Transcript Diapositiva 1 - Associazione Medici Endocrinologi

L’evoluzione della terapia medica: dagli
analoghi della somatostatina alle terapie
a bersaglio molecolare
Salvatore Artale
Oncologia Medica Falck
Ospedale NIguarda Ca’ Granda
Milano
Milano 25.05.2007
WHO Classification
2000

Well differentiated endocrine tumors
(benign or low grade malignancy)

Well differentiated endocrine carcinomas

Poorly differentiated endocrine carcinomas
(small cell carcinomas)

Mixed exocrine and endocrine carcinomas

Tumor-like lesions
WHO Classification
2000
THE DIFFERENTIATION IS BASED ON :
HISTOMORPHOLOGY
PRESENCE/ABSENCE OF LOC.INVASION/METASTASIS
PROLIFERATION INDEX (Ki67):
< 2% Well Diff.Tumors
> 2% / <15% Well.Diff.Carcinomas
> 15 % Poorly Diff.Carcinomas
Neuroendocrine tumors
Frequency
Incidence: 1-2/ 100.000
Autopsy series 8/100.000
Carcinoid tumors are the most frequent type
(40% of all NETs)
5-year survival rate:
70%
WHO Classification
2000

Well differentiated endocrine tumors
(benign or low grade malignancy)

Well differentiated endocrine carcinomas

Poorly differentiated endocrine carcinomas
(small cell carcinomas)

Mixed exocrine and endocrine carcinomas

Tumor-like lesions
WHO Classification
2000

Well differentiated endocrine carcinomas
Which is the best treatment ?
Medical treatment

Biotherapy ?

Chemotherapy ?
Medical treatment
Somatostatin analogs

Biotherapy
Interferon-a
Targeted therapy
Objectives of Medical Treatment

Efficacy
– Symptom control
– Biochemical control
– Control of tumor burden
Criteria for evaluating the tumor response
According to ITMO Group. Bajetta et al Q J Nucl Med 2000
Clinical Presentation:
non functioning tumours
– Symptoms related to the mass effect:
– Bowel obstruction
– GI bleeding (rare)
Clinical Presentation:
functioning tumours
– Carcinoid syndrome < 20%:
– Cutaneous flushing: upper part of the body
(80%)
 Watery diarrhea and abdominal cramp
(80%)
 Bronchospasm
 Endocardial fibrosis( 30-40 %):
arrhythmia. Right heart insufficiency.
Well Differentiated carcinoma
and biotherapy

Rationales:
NETs carry receptor(s) for growth factor
responsable in cellular proliferation,
angiogenesis,hormone secretion and clinical
symptoms:
– Insulin like growth factor-1
– PDGF-alpha
– TGF-alpha
– TGF-beta
– VEGF expression
80-90% of NETs show high-affinity somatostatin
receptors
Somatostatin Analogues





