Gastrointestinal Neuroendocrine Tumors: A Closer Look at the Characteristics of These Diverse Tumors
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1 Gastrointestinal Neuroendocrine Tumors: A Closer Look at the Characteristics of These Diverse Tumors Jaume Capdevila, MD, PhD Vall d'hebron University Hospital Vall d'hebron Institute of Oncology (VHIO) Barcelona, Spain
2 Neuroendocrine Tumors (NETs): A Diverse Group of Malignancies Tumors arising from enterochromaffin cells located in neuroendocrine tissue throughout the body 1 NETs can be functional or nonfunctional and include a heterogeneous group of neoplasms 2,3 Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) 3 Islet cell tumors 2 Typical/atypical/poorly differentiated lung carcinoid 2 Small cell carcinoma of the lung 2,3 Pheochromocytoma/paraganglioma 2,3 Medullary thyroid carcinoma Merkel cell carcinoma 2,3 Kidney, bladder, breast, prostate, thymus 1. Caplin ME, et al. Lancet. 1998;352(9130): ; 2. NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors V2.2016; 3. Modlin IM, et al. Gastroenterology. 2005;128(6):
3 Neuroendocrine Tumors (NETs): A Diverse Group of Malignancies Tumors arising from enterochromaffin cells located in neuroendocrine tissue throughout the body 1 N NETs can be functional or nonfunctional and include a heterogeneous group of neoplasms 2,3 Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) 3 E Islet cell tumors 2 Typical/atypical/poorly differentiated lung carcinoid 2 Small cell carcinoma of the lung 2,3 Pheochromocytoma/paraganglioma 2,3 Medullary thyroid carcinoma T EAR VERYWHERE UMORS Merkel cell carcinoma 2,3 Kidney, bladder, breast, prostate, thymus 1. Caplin ME, et al. Lancet. 1998;352(9130): ; 2. NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors V2.2016; 3. Modlin IM, et al. Gastroenterology. 2005;128(6):
4 The Increasing Incidence of NET Lung and bronchus Incidence per Year Rectum Small intestine Pancreas Stomach Cecum Colon Appendix 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 Yao JC, et al. J Clin Oncol. 2008;26(18):
5 The Gastrointestinal Tract (GI) Is the Most Common Primary Location of NET (US SEER Data) Other/ unknown Lung 15% 27% Digestive system 58% Percent distribution (%) 17.2 Rectum 13.4 Jejunum/ileum 6.4 Pancreas 6.0 Stomach 4.0 Colon 3.8 Duodenum 3.2 Cecum 3.0 Appendix 0.8 Liver Yao JC, et al. J Clin Oncol. 2008;26(18):
6 NETs Are the Second Most Prevalent Type of GI Malignancy times more prevalent than pancreatic cancer Colorectal 1 GEP-NET 2 Stomach 1 Pancreas 1 Esophagus 1 Hepatobiliary 1 Prevalence in SEER Database 1. National Cancer Institute: SEER Cancer Statistics Review, Accessed: September 8, Modlin IM, et al. Cancer. 2003;97(4):
7 Complex Disease
8 Constellation of Symptoms Makes a Differential Diagnosis Difficult Nonspecific symptoms are common to multiple diagnoses Menopause Food allergy Neurosis NETs Symptoms Sweating Flushing Diarrhea Intermittent abdominal pain Bronchoconstriction GI bleeding Cardiac disease Functional bowel disease Irritable bowel syndrome Alcoholism Asthma Thyrotoxicosis Anxiety Estimated time to diagnosis: 5 to 7 years 3 Peptic ulcer 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): Modlin IM, et al. J Natl Cancer Inst. 2008;100(18):
9 NETs Are Often Advanced at the Time of Diagnosis Carcinoids M 1 at Dx SV 5 and M 1 Small intestine 70% 55% Colon 71% 20% Appendix 10% 34% Rectum 15% 30% Pancreatic NETs 50%-60% 30%-50% Median survival (years) Local 18.5 Well and moderately differentiated Regional 9.25 Metastatic 2.75 Poorly differentiated metastatic Yao JC, et al. J Clin Oncol. 2008;26(18): Soga J. Cancer. 2005;104(6): Alexiev BA, et al. Diagn Pathol. 2007;2: Modlin IM, et al. Lancet. 2008;9(1):61-72.
