1. ΕΠΙΘΕΤΙΚΕΣ ΘΕΡΑΠΕΙΕΣ ΑΡΓΑ
ΑΝΝΑ ΚΟΥΜΑΡΙΑΝΟΥ MD PhD
ΠΑΘΟΛΟΓΟΣ ΟΓΚΟΛΟΓΟΣ
ΑΙΜΑΤΟΛΟΓΙΚΗ-ΟΓΚΟΛΟΓΙΚΗ ΜΟΝΑΔΑ
Δ’ ΠΑΝΕΠΙΣΤΗΜΙΑΚΗ ΠΑΘΟΛΟΓΙΚΗ ΚΛΙΝΙΚΗ ΓΠΝΑ ΑΤΤΙΚΟΝ
NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP

2. Approved non-surgical therapies for the treatment of advanced pNET
FDA approval: Lanreotide
in GEP-NET7
Octreotide Depot 9
FDA approval:
Sunitinib in pNET4
1982
1990
2006
2011
2010
2014
2011
2015
FDA approval:
SFZ in pNET1,2
FDA/EMA approval:
Everolimus in pNET5,6
Temozolomide8
1. Zanosar® (streptozocin) SmPC 2011; 2. Blumenthal GM et al. Oncologist 2012;17:1108–1113; 3. Sutent® (sunitinib) SmPC, 2014; 4. Sutent® (sunitinib) PI 2011; 5. Afinitor® (everolimus) PI 2011; 6. Afinitor® (everolimus) SmPC 2015; 7.Somatuline® depot (lanreotide) PI 2014; 8. Strosberg JR, et al. Gastrointest Cancer Res 2008;2: ; 9 Rinke JCO 2009
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

3. NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP
Στόχοι θεραπείας
Achieve best radiological response
Stabilise disease
Improve overall survival
Maintain/improve QoL
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

4. Biology of tumor (WHO classification, grading)
Guides management
Biology of tumor (WHO classification, grading)
Extent of disease (TNM, stage)
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

5. NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

6. Survival according to differentiation
1.0 G1
0.8
Grading NET*
Grade
Mitotic count (10 HPF)
Ki67 index (%) G1
≤ 2 G2
3–20 G3
> 20 G2
0.6
Chance of survival
0.4
G1 vs G2 G1 vs G3 G2 vs G3
P = P < P < 0.001
0.2
Retrospective data from 158 patients with histopathological confirmed diagnosis of gastric, duodenal or pancreatic NET underwent survival analysis according to the ENET/AJCC grading system.
The analysis indicated that survival was significantly poorer for patients who had grade 3 tumours compared with patients who had grade 1 and grade 2 tumours and for patients who had grade 2 tumours compared with patients who had grade 1 tumours.
References:
1. Rindi G, Klöppel G, Alman H, et al. Virchows Arch. 2006;449:
2. Rindi G, Klöppel G, Couvelard A, et al. Virchows Arch. 2007;451:
3. Pape UF, Jann H, Müller-Nordhorn J, et al. Cancer. 2008;113: G3
0.0
* ENET and AJCC grading system 50
100
150
200
250
Time (months)
Rindi G, et al. Virchows Arch. 2006;449:
Rindi G, et al. Virchows Arch. 2007;451:
Pape UF, et al. Cancer. 2008;113:
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP 6

7. TNM classification for GEP-NETs
Stage 0*
Τis N0 M0
Stage I
T1**
Stage IIa T2
IIb T3
Stage IIIa T4
IIIb
Any Τ Ν1 Μ0
Stage IV
Any Ν Μ1
Classification according to the anatomic origin
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

8. Molecular Biology Underlying NET
Yao JC, et al.
Cancer Res
2013;73:

9. Radical resection vs. other therapies
Radical resection (n= 90)
Other therapies (n= 83)
p =
Median: 40.4 months
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

10. Systemic therapy of advanced pNET: the patient continuum
Favour
chemotherapy
Disease volume
Rate of progression
Favour targeted therapy/SSA
Ki-67
+ circulating tumour cells?
+ molecular profiling?
+ circulating biomarkers?
Figure adapted from Lamarca A et al. TJOP 2014;2:15–25
Diez M et al. Ann Gastroenterol 2013;26(1):29-36