Octreotide
Octreotide LAR
Pasireotide SOM 230
Lanreotide
Lanreotide autogel (Lan ATG)
Well differentiated neuroendocrine carcinomas:
Results of studies of somatostatin analogs
Non randomized studies
Kvols et al 1986
Octreotide 450 µg/day
Souquet et al 1987
Octreotide 300 µg/day
Janson and Oberg 1993
Octreotide,variable
Di Bartolomeo et al 1996
Octreotide 1500-3000 µg/day
Arnold et al 1996
Octreotide 600-1500 µg/day
Scherubl et al 1994
Lanreotide 30 mg /14 days
Ruszniewski et al 1996
Lanreotide 30 mg /14 days
Wymenga et al 1999
Lanreotide 30 mg /14 days
Well differentiated neuroendocrine carcinomas:
Results of studies of somatostatin analogs
Non randomized studies
Ricci et al 2000
Lanreotide 30 mg /14 days
Tomassetti et al 2000
Octreotide LAR 20 mg /28 days
Welin et al 2004
Octreotide pamoate 160 mg /14
days
Ruszniewski et al 2004
Lanreotide autogel 60-120 mg/28
days
Somatostatin analogs
SR: 30-75%
OR: 5%
Standard dose
BR: 30-60%
SD: 35-50%
Med Dur SD: 18 months
Somatostatin analogs
OR: 13%
High dose
SR: 42%
BR: 75%
Carcinoid Syndrome and
somatostatin analogs
Efficacy Studies
Randomized trials: 5
Carcinoid Syndrome and
somatostatin analogs
Randomized
Lanreotide
ATGtrials
120
SOM 230
is effective
inmg
metastatic
Oberg
et al.6tumors
1989
Octreotide
scmg
vs
every
weeks =
Lanreotide
Carcinoid
refractory
or60resistant
placebo
every
3
weeks
to octreotide LAR
in welland
differentiated
neuroendocrine
Jacobsen
Octreotide
sc vs
tumors
Hanssen 1995
placebo
Kvols et al. ASCO 2006
Saslow et al.1997
Octreotide sc vs
Bajetta et al .Cancer 2006
Placebo
Rubin et al.1999
Octreotide LAR vs
Octreotide sc
O’Toole et al.2000
Octr. sc
Lanreot im
What about interferon ?
Interferon-α
Regular dose 3–9 MU 3–7 times a week
Response.
Subjective
40–70%
Biochemical
40–50%
Tumor
10–15%
Interferon-α/somatostatin analogues
in combination: randomized trials
Responses
Authors
N°Pts
Arms
Sympt
Bioch
Kolby
2003
68Pts
Faiss
2003
80
IFN
LAN
IFN+LAN
Better
P=0.0037
No Diff
Arnold
2005
109
OCT
OCT+IFNa
NR
NR
Rad
IFN with IFN
NR had reduced
NR
treated
risk NR
of
OCT+IFNa
Tumour progression P= 0.008
PR4/SD8
PR4/SD26
PR7/SD18
5-y Surv
%
36
58
NO
DIFF
1-y
PFS
P=0.132
35
51
Med sur
(months)
P=0.55
Fazio et al. Annals of Oncol 2006 ( review)
Interferon-α/somatostatin analogues
in combination: Non randomized trials
Author
N. pts Subjective
response
n. pts (%)
Biochemical
response
n. pts (%)
Radiological
response
n. pts
Janson et al.
(1992)
24
NR
17/22 (77)
15
Frank et al.
(1999)
21
NR
9/13 (69)
14
Fjällskog et al
(2002)
16
NR
10/16 (63)
11SD
3 PR
Artale et al
(2005)
11
3/4(75)
6/9 (66%)
7 SD
4PR
Pavel et al
(2006)
17
NR
6/15 (40%)
11 SD
2 PR
WHO Classification
2000

Well differentiated endocrine tumors
(benign or low grade malignancy)

Well differentiated endocrine carcinomas

Poorly differentiated endocrine carcinomas
(small cell carcinomas)

Mixed exocrine and endocrine carcinomas

Tumor-like lesions
WHO Classification
2000

Poorly differentiated endocrine carcinomas
Which is the best treatment ?
Medical treatment

