NETs Current Challenges and Advances

NETs Current Challenges and Advances Prof. Eric Raymond, MD, PhD Professor of Oncology at Paris 7 University, France Professor of Oncology at University of Lausanne, Switzerland Montreal, Quebec (Canada) – October 13-15, 2015

Neuroendocrine tumors

GENERAL CONSIDERATIONS

Incidence of NETs in the Western World Age-adjusted incidence in US: 5.7/100,000 in 2007 2.5–5.0/100,000 Inhabitants 1.4

Per 100,000 populaCon

1.2 1.0 0.8

Lung and bronchus Small intestine Rectum Other non-epithelial skin Stomach Appendix Caecum Pancreas Sigmoid colon Rectosigmoid junction

Lung Ileum Rectum

GEP NET ~75%

0.6 0.4 0.2 0 1970

1975

1980

1985

1990

1995

2000

2005

Year Surveillance, Epidemiology and End Results (SEER), US populaCon 1974–2005 Modlin IM, et al. Lancet Oncol. 2008;9:61–72.

Neuroendocrine tumors

CLINICAL MANIFESTATIONS

Incidence of NETs in the Western World Age-adjusted incidence in US: 5.7/100,000 in 2007 2.5–5.0/100,000 Inhabitants 1.4

Per 100,000 populaCon

1.2 1.0 0.8

Lung and bronchus Small intestine Rectum Other non-epithelial skin Stomach Appendix Caecum Pancreas Sigmoid colon Rectosigmoid junction

Lung Ileum Rectum

GEP NET ~75%

0.6 0.4 0.2 0 1970

1975

1980

1985

1990

1995

2000

2005

Year Surveillance, Epidemiology and End Results (SEER), US populaCon 1974–2005 Modlin IM, et al. Lancet Oncol. 2008;9:61–72.

PancreaCc NETs • 

PancreaPc NETs oRen arise sporadically and can be divided into ‘funcPonal’ and ‘non-funcPonal’ tumours1 Subtypes of pancreatic NET

–  Non-funcConal:2 •  60–70% of cases; increasing number found incidentally •  ORen present at a late stage •  Symptoms related to tumour mass

VIP

rP

•  30–40% of cases •  Associated with symptoms of hormone hypersecrePon •  Symptoms oRen responsive to somatostaPn analogues

PTH

–  FuncConal:2

Insulin Glucagon

Gastrin

Non-functioning

• 

Typically slow-growing with an insidious presentaPon

• 

Can be associated with a hereditary syndrome (MEN1; von Hippel–Lindau; NFtype 1, tuberous sclerosis) Liver is predominant site of metastasis (32–73% at diagnosis)

• 

1. NCCN. Neuroendocrine tumors, V.2.2010, http://www.nccn.org 2. Strosberg J, et al. Pancreas 2009;38:255–58

Neuroendocrine tumors

CLASSIFICATION

Biochemical markers used to monitor funcConal pancreaCc NETs Gastrinoma

Gastrin

Glucagonoma

VIPoma

Insulinoma

Glucagon

VasoacPve intesPnal pepPde

Insulin Pro-insulin C-pepPde

• 

Malignant tumours can produce mulPple hormone syn- or metachronously; others markers such as ACTH, GHRH, PTHrp, U-5-HIAA upon suspicion O’Toole D, et al. Neuroendocrinology 2009;90:194–202; NCCN. Neuroendocrine tumors, V.2.2010, http://www.nccn.org;

NET Categories 2010 1 DifferenCaCon (aspects of Cssues)

Well or poorly differenCated

2 ProliferaCon

(MitoCc index or Ki67)

Slide kindly provided by T. Sano, Tokushima University, Japan

High, intermediate or low grades

WHO classificaCon criteria 2010 •  Neuroendocrine tumour (NET)

–  Well-differenPated morphology §  All have malignant potenPal



•  Neuroendocrine carcinoma (NEC)

–  Poorly differenPated morphology §  Small cell §  Large cell

•  Mixed adeno-neuroendocrine carcinoma (MANEC) WHO ClassificaPon of Tumours of the DigesPve System, 4th ed., 2010; Images taken from Capelli P, et al. Arch Pathol Lab Med 2009;133:350–64

PNET

TARGETED AGENTS FOR THE TREATMENT OF ADVANCED PANCREATIC NET

PNET and Pancreatic ductal adenocarcinomas display very different genetic profiles

Neuroendocrine tumors

CLINICAL MANIFESTATIONS

Unspecific presenCng symptoms are commonly misdiagnoses

DiagnosCc Errors

Delayed diagnosis

Radiological Response EvaluaCon: SD (by RECIST) but Early and Major Hypodensity Aier Treatment Baseline

•  MulPnodular and heterogeneous bilateral hypervascular lesions

Post cycle 1

•  InducPon of hypodensity indicaPng lesional necrosis on all target lesions Sandrine Faivre, Beaujon, Study A6181111

Toxicity profile of suniCnib 90 Sunitinib

80

Placebo

Patients (%)