11. Neuroendocrine Tumors (NET)
Most patients are diagnosed with advanced NET.
Conventional chemotherapy has limited efficacy for patients with advanced grade 1 & 2 NET.
Octreotide LAR and Lanreotide are the first targeted therapies that are historically used for symptom control & prolong time to progression
Neuroendocrine tumours can arise in a variety of primary sites in the foregut, midgut, and hindgut regions.
The numerous sites of origin demonstrate the heterogeneous nature of the disease.
Currently, octreotide LAR is approved by the health authorities for the treatment of secretory symptoms caused by neuroendocrine tumours.
However, currently there are no approved agents for anti-tumour therapy for patients with neuroendocrine tumours.
Reference:
Yao et al. J Clin Oncol. 2008;26(May 20 suppl):
Modlin IM, et al. J Clin Gastroenterol. 2006;40:
Rinke A, et al. J Clin Oncol. 2009;27:
Yao JC, et al, J Clin Oncol. 2008;26: 11

12. Somatostatin receptors are highly expressed in NET
Somatostatin analogues
Targeting somatostatin receptors provides symptom and tumour control
References: 1. Susini C, Buscail L. Ann Oncol. 2006;17(12): Mougey AM, Adler DG. Hosp Phys. November 2007:12-20,5 3. Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Eur J Nucl Med. 1993;20(8):
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

13. SST 1-5 Expression in NETs
NETs
Pancreas
Small bowel
sst1 68 80
sst2 86 95
sst3 46 65
sst4 93 35
sst5 57 75
sst1
sst2
sst3
sst4
sst5
Kulakasiz et al. ont étudié l’expression des récepteurs sst avec des Ac dans des cellules de TNE in vitro.
Nasir A et al. Cancer Control 2006;13:
Öberg K et al. Annals Oncol 2004;15: ; Kulakasiz H et al. Gut 2002;50:52-60
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP 13

14. NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP
Ασθενής με
επεισόδιο flushing
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

15. Antitumoral effects Somatostatin DIRECT EFFECT INDIRECT EFFECT
Octreotide
Lanreotide
sst2
Modulation of immune system
(Natural killers)
Inhibition of secretion of trophic factors
Arrest of cell cycle
Cell death by apoptosis
L’effet antitumoral de la somatostatine peut être direct ou indirect.
On entend par « effets directs » la régulation par la somatostatine via son interaction avec un ou plusieurs de ses récepteurs exprimés à la surface de la cellule tumorale cible, de voies de signalisation conduisant à une inhibition de la progression tumorale (arrêt du cycle cellulaire, induction de l’apoptose), stimulée par des facteurs de croissance que la cellule tumorale sécrète elle-même ou présents dans son microenvironnement au sein de la tumeur.
On entend par « effet indirect » l’inhibition par la somatostatine de la sécrétion de facteurs trophiques pro-tumoraux (de croissance, angiogénique) sécrétés par les cellules tumorales ou des cellules du microenvironnement qui jouent un rôle dans la progression tumorale (notamment les cellules endothéliales et le système immunitaire).
Inhibition of growth factors
Inhibition of angiogenesis (VEGF)
Buscail et al 1994, Sharma et al. 1998, Danesi et al. 1997, Albini et al. 1998, Pages et al. 1999, Florio et al 2003
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP 15

16. NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP
Dong M, et al. Clin Cancer Res 2012;18:

17. Octreotide LAR 30 mg extends TTP in patients with functioning or non-functioning tumours
Patients with non-functioning tumours
Patients with functioning tumours
Octreotide LAR: 25 patients / 9 events
Median TTP 28.8 months
Placebo: 27 patients / 24 events
Median TTP 5.91 months
Octreotide LAR: 17 patients / 11 events
Median TTP months
Placebo: 16 patients / 14 events
Median TTP 5.45 months 1 1
0.75
0.75
0.5
0.5
Proportion without progression
Proportion without progression .
0.25
0.25 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90
Time (months)
Time (months)
P=0.0008; HR=0.25 [95% CI: 0.10–0.59]
P=0.0007; HR=0.23 [95% CI: 0.09–0.57]
Rinke A et al. J Clin Oncol 2009

19. NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP
Somatostatin analogs
Μονοθεραπεία
Αναβολή επιθετικών θεραπειών για αργότερα
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

20. Management of locoregional unresectable and/or metastatic disease
Distant metastases
IMAGING
Multiphasic CT or MRI
Consider Octreoscan
BIOCHEMICAL
Consider 5-HIAA
Consider CgA
Complete resection possible
Asymptomatic Low tumor burden
Locally symptomatic from primary tumor
Clinically significant tumor burden
Carcinoid syndrome
Resect Primary + metastases
Observe with markers and imaging every 3-6 mo or SSA’s
Consider Resection of Primary tumor
SSA’s
ECHOcardiogram
Clinically Significant Progressive disease
*SSAs, if not already receiving
Consider hepatic regional therapy: - Arterial embolization - Chemoembolization - Radioembolization - Ablative therapy)
Consider Cytoreductive surgery
Consider everolimus 10mg/day
Consider chemotherapy if no other options feasible