Chemotherapy
Cytotoxic therapy for carcinoid tumors
S
I
N
G
L
E
A
G
E
N
T
S
Drug
N° Pts
Overall
Response %
Doxorubicin
81
21
Median
Duration
(months)
6
Fluorouracil
30
17-26
3
Streptozotocin
14
0-17
2
Dacarbazin
15
13
4.5
Cisplatin
16
6
4.5
Oberg. K. Annals of Oncol 2004
P
O
L
I
C
H
E
M
O
T
H
E
R
A
P
Y
Cytotoxic therapy for carcinoid tumors
Drug
N° Pts
Overall
Response %
Strepto+Fluor
175
7-33
Median
Duration
(months)
3-7
Strepto+Doxo
10
40
5
Strepto+Ciclo
24
39
6
Fu+Det+Epi
70
26
10
Oberg. K. Annals of Oncol 2004
Chemotherapy of endocrine pancreatic tumors
Drug
Strepto+Fluor
Objective
Response %
170
Toxicity:45-63
Strepto+Doxo
50
N° Pts
Strepto-Doxo
40-69
Duration
(months)
18-36
Chronic
renal
insufficiency
Cispl+Etop
14
50
Cardiotoxicity
Dacarbazine
11
9
Vomiting
Paclitaxel
15
7
12-24
9
6
5
Oberg. K. Annals of Oncol 2004
Failure to Confirm Major Objective Antitumor Activity for
Streptozotocin And Doxorubicin in the treatment of
Patients with Advanced Islet Cell Carcinoma
MSKCC. 2/92-2/98
16 patients with ICC treated with STZ + Doxo
Results:
1/16 ( 6%) with imaging PR
9/16 (56%) with stable disease
6/16 (38%) progressed during treament
Cheng et al Cancer 1999
Lack of Efficacy of Streptozocin and Doxorubicin in Patients
With Advanced Pancreatic Endocrine Tumors.
McCollum, A David MD *; Kulke, Matthew H. MD +; Ryan, David P. MD [S]; Clark, Jeffrey W. MD
[S]; Shulman, Lawrence N. MD +; Mayer, Robert J. MD +; Bartel, Sylvia RPH ++; Fuchs, Charles S.
MD, MPH +
Conclusions:
In this retrospective cohort, the combination of
Methods: We retrospectively reviewed the records of 16 consecutive patients who received
streptozocin and doxorubicin
for advancedand
PETs doxorubicin
at Dana Farber/Partners
Cancer Care institutions.
treptozocin
failed
Baseline patient characteristics, radiographic response to therapy, treatment-related toxicity,
to demonstrate substantial antitumor
progression-free and overall survival were analyzed.
activityin patients with advanced PET.
Results: One patient demonstrated an objective partial response to therapy (objective response
Our findings underscore the need for
rate [ORR], 6%; 95% confidence interval [CI], 0-18%). Six patients achieved stable disease (38%;
95% CI, 14-62%) and
9 patients demonstrated
diseasein
progression
on initial restaging
(56%; 95%
therapeutic
options
this patient
population.
CI, 33-77%). The median progression-free survival and overall survival were 3.9 months (95% CI,
2.8-8.8) and 20.2 months (95% CI, 9.7-37.4), respectively.
American Journal of Clinical Oncol 2004
Cisplatin Based Therapy
RESPONSE TO CISPLATIN AND ETOPOSIDE
COMBINATION ACCORDING TO CELLULAR
DIFFERENTION
Well differentiated
Poorly differentiated
Patient no.
4
11
Overall response
% 45
% 67
Biochemical
% 45
%0
Radiological
% 27
% 50
Stable
% 36
% 25
Progressive
% 18
%0
Fjallskog Cancer 2001
Well diff
Poorly diff
A
N
T
I
C
A
N
C
E
R
R
E
S
E
A
R
C
H
2005
36%
37%
A
N
T
I
C
A
N
C
E
R
R
E
S
E
A
R
C
H
2005
88%
67%
66%
0%
Artale et al. Anticancer Research 2005
Targeted Therapy


Monoclonal antibody anti-VEGF:
Bevacizumab: suppression of tumor blood flow
and prolungation of PFS. Yao et al ASCO 2005
Small multi-TK inhibitors:
Sunitinib:RR 15% islet cell, 2% carcinoid, SD JCO 2006
Sorafenib, Vatalanib : Phase II ongoing
Imatinib (Gleevec): no activity
Gross et al .Endocrine related Cancer 2006
Endostatin: only SD. Kulke et al JCO 2006

EGFR inhibitors:
Gefitinib: no Object.resp. ASCO 2005
Mammallian target of rapamycin inhibitors
EVEROLIMUS (RAD 001)
TEMSIROLIMUS ( CCI-779)
Role of angiogenesis in NET

Angiogenic growth factors contribute to tumor growth
– VEGF is found in 84% of carcinoid and 59% of islet cell tumors
– VEGFR is found in 71% of carcinoid and 67% of islet cell tumors
– Suggests autocrine stimulation in carcinoid and islet cell tumors

The mTOR pathway regulates production of
angiogenic growth factors and the proliferation
of vascular endothelial cells
Hobday et al. Proc ASCO. 2003;22:269. Abstract 1078.
mTOR in neuroendocrine tumors
IGF
Somatostatin
analogue
IGFR/VEGFR
VEGF
PI3K
Nutrient
PKDI
PTEN
Autophagy
AKTcell death
Type 2 program
Rapamycin
analogue
mTOR
TSC1
p53
TSC2
RAD001, CCI-779
Translation
p70S6K
Tuberous sclerosis is
associated with islet
cell carcinoma
mTOR and angiogenesis
Growth factors
Endothelial cell
Smooth muscle cell (pericyte)
Tumor cell
PI3-K
PI3-K
PTEN
PI3-K
Akt
Akt
Akt
TSC1/TSC2
mTOR
mTOR
mTOR
Protein production
VHL
HIF-1a
Angiogenic
growth factors
Cell growth and proliferation
Angiogenesis
mTOR inhibition
Anti-NET activity via HIF-1a suppression