70

59

60 50

45

39

40 30

0

34 30

32 27

29

17

20 10

34 27

29

8

5

11 All

Diarrhoea

11

2

Severe

54

All

Severe Nausea

All

Severe

Asthenia

5

2 All

Severe Vomiting

All

8

Severe Fatigue

1 All

1 Severe

Hair-colour changes

The toxicity profile for sunitinib is favourable, with a low incidence of severe events Most common AEs reported in the safety populaPon 50 Raymond E et al. N Engl J Med 2011;364:501–513;

ComplicaCons associated with funcConal pancreaCc NETs Major clinical symptom

Predominant hormone

Malignancy (%)

Insulinoma

Hypoglycemia

Insulin

5–15

Gastrinoma

Recurrent peptic ulcer, diarrhea

Gastrin

60–90

Diabetes mellitus, migratory necrolytic erythema

Glucagon

60

Watery diarrhea, hypokalemia, achlorhydria

Vasoactive intestinal polypeptide

Diabetes mellitus, diarrhea/steatorrhea

Somatostatin

60

ACTH GHRH U-5-HIAA PTHrp

30–90

Tumour

Glucagonoma

VIPoma Somatostatinoma Ectopic syndromes; Cushing’s, acromegaly, carcinoid, hypercalcemia

80

Metz DC and Jensen R. Gastroenterology 2008;135:1469–92

But, NETs are oien diagnosed late •  Symptoms of NETs are oRen non-specific •  Prompt idenPficaPon of worsening symptoms is needed to detect progressive disease

Non-specific abdominal symptoms

Hormonal symptoms General tumour symptoms Metastases Primary tumour

Time

9 years (median) Diagnosis

Vinik A, Moattari AR. Dig Dis Sci 1989;34[Suppl]:14S–27S

Neuroendocrine tumors

BLOOD BIOMARKERS

PancreaCc NETs express tumor markers that can be used to monitor disease progression General markers: •  Chromogranin A (CgA) (increased in 80–100%)

–  The most effecPve tumour marker for NETs –  Correlates with tumor burden except in gastrinoma, in which it has been shown to be produced by enterochromaffin-like cells (ECL) –  Can also be induced by atrophic gastriPs-induced hypergastrinemia –  Unreliable in paPents with inflammatory bowel diseases, kidney dysfuncPon or receiving somatostaPn analogs, steroids or proton pump inhibitors

•  Neuron-Specific Enolase (NSE)

–  Less sensiPve than CgA –  May be useful in poorly-differenPated pancreaPc NETs O’Toole D, et al. Neuroendocrinology 2009;90:194–202 Ehehalt F, et al. Oncologist 2009;14:456–67

Biochemical markers used to monitor funcConal pancreaCc NETs Gastrinoma

Gastrin

Glucagonoma

VIPoma

Insulinoma

Glucagon

VasoacPve intesPnal pepPde

Insulin Pro-insulin C-pepPde

• 

Malignant tumours can produce mulPple hormone syn- or metachronously; others markers such as ACTH, GHRH, PTHrp, U-5-HIAA upon suspicion O’Toole D, et al. Neuroendocrinology 2009;90:194–202; NCCN. Neuroendocrine tumors, V.2.2010, http://www.nccn.org;

SomatostaCn receptor imaging can be used to detect metastaCc disease •  >90% of NETs contain high concentraPons of somatostaPn receptors1 •  SomatostaPn receptors can be imaged with a radiolabelled somatostaPn analog – octreoPde (OctreoscanTM)1; PET with 68Galabeled somatostaPn analogues •  SomatostaPn receptor imaging can be used for:2 –  DetecPng, localising and staging NETs and metastases –  PredicPng clinical response to somatostaPn analog therapy –  SelecPng paPents for pepPde receptor radionuclide therapy 1. Kulke MH. Endocri Relat Cancer 2007;14:207–19 2. Kwekkeboom DJ, et al. Neuroendocrinology 2009;90:184–9

Neuroendocrine tumors

THERAPEUTIC OPTIONS

For Treatments There is Basically Three Typical Situa3ons: POORLY DIFFERENTIATED NETS

PANCREATIC NETS OTHER NETS

Poorly differenCated NETS •  PlaPnum-etoposide (VP-16) remains the the most frequently prescribed combinaPon chemotherapy •  Topoisomerase-I-inhibitor-based chemotherapy is oRen given as second line therapy •  Other treatments are discussed on a case-by-case basis

Neuroendocrine tumors

PANCREATIC NET * CHEMOTHERAPY * TARGETED AGENTS

Variable response seen with chemotherapy in advanced pNET Study

Treatment

Median OS

Complete response, %

Any response, %

Median duration of response

Moertel 1992

Chlorozotocin

1.5 years*

6‡

30‡

21 months

Streptozocin + fluorouracil

1.4 years†

4‡

45‡

13 months

Streptozocin + doxorubicin

2.2 years

14‡

69‡

22 months

16.5 months

12

36

NR§

26 months

33

63

NR§

Moertel 1980

Streptozocin Streptozocin + fluorouracil

•  Efficacy of chemotherapy in pNET is variable and limited •  Response in these studies was not assessed using RECIST criteria *p