Gastrointestinal Neuroendocrine Tumors: A Closer Look at ... · Gastrointestinal Neuroendocrine...
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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
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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.
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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
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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
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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
Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.
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.
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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
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Complex Disease
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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
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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%
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Correlation of Primary Tumor Site With Survival
Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.
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
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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.
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But Differentiation Is Also Important
Poorly differentiated histology
Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.
HistologyWell- and moderately-differentiated histology
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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.
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Best Treatment Option Based on MDT Evaluation
SurgeonPathologist
Endocrinologist
Nuclear Medicine
Gastroenterologist
Oncologist
Every one helps…
Best treatment option
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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
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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
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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