NETs are rare diseases.
There is a lack of robust source data on epidemiology
Nothing exists to describe the overall European situation:
Only individual country data exists
ENETS in process of establishing a pan-European registry.
Liver and biliary system (0.59%)
Gall bladder (0.31%)
Meckel’s diverticulum (0.27%)
Lack of awareness frequently leads to misdiagnosis or no diagnosis
Higher incidence in African-American than Caucasian patients
Potential genetic factors influencing this are currently unknown.
Rectal NETs are more common in Asian/Pacific Islander, American Indian/Alaskan Native and African American patients(4).
Race predicts outcome in patients with well-differentiated to moderately differentiated NETs (P<0.001)(4).
Tumor types and clasification
NENs -malignant tumours that arise from the diffuse neuroendocrine cell system.
May or may not show hypersecretion of peptides or amines causing hormonal symptoms.
Functional vs non-functional
The term NENs= the whole family of low, intermediate and high grade tumours:
NETs - low to intermediate grade neoplasms
NEC - only be used for high grade neoplasms.
Categorised according to their embryonic origin:
Biologically relevant differences in tumours not distinguished:
Current practice describe GEP-NETS according to their location of primary origin:
e.g., pancreas, duodenum, small intestine etc.
e.g., gastrinoma, insulinoma, carcinoid syndrome etc.
TNM staging (ENETS)
Assessment of mitotic rate: Ki67
In Europe - Ki67 is mandatory for all cases (ENETS and WHO 2010)(1)
There is insufficient biopsy material to differentiate between Grade 1 and 2 NETs
When a large amount of crush artefact present.
Cell cycle-dependent marker found in higher concentrations in dividing cells.
An antibody called MIB1 can reveal Ki67, indicating the level of proliferation.
A high Ki67 index indicates a fast-growing tumour - the worse the prognosis.
Immunohistochemical NE – markers
Can secrete pancreatic polypeptide, chromogranin A, neuron specific enolase, human chorionic gonadotrophin subunits, calcitonin, neurotensin or other peptides
Do not produce specific symptoms.
Are named based on the specific hormone they produce (i.e. insulin, gastrin, somatostatin, glucagon etc.)
Most common are insulinoma and gastrinoma (Zollinger-Ellison syndrome [ZES])
Other types of functional pNETs are grouped as rare functional pNETs (RFTs)
Chromogranin A (Cga)
Chromogranins A and B are protein precursors involved in the regulation of hormone secretion(1).
CgA is expressed in well-differentiated tumours(2). Can be expressed in less well-differentiated tumours that do not secrete known hormones(3).
NSE - in G3
Common conditions can increase the levels of CGA
Decreased renal function
Treatment with Proton Pump Inhibitors (PPIs)
Measurement of CgB as a complement to CgA has been suggested(1,2).
CgA blood levels vary according to tumour characteristics
Tumour mass -small tumours may be associated with normal CgA levels
Progression and malignant nature of the tumour.
Many NETs of non-pancreatic origin release vasoactive peptides and amines into the systemic circulation and cause a characteristic set of symptoms called “carcinoid syndrome”(1):
e.g., serotonin and tachykinins.
It occurs in approximately 10% of patients with metastatic NETs(1)
Characterised in patients by:
Abdominal pain (10-55%)
Carcinoid heart disease.
NETS FUNCTIONING pNETS - SyMpTOMS AND SYNDROMES
Management of locoregional unresectable or/and metastatic disease ases
Total tumor eradication
If total eradication not possible, then:
Prevention of complications related to the carcinoid syndrome( carcinoid heart disease, carcinoid crisis)
Inhibition of tumor growth/prolongation of survival.
Surgical Approaches - curative ablative
TACE, TAE, RFA, SIRT etc.
·somatostatin analogues ( octreotide, lanreotide, pasireotide)
Molecular targeted therapies
·angiogenesis inhibitors: sunitinib, sorafenib, bevacizumab
·mTOR inhibitors: everolimus
·GF- rec inhibitors: EGF-R TKI etc.
