understanding gep net cancer
DESCRIPTION
Presentation by Dr Lim Hwee Yong, Medical Oncologist, National Cancer Centre Singapore, at a NET cancer awareness seminar in Singapore on 20 November 2010.TRANSCRIPT
NEUROENDOCRINE TUMORS
NEUROENDOCRINE CELLS
Cells that are cross between endocrine and nerve cells. Produces peptides and neuropeptides.
OVERVIEW OF NEUROENDOCRINE TUMORS
Generally characterized by their ability to produce peptides that may lead to associated syndromes (functional vs nonfunctional)
Include a heterogeneous group of neoplasms– Gastroenteropancreatic neuroendocrine tumors
(GEP-NETs)
– Islet cell tumors (pNET)– Pheochromocytoma / paraganglioma
– Lung NET (carcinoid): typical, atypical, poorly differentiated
– Small cell carcinoma of the lung
– Merkel cell carcinoma
– Medullary carcinoma of the thyroid
GI NEUROENDOCRINE TUMORS Majority of NET are carcinoid
tumors May go undetected for years
without obvious signs or symptoms
• NETs can be characterized by their ability to produce peptides that lead to their syndromes2
• NETs can be classified as foregut, midgut, or hindgut depending on their embryonic origin1,3
Pancreatic NETs• Insulinoma• Glucagonoma• VIPoma• Pancreatic polypeptidoma
Foregut• Thymus• Esophagus• Lung• Stomach• Duodenum
Midgut• Appendix• Ileum• Cecum• Ascending colon
Hindgut• Distal large bowel• Rectum
Other NETSOther NETS
References: 1. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Gastroenterology. 2005;128(6):1717-1751. 2. Modlin IM, Oberg K, Chung DC, et al. Lancet Oncol. 2008;9(1):61-72. 3. National Comprehensive Cancer Network. NCCN Practice Guidelines in Oncology: Neuroendocrine Tumors. V.1. 2008.
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All malignant neoplasms
Neuroendocrine tumors
Yao JC et al. J Clin Oncol. 2008;26:3063-3072.
INCIDENCE OF NETS INCREASING
INCREASING INCIDENCES OF NET
Increased incidence of carcinoid tumours, US population 1973–2005Overall increase recorded for all primary sites during this period. Data from SEER database, US National Cancer Institute
Modlin et al. Lancet Oncol 2008; 9: 61–72
NETS ARE THE SECOND MOST PREVALENT TYPE OF GI MALIGNANCY
2x more prevalent than pancreatic cancer
]
1. National Cancer Institute. SEER Cancer Statistics Review, 1975-2004. http://seer.cancer.gov/csr/1975_2004. 2. Modlin IM, Lye KD, Kidd M. Cancer. 2003;97(4):934-959.
]
NET MAY PRESENT LATE
CONSTELLATION OF SYMPTOMS CAN MAKE A DIFFERENTIAL DIAGNOSIS DIFFICULT1,2
Menopause
Irritable Bowel Syndrome
Functional Bowel Disease
Anxiety
Neurosis
Food Allergy
Asthma
Alcoholism
Thyrotoxicosis
Peptic Ulcer
NET
Symptoms• Sweating• Flushing• Diarrhea• Intermittent abdominal pain• Bronchoconstriction• GI bleeding• Cardiac disease
Nonspecific Symptoms Are Common to Multiple Diagnoses
1. Vinik A, Moattari AR. Dig Dis Sci. 1989;34(3)(suppl):14S-27S. 2. Toth-Fejel S, Pommier RF. Am J Surg. 2004;187(5):575-579.
