Aucun titre de diapositive

1
Treatment of liver metastases of digestive
endocrine tumors
G Cadiot
Reims
Beyrouth, 2005
2
Main prognostic  clinical  factors of
metastatic digestive endocrine tumors
3
Survival according to differentiation
Madeira et al. Gut 199843422-7
4
Survival according to the growth of liver
metastases
100
No growth
80
P0.063
60
Survival ()
40
Increase in size/number
20
0
0
50
100
150
200
250
months
M Mignon et al
5
Survival of metastatic endocrine tumors according
to the primary pancreas vs ileum
Ileum
Survival
Pancreas
years
Johanson et al. Br J Cancer 1999801259-61
6
Bone metastases survival
100
80
60
Survival ()
40
20
0
0
10
20
30
40
months
15
M Mignon et al
7
Pretherapeutic assessment

• Histological classification WHO 2000
  differenciation, proliferation
• Imaging CT-scan, MRI
• Octreoscan imaging of new hot spots
• Chromogranin A and/or specific biological marker
• Cardiac US carcinoid syndrome or high 5-HIAA

8
WHO 2000 histological classificationfor
pancreatic tumor

• Well-differentiated endocrine tumor
• Benign behaviour lt 2 cm, lt 2 mitoses/10 HPF et
  lt 2 Ki67
• Uncertain behaviour 1 above criteria missing or
  vascular invasion ou functioning not insulinoma
• Well-differentiated endocrine carcinoma (low
  grade malignant)
• Gross local invasion and/or metastases
• (often cellular atypia, 2-10 mitoses, Ki67 gt 5,
  gt 3 cm)
• Poorly-differentiated endocrine carcinoma (high
  grade malignant)
• Often necrosis, gt 10 mitoses, Ki67 gt 15, p53

9
Well-differentiated endocrine carcinoma with high
proliferation index Survival
1
Well-differentiated EC MiB lt 10
,8
(plt0.001)
Well-differentiated EC MiB 10
,6
,4
Poorly-differentiated EC
,2
0
0
20
40
60
80
100
120
140
Time (months)
O Hentic et al. JFPD 2005
10
Treatment

• Multidisciplinary
• Treatment of symptoms
• Antitumoral treatment

11
Treatment of symptoms

• Reference
• ZES proton pump inhibitors
• Insulinoma glucose, diazoxide
• Carcinoid syndrome, symptomatic VIPoma or
  glucagonoma somatostatin analogs adaptation of
  dosage to symptoms
• Symptomatic effect of antitumoral therapies

12
General rules of antitumoral treatment
Differentiation WHO 2000
Poorly-differentiated carcinoma
Well-differentiated carcinoma
No surgery Chemotherapy
13
Poorly-differentiated endocrine carcinoma
Etoposide cisplatin
14
Irinotecan cisplatin ?

• Lung (small-cell lung carcinoma)
• irinotecan cisplatin gt etoposide cisplatin
• Hou et al (ASCO 2003) 43 partial responses (14
  patients)
• Trial in project in Fédération Francophone de
  Cancérologie Digestive (FFCD)

15
General rules of antitumoral treatment
Differentiation WHO 2000
Poorly-differentiated carcinoma
Well-differentiated carcinoma
Is tumor resection/destruction possible ?
16
Surgical resection of liver metastases
17
Recurrence after surgical resection of liver mets
Recurrence ()
Years after resection
Sarmiento et al. J Am Coll Surg 200319729-37
18
Survival after resection of liver metastases
 Carcinoid tumors 
Survival ()
Pancreas
Years after resection
Sarmiento et al. J Am Coll Surg 200319729-37
19
Radiofrequency
laparoscopic surgery percutaneous ou
peroperative
20
General rules of antitumoral treatment
Well-differentiated carcinoma
Is resection possible ?
Yes surgery
No Growth evaluation
No growth surveillance
Growth treatment

