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
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Approved non-surgical therapies for the treatment of
advanced pNET
FDA approval: Lanreotide
in GEP-NET7
FDA approval:
Sunitinib in pNET4
Octreotide
Depot 9
1982
FDA approval:
SFZ in pNET1,2
1990
2006 2011
Temozolomide8
2014
2011
2010
2015
FDA/EMA approval:
Everolimus in pNET5,6
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;2:113-125; 9 Rinke JCO 2009
NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP
Στόχοι θεραπείας
1. Achieve best radiological response
2. Stabilise disease
3. Improve overall survival
4. Maintain/improve QoL
NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP
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Guides
management
Biology of tumor (WHO classification, grading)
Extent of disease (TNM, stage)
NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP
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NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP
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Survival according to differentiation
1.0
G1
Chance of survival
0.8
Grading NET*
G2
0.6
0.4
G1 vs G2
G1 vs G3
G2 vs G3
0.2
P = 0.040
P < 0.001
P < 0.001
G3
0.0
0
50
100 150
200
Time (months)
Grade
Mitotic count
(10 HPF)
Ki67 index
(%)
G1
≤2
≤2
G2
3–20
3–20
G3
> 20
> 20
* ENET and AJCC grading system
250
Rindi G, et al. Virchows Arch. 2006;449:395-401.
Rindi G, et al. Virchows Arch. 2007;451:757-762. NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP
Pape UF, et al. Cancer. 2008;113:256-265.
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TNM classification for GEP-NETs
Stage 0*
Τis
N0
M0
T1**
N0
M0
Stage IIa
T2
N0
M0
IIb
T3
N0
M0
Stage IIIa
T4
N0
M0
Any Τ
Ν1
Μ0
Any Τ
Any Ν
Μ1
Stage I
IIIb
Stage IV
Classification according to the anatomic origin
NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP
Molecular Biology Underlying NET
Yao JC, et al.
Cancer Res
2013;73:1449-1453.
Radical resection vs. other therapies
Radical resection (n= 90)
Other therapies (n= 83)
p = 0.0001
Median: 40.4 months
NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP
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Systemic therapy of advanced pNET:
the patient continuum
Favour
chemotherapy
Disease volume
+ molecular
profiling?
+ circulating
tumour cells?
Favour
targeted
therapy/SSA
+ circulating
biomarkers?
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
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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
Modlin IM, et al. J Clin Gastroenterol. 2006;40:572-582.
Rinke A, et al. J Clin Oncol. 2009;27:4656-4663.
Yao JC, et al, J Clin Oncol. 2008;26:3063-3072
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):1733-1742 2. 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):716-731.
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN
INTERACTIVE WORKSHOP
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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
sst3
sst1
sst2
sst4
sst5
Nasir A et al. Cancer Control 2006;13: 52 -60
Öberg K et al. Annals Oncol 2004;15:966-973; Kulakasiz H et al. Gut 2002;50:52-60
NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP
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Ασθενής με
επεισόδιο flushing
NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP
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Antitumoral effects
Somatostatin
DIRECT EFFECT
Octreotide
Lanreotide
Arrest of
cell cycle
INDIRECT EFFECT
sst2
Cell death by
apoptosis
Inhibition of growth factors
Inhibition of
secretion of
trophic factors
Modulation of
immune system
(Natural killers)
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
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NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP
Dong M, et al. Clin Cancer Res 2012;18:1830-1836
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Octreotide LAR 30 mg extends TTP in patients with functioning or
non-functioning tumours
Patients with functioning tumours
Patients with non-functioning tumours
Octreotide LAR: 17 patients / 11 events
Median TTP 14.26 months
Octreotide LAR: 25 patients / 9 events
Median TTP 28.8 months
Placebo: 27 patients / 24 events
Median TTP 5.91 months
0.75
0.5
0.25
0
0
6
Placebo: 16 patients / 14 events
Median TTP 5.45 months
1
12 18 24 30 36 42 48 54 60 66 72 78 84 90
Proportion without progression
Proportion without progression
1
0.75
0.5
0.25
0
0
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
