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.

Rare locations:

  •  Liver and biliary system (0.59%)

  •  Gall bladder  (0.31%)

  •  Meckel’s diverticulum (0.27%)

  •  Oesophagus (0.2%)

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:

  •  Foregut

  •  Midgut

  •  Hindgut.

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.

In the case of hormone secreting tumours, it should include reference to the resultant hormone secretion or associated symptoms/syndrome:
  •  e.g., gastrinoma, insulinoma, carcinoid syndrome etc.

 

WHO clasification

TNM staging (ENETS)

Grading (ENETS)

Asset 1
Asset 1
 
NET-TUMOUR GRADING AND CLASIFICATIONS. ENETS PROPOSAL
NET-TUMOUR GRADING AND CLASIFICATIONS. ENETS PROPOSAL

Assessment of mitotic rate: Ki67

In Europe - Ki67 is mandatory for all cases (ENETS and WHO 2010)(1)

Difficulties when:

 

  • 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.

Immunohistochemistry methods:

  • 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.

Asset 2
Asset 2

Diagnosis

Immunohistochemical NE – markers

 

Asset 3
Asset 3

Non-functional pNETs

 

  • Can secrete pancreatic polypeptide, chromogranin A, neuron specific enolase, human chorionic gonadotrophin subunits, calcitonin, neurotensin or other peptides

  •  Do not produce specific symptoms.

Functional pNETs

 

  • 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)

  •  Chronic gastritis

  •  Essential hypertension.

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

  •  Tumour burden

  • Progression and malignant nature of the tumour.

CgA tissue expression varies according to the primary tumour type
CgA tissue expression varies according to the primary tumour type


 

pNET  types_1
pNET types_1

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:

  •  Flushing (63-94%)

  •  Diarrhoea (68-84%)

  •  Abdominal pain (10-55%)

  •  Telangiectasia (25%)

  •  Bronchoconstriction (3-19%)

  •  Carcinoid heart disease.

NETS FUNCTIONING pNETS - SyMpTOMS AND SYNDROMES

Asset 1
Asset 1


Treatment options 

Management of locoregional unresectable or/and metastatic disease ases

Total tumor eradication

If total eradication not possible, then:

  •  Symptomatic control

  •  Prevention of complications related to the carcinoid syndrome( carcinoid heart disease, carcinoid crisis)

  •  Inhibition of tumor growth/prolongation of survival.

Surgical Approaches - curative ablative

Debulking procedures

  •  TACE, TAE, RFA, SIRT etc.

Medical therapy.

  •  Biotherapy

 ·somatostatin analogues ( octreotide, lanreotide, pasireotide)

 ·a IFN.

  •  Systemic chemotherapy

  •  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
 

Asset 1
Asset 1

ESMO clinical guidelines
 

Asset 2
Asset 2

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.

Asset 1
Asset 1

Significant improvement in TTP regardless of the presence of carcinoid syndrome
 

Asset 2
Asset 2


 

Asset 3
Asset 3

 

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).

CHEMOTHERAPY

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;

  •  CAPOX/FOLFOX/FOLFIRI.

 

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

Results

44 patients

Prior treatment- multitarget therapy( sunitinib)

  •  mTOR inhibitors

  •  both agents

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)
 

177Lu-DOTATATE:177Lu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid0 (DOTA), Tyr3-octreotate; 90Y DOTATOC: [90Y-DOTA]-D-Phe1-Tyr3-octreotide. 1. Kwekkeboom DJ et al. J Clin Oncol. 2008;26:2124-2130. 2. Waldherr C et al. Ann Oncol. 2001;12:941-944.
177Lu-DOTATATE:177Lu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid0 (DOTA), Tyr3-octreotate; 90Y DOTATOC: [90Y-DOTA]-D-Phe1-Tyr3-octreotide. 1. Kwekkeboom DJ et al. J Clin Oncol. 2008;26:2124-2130. 2. Waldherr C et al. Ann Oncol. 2001;12:941-944.

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