•  Pancreatic  tumors
• Intestinal tumors

21
Reference therapies Well-differentiated endocrine
carcinoma

• Pancreas
• Doxorubicin-streptozotocin
• If CI 5-FU streptozotocin or chemoembolization
• Trial Avastin (Bevacizumab anti-VEGF)
• Intestine
• Chemoembolization
• 5 FU-streptozotocin ?
• Trial Avastin

22
Well-differentiated endocrine carcinoma of the
duodeno-pancreas Reference therapy
doxorubicin-streptozotocin
23
Chemotherapy of non-pancreatic endocrine
well-differentiated carcinomas 5 FU-streptozotocin

• Reference for chemotherapy
• Not the reference therapy
• Objective responses15-30

24
Chemoembolization
Author Type, n OR () Duration
(months) Cl
ouse, 94 Carc/pancr, 30 78 6-9 Kim,
99 Carc, 16 50 17
Pancr, 14 71 24 Dominguez,
00 Carc, 8 50 13 P
ancr, 7 57 7 Roche,
04 Non-pancr, 49 74 18
Pancr, 15 73
25
Chemoembolization Effects on carcinoid syndrome
26
Other treatments

• Embolization
• Alone
• iv chemotherapy
• Other chemotherapies
• Dacarbazine alone
• Dacarbazine 5-FU epirubicin
• Continuous 5-FU
• Oxaliplatin capecitabin
• Biotherapies
• Chemotherapies biotherapies

27
Interferon Experience from Sweden
n OR MR/Stab Biochem OR Survival resp. durati
on Carc 111 15 66 42 34 mos 80
mos Pancr 57 12 24 51 20 mos -
IFN a2b or natural 5-6 MU x 3-5/week
28
Somatostatin analogs Antitumoral effect
Type n OR Stab Stab () () duration Arnol
d Oct 52 0 37 18 mos Saltz Oct 34 0 50 5 mos Di
Bartolomeo Oct 58 3 47 gt 6
mos Aparicio Oct/Lan 35 3 57 11
mos Ducreux Lan 39 5 49 10 mos NIH Oct 15 6 47 2
5 mos
29
Antitumoral effect of somatostatin analogues as a
function of the rate of tumoral growth
100
76
80

60
33
40
20
0
gt 50
lt 50
Increase in tumoral surface in 3 months
Aparicio. Eur J Cancer 2001
30
Lanreotide vs IFN vs association

6
0
5
0
4
0
Lanreotide
3
0
I
F
N
A
s
s
o
c
i
a
t
i
o
n
2
0
12 months
1
0
0
STOP
R
P
S
D
P
R
O
G
Different type of progressive endocrine tumors,
first line, n80
Faiss et al. J Clin Oncol 2003211289-96
31
Unresolved questions

• Well-differentiated carcinomas with high
  proliferation index ?
• Low growth rate somatostatin analogues ?
• Treatment of extra-hepatic metastases
• Second line therapies ?
• Indications/results of radionuclide therapy ?
• Indications of liver transplantation ?

32
Liver transplantation Analysis of 103 cases
N bad 5-year survival Median prognostic
() survival factors (mos) 2 0 7 1 30 24 0
65 gt 96
age gt 50 years, extensive resection of the
primary
Th. Lehnert. Transplantation 1998661307-12
33
Radionuclide therapy
Waldherr et al. Ann Oncol 200112941-5 Kwekkeboom
et al. J Clin Oncol 2005232754-62
34
Perspectives

• New drugs anti-VEGF
• Take into account biological prognostic markers
• Published recommandations SNFGE, FFCD

35
Traitement séquentiel
Occlusion artérielle hépatique chirurgicale ou
par embolisation chimio séquentielle adria
DTIC et 5 FU STZ
n RO Durée RO Survie Pancréas Occlusion 17 43 3
,6 mois 9 mois Occl chimio 29 78 20 mois 35
mois  Carcinoïdes  Occlusion 23 56 6,6 mois 27
mois Occl chimio 42 75 19,8 mois 49 mois
Moertel et al. Ann Intern Med 1994120302-9
36
Liver metastases
Iliac metastasis
R Lebtahi, Bichat