Peptide Receptor Radionuclide Therapy (PRRT).
NCCN guidelines for metastatic NET
ESMO clinical guidelines
Treatment approach to liver MTS without ENETS Consensus Guidelines for LIVER MTS
Treatment algoritm NET - based on classification
Biotherapy - somatostatin analogues
the use of SSA is the standard therapy in functioning NETs of any site
octreotide and lanreotide are considered equally effective for syndrome control (70-90% of cases)
a standard dose of long-acting formulations is octreotide 20-30 mg/4 weeks i.m. and lanreotide autogel 90-120mg/4 weeks s.c.
doses are adapted to the individual needs and depend on tumor burden
preventive SSA therapy prior to surgery or use of locoregional therapies ( s.c. bolus and/or i.v. 50-100 µg/h perfusion) is usually effective.
Significant improvement in TTP regardless of the presence of carcinoid syndrome
Biotherapy - IFN
may also be considered for symptom control, if SSA are not well tolerated
symptomatic remission - 30-70%
stabilisation/remission of tumor markers - 40%
tumor PR/SD - 10%
onset of response is more delayed than with SSA
recommended dose of 3-5 milion units 3 times per week
pegylated IFN may be considered for better tolerability ( 80-150 µg once weekly).
Few data to support the use of any existing cytotoxic chemotherapy agents.
Result are poor in patients with well-differentiated tumors, with RR of 15% in the largest published study
Option exclusively in advanced intestinal NET after failure to previous treatment lines.
Chemotherapy is the first-line therapy in NEC G3.
No clear cut-off value for Ki67 for indication of chemotherapy.
In cases of liver MTS from NEC G3, regardless of the site of the primary tumor combination chemotherapy - CISPLATIN + ETOPOSIDE is recommended early.
There is no established second line for G3 NEC
Temozolomide + capecitabine +/- bevacizumab;
Molecular targeted therapies
Angiogenesis inhibitors: sunitinib, sorafenib, bevacizumab.
mTOR inhibitors: everolimus.
GF–rec inhibitors: EGF-R TKI etc.
RADIANT-2 study design
Phase III double-blind placebo-controlled trial
Sunitininb in net
Phase III double-blind placebo-controlled trial
Pazonet study - pazopanib in pretreated advanced neuroendocrine tumors - a phase II, open-label trial of the Spanish task Foirce Group for NETs
Prior treatment- multitarget therapy( sunitinib)
Treatment- pazopanib 800 mg/zi, 28 days, +/- SSA
25 patients - was progression free at 6 m/mPFS - 9.5 months
21 patients -SD
· 73% for patients treated with multitarget inhibitor.
· 60% for patients treated with mTOR inhibitor.
· 25% -for patients treated with both agents.
Evaluated pazopanib as single agent in advanced NETs after failure of the other systemic treatments
Pazopanib - multitargeted for:
·Vascular endothelial growth factor receptor 1, 2, 3 VEGFR
·Platelet derived growth factor receptor alfa and beta PDGFR
· Proto-oncogene c Kit.
Primary end point - CLINICAL BENEFIT RATE (CR +PR+SD) at 6 months
Was evaluated translational corelation of radiology response and PFS with circulating and tissue biomarkers.
Results - biomarkers
Non-significant increase of PFS was observed in patients presenting:
lower baseline circulating tumor cell
decreased levels of soluble VEGFR 2
VEGFR 3 GENE polimorphisms.
(Potential biomarkers for selecting patients for pazopanib)
Peptide Receptor Radiotherapy (PRRT)
Systemic radiotherapy targeting somatostatin receptors
Compounds vary by isotope and carrier molecule
177Lu DOTATATE(1) and 90Y DOTATOC(2) more frequently used
RR (0-37%) is higher in pNET compared to midgut NET.
The use of PRRT is after failing the first line medical therapy.
The presence of expression of SSRT2 is a prerequisite for the use of PRRT.
A better effect is reported with increasing SSTR expression according to SRS.
Serious side effects: severe bone marrow disease, kidney failure, liver failure.
Multidisciplinary approach in the management of NETs