Orleans

Ritz Carlton Hotel

St. Louis, MO

September 12th, 2009

Questions

Is further work-up for systemic disease needed in all

patients with neuroendocrine tumors of the gut?

What kind of further evaluation is needed if the gut

lesion is:

– Carcinoid tumor?

– Gastrinoma?

– Non-functioning NE tumor?

How to evaluate patients with serum hypergastrinemia

– What to do if no gastrin producing lesion is identifiable?

Carcinoid Tumors Are Most

Common (50% of all NETs)

Digestive

system

Bronchopulmonary

system

Other

%Other

Colon

and

Rectum

Small

Intestine

Stomach

2.3

28

28.5

4.6

1. Modlin IM et al. A 5-decade analysis of 13,715 carcinoid tumours. Cancer 2003;97:934-59.

Duodenum –3

Jejunum – 2

Ileum – 15

NOS – 8

Other – 0.5

Colon, except

the appendix – 9

Appendix – 5

Rectum – 14

NOS=not otherwise specified

28%

8%64%

0.00

1.00

2.00

3.00

4.00

5.00

6.00

1973

1974

1975

1976

1977

1978

1979

1980

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

Year

An

nu

al

in

cid

en

ce

pe

r 1

00 0

00

Incidence of neuroendocrine tumors

Incidence Of Neuroendocrine Tumors

Over Time – Analysis Of The SEER

Database (1973–2004)

1. Yao JC et al. One hundred years after "Carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol

2008;26(18):3063–72.

Prevalence of NETs

1. American Cancer Society. Cancer Reference Information. Cancer Prevalence: How Many People Have Cancer? © 2008 American Cancer Society Inc. Available at

http://www.cancer.org/docroot/CRI/content/CRI_2_6x_Cancer_Prevalence_How_Many_People_Have_Cancer.asp?sitearea=&level=. Accessed November 2008.

2. Yao JC et al. One hundred years after "Carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;

26(18): 3063–72.

0

0.2

0.4

0.6

0.8

1

1.2

Colon & Rectum Neuroendocrine Stomach Pancreas Esophagus Hepatobiliary

103,312cases

100,000

1,100,000

1,200,000

1,168,000 cases

65,836 cases

32,353cases

28,664 cases 21,427

cases

NETs: 2004/2005 US Prevalence

29-year limited duration prevalence analyses based on SEER1,2

6

Carcinoid syndrome – causes and

symptoms

Carcinoid heart disease

Diarrhea

Vasodilation/bronchoconstriction

Flushing

Hypersecretion of biogenic amines and peptides e.g. serotonin, tachykinin

Carcinoid Syndrome – Symptom

Overview

Work-up for Carcinoid Tumors Encountered

During Endoscopy or Abdominal Imaging

Additional work-up for carcinoid tumors includes:1,2,3

Gastric Appendix Small bowel Colon Rectal

Endoscopy / A.I.

Serum Gastrin

EUS

A / P CT / MRI

SRS for patients

with normal gastrin

or syndrome sx

B12 level if

hypergastrinemic

With syndrome sx:

serotonin, 5-HIAA,

histamine, VIP

Laparoscopy /

Laparotomy / A.I.

A / P CT / MRI

For tumors > 2

cm or syndrome

present:

- SRS

- 5-HIAA, CGA

Endoscopy / Enteroscopy

/ CLN / Video endoscopy /

A.I.

A / P CT – consider triple

phase helical imaging /

MRI

GI series with SBFT as

indicated

Enteroclysis (optional)

SRS

5-HIAA, CGA

Echocardiography (with

inc 5-HIAA)

Colonoscopy / A.I.

SRS

A / P CT –

consider triple

phase helical

imaging / MRI

5-HIAA, CGA

Colonoscopy /

Sigmoidscopy / A.I.

EUS

A / P CT – consider

triple phase helical

imaging / MRI

With syndrome sx:

- SRS

- 5-HIAA, CGA

• If negative SRS and

+CT/MRI: FDG-PET

1. The NCCN Guideline Neuroendocrine Tumors. Clinical Practice Guidelines in Oncology (Version 2.2006). © 2006 National Comprehensive Cancer Network, Inc. Available at

http://www.nccn.org. Accessed Nov 07 2008. To view the most recent and complete version of the guideline, go online to www.nccn.org.

2. Jensen RT et al. Well-Differentiated Duodenal Tumor/Carcinoma (Excluding Carcinomas) [ENETS guidelines]. Neuroendocrinology 2006;84:165-172

3. Personal experience, Lowell Anthony.

A.I. = abdominal imaging

Work-up for Less Encountered NETs During

Endoscopy or Abdominal Imaging

Additional work-up for carcinoid tumors includes:1

Esophageal Liver Gall Bladder Extra-Hepatic

Biliary Ducts

Ampullary

Endoscopy / A.I.