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Somatostatin analogs
• Μονοθεραπεία
• Αναβολή επιθετικών θεραπειών για αργότερα
NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP
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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
Resect Primary +
metastases
Asymptomatic
Low tumor burden
Observe with
markers and
imaging every 3-6
mo or SSA’s
Locally symptomatic
from primary tumor
Clinically significant
tumor burden
Carcinoid
syndrome
Consider
Resection of
Primary tumor
SSA’s
• *SSAs, if not already
receiving
Clinically
Significant
Progressive
disease
• Consider hepatic regional
therapy:
- Arterial embolization
- Chemoembolization
- Radioembolization
- Ablative therapy)
• Consider Cytoreductive
surgery
• Consider everolimus
10mg/day
SSA’s
ECHOcardiogram
• Consider chemotherapy if
no other options feasible
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Management of locoregional unresectable and/or metastatic disease
Complete
resection possible
Resect Primary +
metastases
• Everolimus 10mg/day
• Sunitinib 37,5mg/day
• Cytotoxic Chemotherapy
Locoregional
unresectable
disease and/or
distant metastases
Asymptomatic
Low tumor burden
and STABLE disease
Symptomatic or
Clinically significant
tumor burden or
Clinically significant
progressive disease
Observe with
markers and
imaging every 312 months
Clinically
Significant
Progressive
disease
• Hepatic regional therapy
- Arterial ermbolization
- Chemoembolization
- Radioembolization
- Ablative therapy
• Cytoreductive surgery
Manage clinically
significant
symptoms as
appropriate
NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP
• Consider SSA’s if not
already receiving
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Stage IV NETs – ηπατικέs μεταστάσεις
NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP
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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
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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
ECOG: Eastern Cooperative Oncology Group; PS: performance status
NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP
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Systemic therapy of advanced pNET:
the patient continuum
Favour
chemotherapy
Disease volume
+ molecular
profiling?
+ circulating
tumour cells?
Favour
targeted
therapy/SSA
+ circulating
biomarkers?
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
26
Systemic therapy of advanced pNET:
the patient continuum
Disease volume
Favour
chemotherapy
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
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Treatment options for advanced pNET
Advanced/inoperable
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
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Via MDT – consider clinical trials
G1/G2
Functioning
GI
NET
SS analogs
Investigational
drugs **
High volume*
Slow growth
SS analogs
High volume*
Rapid growth
Non-functioning
Everolimus
? PRRT
Low volume
Rapid growth
Low volume
Slow growth
GEP
NET
Functioning
Investigational
drugs
Chemotherapy
PRRT
SS analogs
SS analogs, PPi,
everolimus
High volume
Slow growth*
MT**
pNET
High volume*
Rapid growth
Chemotherapy
Non-functioning
Low volume
Rapid growth
*Cytoreductive techniques
**MT=Molecular targeted therapy
Low volume
Slow growth
PRRT
Investigational
drugs
Second line
chemotherapy
MT**
NET MASTERCLASS: ‘WHAT’S NEW IN 2015: AN INTERACTIVE WORKSHOP
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Treatment decisions: criteria for choosing
the right systemic treatment for advanced pNET
Criteria for
choosing
chemotherapy
•
•
•
•
Bulky disease
More rapid disease progression
G2/G3 tumours (occasionally G1 tumours)
Radiological response required
Criteria for
choosing
somatostatin
analogues
•
•
•
•
•
Functional tumours
Low-volume disease
G1 and subset of G2 (Ki67 <10%)
Little/no disease progression
Aim is to delay time to disease progression
Criteria for
choosing
targeted
therapies
•
•
•
•
Low-volume disease
G1/G2 tumours (Ki67 <20%)
Low rate of disease progression
Aim is to delay time to disease progression
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Ευχαριστώ!
NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP
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TELEVOTING
NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP
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NET MASTERCLASS: ‘WHAT’S NEW IN 2015:
AN INTERACTIVE WORKSHOP
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