Download C t d ti S l HIPEC Cytoreductive Surgery plus HIPEC for Peritoneal

C t
Cytoreductive
d ti Surgery
S
plus
l HIPEC
for Peritoneal Tumors
Diane Goéré, MD, PhD
Department of Surgical Oncology
Gustave Roussy Institute
University Paris XI
Villejuif - France
 Since 1990s
 New concept : CRS + HIPEC
complete CytoReductive Surgery followed by
Hyperthermic IntraPeritoneal Chemotherapy
 Indications (Consensus Milan 2006)




Carcinomatosis from colorectal cancer
Peritoneal pseudomyxoma
Carcinomatosis from appendix carcinoma
Peritoneal mesothelioma
2
Cytoreductive Surgery
plus HIPEC
HIPEC : The Concept
Treat all the macroscopic disease => SURGERY
+
Treat the microscopic disease => IP CHEMOTHERAPY
+
Potentiate local action => HYPERTHERMIA
Surgery to treat all the MACROscopic disease
- Exploration of all the abdominal cavity
- Determination of the Peritoneal Cancer Index (PCI)
- Resection or destruction of all the invaded areas
Complete cytoreductive surgery R0/R1
Extent of the peritoneal disease
Peritoneal cancer index
13 areas
score LS : 0 to 3 attributed to each area
LS1 : 0 à 5 mm
LS2 : 5 mm à 5 cm
LS3 : > 5 cm
Max = 39
IP CHEMOTHERAPY to treat all the MICROscopic disease
• Tissue penetration by diffusion and convection
• Accumulation of the drug
g into tumor cells
• Peritoneal concentrations much higher than plasma concentrations
Ceelen et al. Nature Reviews 2010
IP CHEMOTHERAPY to treat all the MICROscopic disease
Penetration of the drug into
tumor is very low, from a few
cell
ll layers
l
to
t 5 mm
 We need a COMPLETE resection =
Maximal residual volume = 1
1-2
2 mm
Ceelen et al. Nature Reviews 2010
Which type of IP CHEMOTHERAPY
 Mitomycin
 Oxaliplatin IP + 5FU IV
 High
g local concentration of oxaliplatin
p
Progressive doses of oxaliplatin
X 17,8
Elias et al. Ann Oncol 2002
HYPERTHERMIA to potentiate the local action
- cytotoxicity of cytostatic agents
- blood flow and oxygenation => increases chemosensitivity
- drug penetration into the tumors
 Temperature
p
between 42 and 43°C
The Procedure
- After complete resection of the disease (<2 mm)
- Open abdominal procedure or Closed
-
At least 30 min at 42°C
42 C in open procedure
-
Up to 90 min at 41°C in closed procedure
Elias et al. Chirurgie 1999
Elias et al. Int J Surg Invest 2000
Closed or Open Procedure
No randomized study
French Surgical Society: 1154 patients
Type of procedure was not an independant prognostic factor
Glehen et al. Cancer 2010
The Procedure in Gustave Roussy
- After complete resection of the disease (<2 mm)
- Open abdominal procedure (Coliseum)
- Closed circuit, heated liquid (2L / m²)
- For 30 min
- At 42-44°C, with a permanent thermal control
Elias et al. Chirurgie 1999
Elias et al. Int J Surg Invest 2000
The Procedure
The Procedure
-2 drains for instillation
-2 drains for aspiration
-Thermal control
Postoperative complications
Predictive factors
age
PCI
Centre
Centre
Mortality: 3,9%
3 9%
Morbidity: 31%
Glehen et al.Cancer 2010
Elias et al. Ann Surg 2010
Quality of life
1993-2005
1993
2005
210 pts with HIPEC
68 pts evaluables
Good
G
d quality
lit off lif
life iin 2/3 off th
the
pts
Depressive symptoms
comparable to patients treated
for cancer
Zenasni et al Support Care Center 2003
Cytoreductive Surgery plus HIPEC
for Peritoneal Carcinomatosis
from Colorectal Cancer
Metastases from Colorectal Cancer
537 patients
5-y recurrence rates « early stage » : 9.5%
« late stage » : 35.7%
Stage I and IIa
Stage IIb and III
Peritoneal Carcinomatosis
Tzikitis et a l. J Clin Oncol 2009
Pathogenesis
( ) Detachment of cancer cells
(A)
(B) Adhesion to mesothelial cells
(C) Invasion into the surrounding stroma
=> Peritoneal dissemination is a form of local rather
than systemic spread in which several biomarkers
could p
play
y a role
Ceelen and Brake Lancet Oncol 2009
Prognosis
2 randomized studies compiled (phase III trials N9741 and N9841)
Stage
g IV pts
p : systemic
y
chemo (Folfox
(
or Folfiri))
2095 pts
t
364 PC +
OS
PFS
12.7 m
58m
5.8
Franko et al. J Clin Oncol 2012
Prognosis
2 randomized studies compiled (phase III trials N9741 and N9841)
Stage
g IV pts
p : systemic
y
chemo (Folfox
(
or Folfiri))
2095 pts
t
P<0.001
364 PC +
OS
PFS
12.7
58
5.8
1731 PC 17.6 m
72m
7.2
Franko et al. J Clin Oncol 2012
Prognosis
125 pts with synchronous PC
24 pts (25%) with PC only underwent R0/R1 resection
R0/R1
Median Survival 25 m
OS 5y 22%
Muslow et al. Br J Surg 2011
Prognosis
31 pts complete resection without IP chemo
122 pts
t incomplete
i
l t resection
ti
5 y OS
36%
0 ((p<.001)
001)
Peritoneal recurrence after R1/R2 : 26%
Matsuda et al. Surgery 2012
A randomized study
5FU – Leucovorin
Surgery + HIPEC > Systemic chemotherapy
Verwall et al. J Clin Oncol, 2003; Ann Surg 2008
A comparative study
48 pts Complete Surgery
R0/R1 + HIPEC
Compared to
48 p
pts Folfox or Folfiri
(HIPEC potentially feasible
But not performed for logistic
reasons)
Elias et al. J Clin Oncol 2008
A comparative study
HIPEC
Chemo IV
81%
Chemo IV
24 m
R0/1 + HIPEC
63 m
OSS(%)
Median OS
p<0,05
51%
65%
13%
Effecti
fs:
CHIP
Standa
rd
Years
Surgery + HIPEC > Systemic chemotherapy
Elias et al. J Clin Oncol 2008
Survivals
> 32 m
30 40%
30-40%
Cotte et al. Cancer Journal 2009
Completeness of resection
N=506 pts (28 institutions, 1987-2002)
Total
Median Survivals (m)
19.2
« Complete » Surg «Incomplete
Incomplete » Surg
32.4
8.4
p<0.001
Glehen et al, J Clin Oncol 2004
Completeness of resection
R2b = Median survival 5m
>2.5mm
>2
5mm => Survival LOWER to that with systemic chemo
=> No HIPEC in case of macroscopic residual disease > 2 mm
Verwaal et al. J Clin Oncol 2003
Extent of the peritoneal disease
N= 440 pts (23 institutions
institutions, 1989-2007)
Complete cytoreductive surgery (R1) + HIPEC
PCI
Elias et al, Ann Surg 2010
Is there a possibility of cure?
Selection from a prospective data base:
•Patients with CCR carcinomatosis
•Macroscopic complete resection + intraperitoneal chemo
•Follow-up of at least 5 years
Patients excluded:
•Postoperative death,
•non cancer-related deaths,
•a follow-up
p < 5 years
y
since the last curative treatment
Patients were considered cured
if the disease-free survival interval lasted at least 5 years
after the treatment of carcinomatosis or its last recurrence
Goéré et al. , Ann Surg 2013
Jan 1995 to Dec 2005
C
Cure
rate
t = 16% off th
the patients
ti t
Multivariate analysis
=> We need to diagnose and treat PC at an early stage
Is there a possibility of cure?
Actual 10 years
102/612 pts =16
=16.6%
6%
After a minimal DFS of 5 y
24/148 p
pts =16.2%
The cure rate of 16% after complete cytoreductive surgery
of CCR carcinomatosis followed by intraperitoneal
chemotherapy, in selected patients, is close to that
obtained after resection of colorectal liver metastases
Prognostic Similarities and Differences in Optimally Resected Liver Metastases
and Peritoneal Metastases From Colorectal Cancers
287 p
pts with liver mets
119 pts with PC
72%
Curative treatment
Median FU 62 months
39%
12%
LM
PC
18%
5y- OS
38.5%
36 6%
36.6%
Elias et al. Ann Surg 2014
Summary
Curative treatment of PC from colorectal cancer is
based on complete cytoreductive surgery, without any
residual
id l disease
di
measuring
i
more than
th 2mm,
2
followed
f ll
d
by HIPEC, either open or closed abdominal procedure,
with mitomycin or oxaliplatin.
The 2 main prognostic factors are the extent of disease
disease,
evaluated with the PCI, and the completness of
resection.
ti
Summary
A complete cytoreductive surgery followed by HIPEC for
colorectal peritoneal carcinomatosis can provide longt
term
survival.
i l
The 5-year
y
survival is about 40%,
%, which is much g
greater
than that obtained with systemic chemotherapy alone.
But, these results are obtained only after strigent
selection of the patients, and after complete resection
of the PC.
Selection of the patients

