Tumorile neuroendocrine - diagnostic şi strategii terapeutice

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.

•  e.g., gastrinoma, insulinoma, carcinoid syndrome etc.

WHO clasification

TNM staging (ENETS)

Grading (ENETS)

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.

Diagnosis

Immunohistochemical NE – markers

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.

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

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
 

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).

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)
 

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