NONSPECIFIC SYMPTOMS OFTEN LEAD TO A DELAYED DIAGNOSIS
1. Modlin IM, Moss SF, Chung DC, Jensen RT, Snyderwine E. J Natl Cancer Inst. 2008;100(18):1282-1289.
Presents to primary care
Vague abdominal
symptoms
• May be diagnosed as IBS
• May be referred to specialists for evaluation when symptoms do not resolve
Presents to primary care
Vague abdominal
symptoms
• May be diagnosed as IBS
• May be referred to specialists for evaluation when symptoms do not resolve
Referred to multiple specialists
Symptomsbecome worse or patientconsultsfor another reason
• Diagnosis remains unclear
Referred to multiple specialists
Symptomsbecome worse or patientconsultsfor another reason
• Diagnosis remains unclear
Seen by gastroenterologist or other specialist who orders imaging
A referral leads to a scan or patientscanned for another reason
• Liver metastasis or primary lesion is visualized
• May be an incidental finding
Seen by gastroenterologist or other specialist who orders imaging
A referral leads to a scan or patientscanned for another reason
• Liver metastasis or primary lesion is visualized
• May be an incidental finding
Surgeon, pathologist perform biopsy or resection
Biopsy provides diagnosis of NET
• Patient is referred to surgical oncologist, medical oncologist, or endocrinologist
• Treatment depends on stage, histology, symptoms
Surgeon, pathologist perform biopsy or resection
Biopsy provides diagnosis of NET
• Patient is referred to surgical oncologist, medical oncologist, or endocrinologist
• Treatment depends on stage, histology, symptoms
Estimated time to diagnosis: 5 to 7 years1
Vague abdominal symptoms
Primary tumor
Flushing
Metastases
Diarrhea
Death
NETS ARE OFTEN DIAGNOSED LATE
Time
Vinik A, Moattari AR. Dig Dis Sci. 1989;34[Suppl]:14S-27S.
DIAGNOSIS
Clinical assessment Clinically directed workup of persistent
symptoms Scans
CT scans, Octreoscans, Galium PET/CT Histopathological diagnosis
TUMOR MARKERS
General NET markers– Chromogranin A
Affected by somatostatin analogues, proton pump inhibitors, kidney function, liver function
– Neuron-specific enolase Midgut (small bowel, appendix,
cecum)– 5 HIAA (24-hr urine collection)– Serotonin (blood, more variable)
5-HIAA = 5-hydroxyindoleacetic acid
OTHER MARKERS IN FUNCTIONAL TUMORS
Gastrinoma
Gastrin
Glucagonoma
Glucagon
Insulinoma
Insulin
Pro-insulin
C-peptide
VIPoma
Vasoactive intestinal peptide
Fasting measurements when possible
CHROMOGRANIN A (CGA): A VALUABLE DIAGNOSTIC AND PROGNOSTIC TOOL
Highly elevated serum CgA and/or immunohistochemical (IHC) staining of tumor for CgA is diagnostic of NETs Offers 85% sensitivity and 96% specificity for
NETs1
CgA can be used to monitor treatment response More sensitive than radiology for measuring
progression2
References: 1. Campana D, Nori F, Piscitelli L, et al. J Clin Oncol. 2007;25(15):1967-1973. 2. Eriksson B, Öberg K, Stridsberg M. Digestion. 2000;62(suppl 1):33-38.
CHALLENGES PRESENT WITH CGA TESTING
Other conditions can cause elevated CgA Risk of false positives Severe hypertension Gastric acid suppression (PPI’s) Renal insufficiency
CgA values vary considerably Between different types of NET
Clinical application of results is challenging
Test kits not universally standardized Different standards, units of measures Different antibodies Different detection system
TREATMENT OPTIONS
Surgery (curative vs debulking) Radiofrequency ablation Chemo-embolization Somatostatin analogue (hormonal
treatment) Chemotherapy or other medical
therapy (targeted kinase inhibitors) Radionuclide therapy
SURGERY
RADIOFREQUENCY ABLATION
CHEMOEMBOLISATION
CHEMOEMBOLISATION
Somatostatin receptors highly expressed by NETs
– Targeting SST receptors can provide symptom and disease control
New targets:– mTOR, PI3K, VEGF
inhibitors Combinations?
TARGETING NETS
PI3K = phosphoinositide 3-kinase; SST = somatostatin; VEGF = vascular endothelial growth factor
PEPTIDE RECEPTOR RADIONUCLIDE THERAPY
Octreotide
111In pentetreotide
DTPA-CO-NH-D-Phe-Cys
S
S
Thr(ol)-Cys
Phe
D-Trp
Lys
Thr
111In
DOTA-CO-NH-D-Phe-Cys
S
S
Thr(ol)-Cys
Tyr
D-Trp
Lys
Thr
90Y DOTATOC
90Y
177Lu DOTATATE
DOTA-CO-NH-D-Phe-Cys
S
S
Thr-Cys
Tyr
D-Trp
Lys
Thr
177Lu
PRINCIPLES OF RADIONUCLIDE THERAPY