EUS

Well-differentiated:

- SRS

- 5-HIAA, CGA

Poorly-

differentiated:

- FDG-PET

Laparoscopy /

Laparotomy / A.I.

A / P CT – triple-

phase helical / MRI

SRS

5-HIAA, CGA

Echocardiography

(inc 5-HIAA)

A.I.

A / P CT - triple-phase

helical / MRI / US

SRS

5-HIAA, CGA

ERCP / A.I.

A / P CT - triple-

phase helical / MRI

/ US

SRS

5-HIAA, CGA

Endoscopy / ERCP /

A.I.

A / P CT - triple-

phase helical / MRI /

EUS

SRS

5-HIAA, CGA

1. Personal suggestions, Lowell Anthony

Stains and Laboratory Studies Used

in the Work-Up of NETs Encountered at

Endoscopy or Abdominal Imaging There is a range of stains

recommended for the work-up of NETs, including:1-4

– Basic stains for diagnosis:

• Chromogranin A

– Qualitative vs quantitative

• Synaptophysin

– Qualitative vs quantitative

• Cytokeratin

Low vs intermediate vs high grade

– # of mitotic cells / 10 HPFs

– Ki-67

There is a range of hormone-related studies recommended for the work-up of NETs, including:1-4

– Carcinoid

• 5-HIAA (24 h urine)

• Chromogranin A

– Gastrinoma

• Gastrin

• Secretin

• Calcium

1. The NCCN Guideline Neuroendocrine Tumors. Clinical Practice Guidelines in Oncology (Version 2.2006). © 2006 National Comprehensive Cancer Network, Inc.

Available at http://www.nccn.org. Accessed Nov 07 2008. To view the most recent and complete version of the guideline, go online to www.nccn.org.

2. Falconi M et al. Well-Differentiated Pancreatic Nonfunctioning Tumors/Carcinoma. Neuroendocrinology 2006;84:196–211

3. Jensen RT et al. Gastrinoma (Duodenal and Pancreatic). Neuroendocrinology 2006;84:173–182

4. Steinmuller T et al. Consensus Guidelines for the Management of Patients with Liver Metastases from Digestive (Neuro)endocrine Tumors: Foregut, Midgut,

Hindgut, and Unknown Primary. Neuroendocrinology 2008;87:47–62

Pathology of NETs

Role of Biologic Markers:

Chromogranin A (CgA)

Carcinoid Syndrome Specific Marker:

5-hydroxyindoleacetic Acid (5-HIAA)

Serotonin-Rich Foods

Additional Work-Up for Metastatic Carcinoid

Tumors

Distant metastases need to

be evaluated by

CT/MRI/SRS imaging1

Fusion software may assist

in lesion localization

Echocardiogram should be

considered if there is a

positive scan or elevated

biomarkers1

1. The NCCN Guideline Neuroendocrine Tumors. Clinical Practice Guidelines in Oncology (Version 2.2006). © 2006 National Comprehensive Cancer Network, Inc.

Available at http://www.nccn.org. Accessed Nov 07 2008. To view the most recent and complete version of the guideline, go online to www.nccn.org.

NCCN Treatment Algorithm for

Carcinoid Syndrome

Neuroendocrine Tumors, Clinical Practice Guidelines in Oncology - Version 2.2006, National Comprehensive Cancer Network.Available at: http://www.caringforcarcinoid.org/carcinoid/documents/nccn.pdf – accessed 28 October 2008.

Distant

metastases

Bone

LiverOctreotide d,e 150 mcg SC

TID• If tolerated and

symptomatic response, consider Octreotide LAR initially 20 mg IM monthly, then may gradually increase dose and frequency

OrManage clinical syndrome

as appropriate

Resect

Observe with

markers and

scans every

3-6 mo, or

Clinical trial

If progression, see below

Hepatic regional therapy

(arterial embolization,

chemoembolization,

or other)

or

Chemoembolization

or

Systemic chemotherapy

with doxorubicin/

streptozocin

or

Ablative therapy (RFA,

cryotherapy)

or

Clinical trial

Resect

RT if symptomatic

or

Clinical trial

or

Consider systemic

chemotherapy

with doxorubicin/

streptozocin

or

Interferon

Systemic chemotherapy

with doxorubicin/

streptozocin

or

Interferon

or

Clinical trial

Resect

Asymptomatic

Symptomatic

or

Progression

If liver and

resectable

Extrahepaticorunresectable

Unresectable

Resectable

Unresectable

Resectable

Lung

Somatostatin

Peptide produced by normal cells and certain tumors

Regulates wide variety of physiologic functions

Controls proliferation of normal and tumor cells

Was one of the first targets for NET therapy

1. Guillermet-Guibert J et al. Somatostatin receptors as tools for diagnosis and therapy: molecular aspects. Best Pract Res Clin Gastroenterol 2005;19:535–51

18

sst receptors and NETs

Somatostatin receptors are G-protein-coupled receptors that mediate the inhibition of a large number of secretory processes

Distributed throughout the body and expressed in 80–90% of NETs

Based on their structure and function, somatostatin receptors can be divided into five subtypes, sst1 5

In NETs, sst2, sst5 and sst1 are most frequently expressed, followed by sst4 and sst3

Schmid et al. Mol Cell Endocrinol 2008;286:69–74

19

Inhibitory effect of somatostatin receptor

subtypes

Inhibitory effect: sst1 sst2 sst3 sst4 sst5

Hormone secretion

GH + + +

ACTH + +

TSH + +

Insulin + +

Glucagon +

Exocrine secretion

Gastric acid +

Amylase +

Intestinal Gl secretion + +

Cell proliferation

Induction of G1 cell cycle arrest + + + +

Induction of apoptosis + +

Somatostatin Biological Effects

Ca2+ channel

Ca2+

Hormone secretion

–

Ca2+ channelCa2+ channel

Ca2+

Hormone secretion

–

Ca2+ channelAdenylate

cyclase

cAMP

–

Adenylate

cyclase

cAMP

–

K+ channel

+

K+ channel

+

1. Guillermet-Guibert J et al. Somatostatin receptors as tools for diagnosis and therapy: molecular aspects. Best Pract Res Clin Gastroenterol 2005;19:535–51

Somatostatin

G i

Somatostatin Antisecretory Effects1

Somatostatin Antiproliferative Effects

U

23

PROMID – octreotide LAR significantly

increases time to tumor progression

Octreotide LAR vs placebo P=0.000072

HR=0.34 [95% CI: 0.20–0.59]

Octreotide LAR: 42 patients / 26 events

Median 14.3 months [95% CI: 11.0–28.8]

Placebo: 43 patients / 40 events

Median 6.0 months [95% CI: 3.7–9.4]

Time (months)

Pro

po

rtio

n w

ith

ou

t p

rog

res

sio

n

0

0.25

0.5

0.75

1

0 6 12 18 24 30 36 42 48 54 60 66 72 78

Based on the conservative ITT analysis

Arnold R. Presented at ASCO-GI 2009

Treatment Options and Follow-Up

Require Cross Discipline Coordination

Examples of the disciplines involved in the treatment and follow-up of NET

patients1-4

1. Caplin M et al. Carcinoid tumour. Lancet 1998; 352:799-805

2. McStay M K G and Caplin M E. Carcinoid tumour. Minerva Med 2002, 93:389-401

3. The NCCN Guideline Neuroendocrine Tumors. Clinical Practice Guidelines in Oncology (Version 2.2006). © 2006 National Comprehensive Cancer Network, Inc. Available at

http://www.nccn.org. Accessed Nov 07 2008. To view the most recent and complete version of the guideline, go online to www.nccn.org.

4. Steinmuller T et al. Consensus Guidelines for the Management of Patients with Liver Metastases from Digestive (Neuro)endocrine Tumors: Foregut, Midgut, Hindgut, and

Unknown Primary. Neuroendocrinology 2008;87:47–62

Discipline Treatment and follow-up options

Surgery team Endoscopic resection, surgical resection, radical gastric resection, lymph node removal, antrectomy, partial hepatectomy, ablative therapy

Gastroenterology team Esophagogastroduodenoscopy, colonoscopy, ileoscopy

Pathology/histology

team

Biopsy of tumor and adjacent mucosa, follow-up of pathology and histology markers

Endocrinology/oncology

team

Medical therapy, systemic chemotherapy

Radiology/radiotherapy/

nuclear medicine team

Radiotherapy, CT/MRI, SRS, imaging studies as required, chemoembolization, ablative therapy

Nurse team Specialist nurses will interact with the patient on an ongoing basis

Requirements for an Improvement in

NETs Outcomes1

Refinement of universal classification and grading

system

Elucidation of cell biology

Development of cell lines and animal models

Acquisition of genetic information

Identification of serum markers for early diagnosis

Definition of tissue markers to identify tumor origin

Development of molecular pathological profiling to define

prognosis

1. Modlin I M et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncology 2008;9(2): p61-72

Requirements for an Improvement in

NETs Outcomes1 (cont’d)

Precise identification of topographic information before

and during surgery

Identification of molecular therapeutic targets

Development of improved (adjuvant) treatment for

residual disease

Establishment of centers of excellence and

multidisciplinary specialty NET clinical teams

Construction of central clinical and tissue database

resources

Government focus on clinical/research funding

1. Modlin I M et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncology 2008;9(2): p61-72

Questions

Is further work-up for systemic disease needed in all

patients with neuroendocrine tumors of the gut?

What kind of further evaluation is needed if the gut

lesion is:

– Carcinoid tumor?

– Gastrinoma?

– Non-functioning NE tumor?

How to evaluate patients with serum

hypergastrinemia

– What to do if no gastrin producing lesion is identifiable?