10 Correlation of Primary Tumor Site With Survival Known prognostic factors include: Distant metastases Location of primary tumor Extent of disease Tumor stage Degree of differentiation/ proliferative index Tumor grade Patient age Survival probability Colon Lung Pancreas Rectum Small bowel Performance status Time, months 65% of patients with advanced NETs will not be alive in 5 years Yao JC, et al. J Clin Oncol. 2008;26(18):
11 Prognostic Value of Ki67 <2% 15% 75% Ekeblad S, et al. Clin Cancer Res. 2008;14(23): Vilar E, et al. Endocr Relat Cancer. 2007;14(2): Grade Mitotic count (10 HPF) Ki-67 index (%) G1 <2 2 G G3 >20 >20 Pape UF, et al. Endocr Relat Cancer. 2008;15(4): Scarpa A, et al. Mod Pathol. 2010;23(6):
12 But Differentiation Is Also Important Well- and moderately-differentiated histology Histology Poorly differentiated histology Yao JC, et al. J Clin Oncol. 2008;26(18):
13 High Complexity for NETs Classification Differentiation Grade Mitotic count Ki67 index Traditional ENETS; WHO Well differentiated Poorly differentiated Low grade (G1) Intermediate grade (G2) High grade (G3) <2 per 10 high power fields (HPFs) 2% Carcinoid, islet cell, pancreatic (neuro)endocrine tumor 2-20 per 10 HPFs 3%-20% Carcinoid, islet cell, pancreatic (neuro)endocrine tumor >20 per 10 HPFs >20% Well differentiated Small cell carcinoma Large cell neuroendocrine carcinoma Poorly differentiated Grade (ENETS) Low (G1) Intermediate (G2) High (G3) Ki67 index (%) >20 Anatomic imaging Funational imaging Octreoscan SPECT or SSTR PET-positive More rapid growth on serial imaging FDG PET-positive Prognosis Indolent (slowly growing) Aggressive Neuroendocrine tumor; grade 1 Neuroendocrine tumor; grade 2 Neuroendocrine tumor; grade 3, small cell Neuroendocrine tumor; grade 3, large cell Bosman FT, eds. WHO Classification of Tumours of the Digestive System. 4 th Ed. Lyon, France: The International Agency for Research on Cancer; Rindi G, et al. Virchows Arch. 2006;449(4): Rindi G, et al. Virchows Arch. 2007;451(4) Jensen RT, et al. Neuroendocrinology. 2006;84(3):
14 Best Treatment Option Based on MDT Evaluation Pathologist Surgeon Every one helps Nuclear Medicine Best treatment option Oncologist Endocrinologist Gastroenterologist
15 Factors Influencing the Therapeutic Decision in NETs Type of NET (pancreatic vs GI) Resectability Patient performance status and comorbidities Uptake on somatostatin receptor scintigraphy TNM stage and grade (G1/G2 vs G3) Functioning vs nonfunctioning tumor Availability of different therapeutic modalities Patient preference and convenience
16 Integrating Grade and Tumor Burden High Treatment goals: Tumor control and QoL Advanced, unresectable, well- to moderately- differentiated NETs: Primary treatment goals Tumor response/control & QoL Tumor response/control Rapid Tumor Response Tumor burden QoL & tumor control Tumor control & QoL Tumor control/ response Low QoL & tumor control Tumor control & QoL Tumor control & QoL Low Tumor aggressiveness (eg, Ki67) Moderate (up to Ki67 = 20%)
17 Progressive Increase in Survival Overall Survival, months OS NR OS NR OS NR 44 months 33 months OS NR OS NR OS PFS Arnold R, et al. J Clin Oncol. 2013;31(suppl): Abstract Caplin M, et al. N Engl J Med. 2014;371(3): Pavel M, et al. Ann Oncol. 21(suppl 8): Abstract LBA-8. Pavel ME, et al. J Clin Oncol. 2015;33(suppl): Abstract Vinik A, et al. J Clin Oncol. 2012;30(15S): Abstract 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.
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