21. Management of locoregional unresectable and/or metastatic disease
Locoregional unresectable disease and/or distant metastases
Complete resection possible
Asymptomatic Low tumor burden and STABLE disease
Symptomatic or Clinically significant tumor burden or Clinically significant progressive disease
Resect Primary + metastases
Observe with markers and imaging every 3-12 months
Manage clinically significant symptoms as appropriate
Clinically Significant Progressive disease
Everolimus 10mg/day
Sunitinib 37,5mg/day
Cytotoxic Chemotherapy
Hepatic regional therapy - Arterial ermbolization - Chemoembolization - Radioembolization - Ablative therapy
Cytoreductive surgery
Consider SSA’s if not already receiving
Lanreotide
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

22. Stage IV NETs – ηπατικέs μεταστάσεις
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

24. Treatment Decisions in GEP-NETs
Options may depend on:
Type of GEP-NET
TNM stage (I-IV), degree hepatic involvement
Tumor grade (G1-3)
Functional status of tumour
Growth rate
Presence familial syndrome (MEN1)
Patient: organ function, ECOG PS, comorbidity
Access to various options
ECOG: Eastern Cooperative Oncology Group; PS: performance status
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP 24

25. Treatment Decisions in GEP-NETs
Treatment decisions require discussion by a multidisciplinary team
Options may depend on:
Type of GEP-NET
TNM stage (I-IV), degree hepatic involvement
Tumor grade (G1-3)
Functional status of tumour
Growth rate
Presence familial syndrome (MEN1)
Patient: organ function, ECOG PS, comorbidity
Access to various options
ΔΙΕΠΙΣΤΗΜΟΝΙΚΗ ΟΜΑΔΑ ΚΑΙ
ΟΓΚΟΛΟΓΙΚΑ ΣΥΜΒΟΥΛΙΑ!!!
ECOG: Eastern Cooperative Oncology Group; PS: performance status
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP 25

26. Systemic therapy of advanced pNET: the patient continuum
Favour
chemotherapy
Disease volume
Rate of progression
Favour targeted therapy/SSA
Ki-67
+ circulating tumour cells?
+ molecular profiling?
+ circulating biomarkers?
Figure adapted from Lamarca A et al. TJOP 2014;2:15–25
Diez M et al. Ann Gastroenterol 2013;26(1):29-36

27. Systemic therapy of advanced pNET: the patient continuum
Favour
chemotherapy
Disease volume
Rate of progression
Favour targeted therapy/SSA
Ki-67
Figure adapted from Lamarca A et al. TJOP 2014;2:15–25
Diez M et al. Ann Gastroenterol 2013;26(1):29-36

28. Treatment options for advanced pNET
Advanced/inoperable
Via MDT – consider clinical trials
G1/G2 G3
Somatostatin analogs
Chemotherapy
Chemotherapy
Platinum/etoposide
Streptozocin-based;
Temozolomide/capecitabine
Targeted agent
Everolimus
Sunitinib
PRRT (if uptake on scan)
177-Lu
90-Y
131-MIBG
Liver-directed
Surgical: transplantation/resection
Embolic: HAE/TACE /RE

29. GEP NET Functioning SS analogs GI NET Non-functioning Functioning pNET
Investigational drugs **
Functioning
SS analogs
High volume*
Slow growth
SS analogs
Investigational drugs
Chemotherapy
PRRT
GI NET
High volume*
Rapid growth
Non-functioning
Everolimus
? PRRT
Low volume
Rapid growth
Low volume
Slow growth
SS analogs
GEP NET
Functioning
SS analogs, PPi, everolimus
High volume
Slow growth*
MT**
pNET
PRRT
Investigational drugs
Second line chemotherapy
High volume*
Rapid growth
Chemotherapy
Non-functioning
Low volume
Rapid growth
*Cytoreductive techniques
**MT=Molecular targeted therapy
Low volume
Slow growth
MT**
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

30. Treatment decisions: criteria for choosing the right systemic treatment for advanced pNET
Criteria for choosing chemotherapy
Criteria for choosing somatostatin analogues
Criteria for choosing targeted therapies
Bulky disease
More rapid disease progression
G2/G3 tumours (occasionally G1 tumours)
Radiological response required
Functional tumours
Low-volume disease
G1 and subset of G2 (Ki67 <10%)
Little/no disease progression
Aim is to delay time to disease progression
Low-volume disease
G1/G2 tumours (Ki67 <20%)
Low rate of disease progression
Aim is to delay time to disease progression

31. NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP
Ευχαριστώ!
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

32. NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP
TELEVOTING
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP

33. NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP