gastrointestinal neuroendocrine tumors: a closer look at ... · gastrointestinal neuroendocrine...

Gastrointestinal Neuroendocrine Tumors: A Closer Look at the Characteristics of

These Diverse Tumors

Jaume Capdevila, MD, PhDVall d'Hebron University Hospital

Vall d'Hebron Institute of Oncology (VHIO)Barcelona, Spain

Neuroendocrine Tumors (NETs): A Diverse Group of Malignancies

• Tumors arising from enterochromaffin cells located in neuroendocrine tissue throughout the body1

• NETs can be functional or nonfunctional and include a heterogeneous group of neoplasms2,3

– Gastroenteropancreatic neuroendocrine tumors (GEP-NETs)3

– Islet cell tumors2

– Typical/atypical/poorly differentiated lung carcinoid2

– Small cell carcinoma of the lung2,3

– Pheochromocytoma/paraganglioma2,3

– Medullary thyroid carcinoma

– Merkel cell carcinoma2,3

– Kidney, bladder, breast, prostate, thymus…

1. Caplin ME, et al. Lancet. 1998;352(9130):799-805; 2. NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors V2.2016; 3. Modlin IM, et al. Gastroenterology. 2005;128(6):1717-1751.

Neuroendocrine Tumors (NETs): A Diverse Group of Malignancies

• Tumors arising from enterochromaffin cells located in neuroendocrine tissue throughout the body1

• NETs can be functional or nonfunctional and include a heterogeneous group of neoplasms2,3

– Gastroenteropancreatic neuroendocrine tumors (GEP-NETs)3

– Islet cell tumors2

– Typical/atypical/poorly differentiated lung carcinoid2

– Small cell carcinoma of the lung2,3

– Pheochromocytoma/paraganglioma2,3

– Medullary thyroid carcinoma

– Merkel cell carcinoma2,3

– Kidney, bladder, breast, prostate, thymus…

1. Caplin ME, et al. Lancet. 1998;352(9130):799-805; 2. NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors V2.2016; 3. Modlin IM, et al. Gastroenterology. 2005;128(6):1717-1751.

N

E

T

EAR

VERYWHERE

UMORS

The Increasing Incidence of NET

Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.

Lung and bronchus

Small intestineRectum

StomachPancreas

AppendixColonCecum

Year

1.4

1.2

1.0

0.8

0.6

0.4

0.2

01973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003

Inci

denc

e pe

r 100

000

• Annual age-adjusted incidence of NETs in the US population by anatomic location• Using regression analysis, it is estimated that the incidence in 2013 could be nearly 8 per 100 000

The Gastrointestinal Tract (GI) Is the Most Common Primary Location of NET (US SEER Data)

58%15%

27%Digestivesystem

Lung

Other/unknown

Percent distribution (%)17.2 Rectum13.4 Jejunum/ileum6.4 Pancreas6.0 Stomach4.0 Colon3.8 Duodenum3.2 Cecum3.0 Appendix0.8 Liver


Chart1

Digestive system

Other

Bronchopulmonary system

Column1

58%

15%

27%

0.58

0.15

0.27

Sheet1

Column1

Digestive system58%

Other15%

Bronchopulmonary system27%

To resize chart data range, drag lower right corner of range.

NETs Are the Second Most Prevalent Type of GI Malignancy

1. National Cancer Institute: SEER Cancer Statistics Review, 1975-2004. http://seer.cancer.gov/archive/csr/1975_2004/. Accessed: September 8, 2016. 2. Modlin IM, et al. Cancer. 2003;97(4):934-959.

Colorectal1 Stomach1 Pancreas1 Esophagus1 Hepatobiliary1GEP-NET2

100 000

Prevalence in SEER Database

1 100 000

1 200 000

0

2 times more prevalent than pancreatic cancer

Complex Disease

Constellation of Symptoms Makes a Differential Diagnosis Difficult

Menopause

Irritable bowel syndrome

Functional bowel disease

Anxiety

Neurosis

Food allergy

Asthma

Alcoholism

Thyrotoxicosis

Peptic ulcer

NETs

Symptoms• Sweating• Flushing• Diarrhea

• Intermittent abdominal pain

• Bronchoconstriction• GI bleeding

• Cardiac disease

1. Vinik A, et al. Dig Dis Sci. 1989;34(3)(suppl):14S-27S. 2. Toth-Fejel S, et al. Am J Surg. 2004;187(5):575-579. 3. Modlin IM, et al. J Natl Cancer Inst. 2008;100(18):1282-1289.

Nonspecific symptoms are common to multiple diagnoses

Estimated time to diagnosis: 5 to 7 years3

NETs Are Often Advanced at the Time of Diagnosis

Local

Regional

Metastatic

Poorly differentiatedmetastatic

Median survival (years)

Well and moderately

differentiated

18.5

9.25

2.75

0.4

1. Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072. 2. Soga J. Cancer. 2005;104(6):1180-1187. 3. Alexiev BA, et al. Diagn Pathol. 2007;2:28. 4. Modlin IM, et al. Lancet. 2008;9(1):61-72.