mTOR regulates HIF-1α and
HIF-2α expression
HIF-1 and HIF-2 are
transcription factors for
hypoxic stress-related genes
HIF-1α/2α are normally
degraded by VHL protein
HIF-1 and HIF-2 condition
the tumor to adapt to
growth under hypoxic
conditions and promote
angiogenesis and metastasis
In pancreatic NET, HIFs may
contribute to tumor growth
through mechanisms
unrelated to VEGF
HIF = hypoxia-inducible factor; VHL = von Hippel-Lindau
Preliminary Results of a Phase 2 study with
RAD001 and Octreotide LAR in patients with
advanced NET (SMSUS52)

Single-arm phase 2
Metastatic or unresectable well-differentiated NET
No prior chemotherapy

5 mg: safe and active dose for phase 2 studies


Week
0
RAD001 5 mg PO daily
4
8
12
Octreotide LAR 30 mg IM q 28 d
Objectives
• Response (RECIST) and PFS every 12 weeks
• Safety
CT / MRI
*Yao et al. ASCO 2006. Abstract 4042.
Inhibiting NET growth pathways with
combination therapy*
Growth Factors
IGF-1, EGF, TGFα, VEGF,
etc
Octreotide LAR
• Inhibits IGF and VEGF
production†‡
PI3-K
PTEN
Oxygen, energy,
and nutrients
Ras/Raf
Akt/PKB
Abl
ER
TSC2 TSC1
RAD001
Ras/Raf
pathway
kinases
• Blocks signaling downstream
of IGF-1, VEGF, and TSC
mTOR
S6K1
4E-BP1
S6
Protein Production
Cell Growth
and Proliferation
Angiogenesis
elF-4E
Efficacy (RECIST):
Phase 2 study in advanced NET
(SMSUS52)
Overall
Carcinoid
Islet Cell
n = 30
No. of Patients (%)
n = 17
n = 13
Partial responses
(PR)
4 (13)
2 (12)
2 (15)
Stable disease (SD)
Progressive disease
(PD)
22 (73)
4 (13)
14 (82)
1 (6)
8 (62)
3 (23)
PFS (24 wk)
64%
*Yao
et al. ASCO 2006. Abstract 4042.
RAD001 in advanced NET:
Waterfall plot
100
Maximum % Reduction in Tumor
Measurement
80
Maximum percent tumor reduction
preliminary data as of ASCO 06
60
40
20
0
-20 1
-40
5
9
13
17
21
25
Patient Num ber
-60
-80
-100
69.7% of patients
29
33
RAD001 Safety:
Phase 2 study in advanced NET
(SMSUS52)

34 patients evaluable for toxicity (CTC v3.0)
– Most frequent AE: mild aphthous ulceration
– Grade 3/4
 Fatigue (n = 3)
 Aphthous ulcers, diarrhea, rash (each n = 2)
 Anemia, thrombocytopenia, neutropenia,
leukocytosis, hyperglycemia, hypoglycemia,
hypokalemia, hypophosphatemia, nausea, pruritus
(each n = 1)
Yao et al. ASCO 2006. Abstract 4042.
Conclusions (I)



Management with either biotherapy and chemotherapy
can be guided by WHO classification in patients with
malignant carcinoid.
Ki-67 proliferation index might be considered as an
additional parameter for choosing between
chemotherapy or biotherapy
Combination chemotherapy with Cisplatin, lederfolin,
fluororuracil represents a valid therapeutic option in
malignant carcinoid, having a good therapeutic index
and favourable toxicity profile
Conclusions (II)

Among targeted therapies, RAD001 may arrest NET
growth by blocking downstream signaling through
IGF-1R, TSC1/2, and mTOR and, in combination with
Octreotide LAR, may act synergistically to arrest NET
growth and alleviate symptoms
Open Questions



A standard chemotherapy is still not in existence
because a small number of patient cases and
consequently a small number of randomized trials
What is the best treatment for Endocrine Pancreatic
Tumors?
How can we select the best method of treatment for
patients in the grey area (Ki-67 2-15%) ?