Carcinoids M1 at Dx SV 5 and M1Small intestine 70% 55%Colon 71% 20%Appendix 10% 34%Rectum 15% 30%Pancreatic NETs 50%-60% 30%-50%

Correlation of Primary Tumor Site With Survival


Known prognostic factors include:• Location of primary tumor• Extent of disease• Tumor stage• Degree of differentiation/

proliferative index• Tumor grade• Patient age• Performance status

65% of patients with advanced NETs will not be alive in 5 years

Distant metastases1.0

0.8

0.6

0.4

0.2

Sur

viva

l pro

babi

lity

0 12 24 36 48 60 72 84 96 108 120

Time, months

ColonLungPancreasRectumSmall bowel

Prognostic Value of Ki67

Pape UF, et al. Endocr Relat Cancer. 2008;15(4):1083-1097.

Scarpa A, et al. Mod Pathol. 2010;23(6):824-833.

20

But Differentiation Is Also Important

Poorly differentiated histology


HistologyWell- and moderately-differentiated histology

High Complexity for NETs ClassificationDifferentiation Grade Mitotic count Ki67 index Traditional ENETS; WHO

Well differentiated

Low grade (G1)

20 per 10 HPFs >20%

Small cell carcinoma Neuroendocrinetumor; grade 3, small

cell

Large cell neuroendocrine

carcinoma

Neuroendocrinetumor; grade 3, large

cell

Well differentiated Poorly differentiated

Grade (ENETS) Low (G1) Intermediate (G2) High (G3)

Ki67 index (%) ≤2 3-20 >20

Anatomic imaging More rapid growth on serial imaging

Funational imaging Octreoscan SPECT or SSTR PET-positive

FDG PET-positive

Prognosis Indolent (slowly growing) Aggressive

Bosman FT, eds. WHO Classification of Tumours of the Digestive System. 4th Ed. Lyon, France: The International Agency for Research on Cancer; 2010. Rindi G, et al. Virchows Arch. 2006;449(4):395-401. Rindi G, et al. Virchows Arch. 2007;451(4)757-762. Jensen RT, et al. Neuroendocrinology. 2006;84(3):173-182.

Best Treatment Option Based on MDT Evaluation

SurgeonPathologist

Endocrinologist

Nuclear Medicine

Gastroenterologist

Oncologist

Every one helps…

Best treatment option

Factors Influencing the Therapeutic Decision in NETs

Type of NET(pancreatic vs GI)

TNM stage and grade(G1/G2 vs G3)

Resectability Functioning vs non-functioning tumor

Patient performance status and comorbidities

Availability of different therapeutic modalities

Patient preference and convenience

Uptake on somatostatinreceptor scintigraphy

Integrating Grade and Tumor BurdenTreatment goals: Tumor control and QoL

Tumor aggressiveness (eg, Ki67)

Tumor burden

High

Low

Moderate(up to Ki67 = 20%)

Low

Advanced, unresectable, well- to moderately- differentiated NETs:Primary treatment goals

Tumor response/control & QoL Tumor response/control

Rapid Tumor Response

QoL & tumor controlTumor control &

QoLTumor control/ response

QoL & tumor control

Tumor control & QoL Tumor control & QoL

0102030405060708090

OSPFS

Ove

rall

Sur

viva

l, m

onth

s

OS NR

OS NROS NR

OS NR

OS NR

44 months

33 months

Arnold R, et al. J Clin Oncol. 2013;31(suppl): Abstract 4030. Caplin M, et al. N Engl J Med. 2014;371(3):224-233. Pavel M, et al. Ann Oncol. 21(suppl 8): Abstract LBA-8. Pavel ME, et al. J Clin Oncol. 2015;33(suppl): Abstract 4091. Vinik A, et al. J Clin Oncol. 2012;30(15S): Abstract 4118. Yao JC, et al. Ann Oncol. 2015;26(suppl 6): Abstract LBA-5. Strosberg J, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract LBA-6.

Progressive Increase in Survival

Slide Number 1Neuroendocrine Tumors (NETs): �A Diverse Group of MalignanciesNeuroendocrine Tumors (NETs): �A Diverse Group of MalignanciesThe Increasing Incidence of NETThe Gastrointestinal Tract (GI) Is the Most Common Primary Location of NET (US SEER Data)NETs Are the Second Most �Prevalent Type of GI MalignancyComplex DiseaseConstellation of Symptoms Makes �a Differential Diagnosis DifficultNETs Are Often Advanced at the Time of DiagnosisCorrelation of Primary Tumor Site With SurvivalPrognostic Value of Ki67But Differentiation Is Also ImportantHigh Complexity for NETs ClassificationBest Treatment Option Based on MDT EvaluationFactors Influencing the Therapeutic Decision in NETsIntegrating Grade and Tumor BurdenProgressive Increase in Survival

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