Age < 70 y

Performance status 0-1

No major
j debulking
g surgery,
g y PCI < 20-25

Disease under control with systemic chemotherapy

N extra-abdominal
No
t
bd i l metastases
t t
Contraindications to HIPEC
R id l disease
Residual
di
> 2 mm
PCI > 20
20-25
25
=
HIPEC
Contraindications to HIPEC
1.
Retroperitoneal lymph nodes invaded
2.
Extended liver metastases (>3)
3.
Massive involvement of the small intestine
4
4.
IInvolvement
l
t off the
th bl
bladder
dd requiring
ii
complete cystectomy
Future : Increase survival
1. Low morbidity and mortality
-
Respective roles of surgery and HIPEC (Prodige 7 trial)
-
Selection of the patients
2. Low rate of recurrences
-
-
Increase local effect
New intraperitoneal treatment?
Associations with systemic chemo?
Selection of the patients
p
Adjuvant chemotherapy
3 Treat
3.
T t Early
E l = make
k the
th diagnosis
di
i earlier
li
Treat earlier to increase survival
1. Completeness
p
of resection
2. Extent of the disease
=> Need to diagnose at an early stage
Diagnosis of PC
1. Few symptoms
• obstruction
• ascitis
2. Biology : none
3. Imaging
Pfannerberg Ann Surg Oncol 2009
=>Diagnosis at an advanced stage
A new Strategy : 2nd look surgery
- Laparotomy : complete exploration
- Diagnosis and early treatment
- Decrease morbidity and mortality
But, aggressive and costly treatment
=> For p
patients at high
g risk of peritoneal
p
carcinomatosis
55%
45%
Patients at high risk of PC
1. Peritoneal carcinomatosis synchronous to primary
2. Ovarian
O
metastasis
3. Perforated cancer (spontaneous or iatrogenic perforation)
4. pT4 tumors
5. Obstructed cancer
6. Positive lateral margins of excision
7. Adjacent organ involvement or cancer-induced fistula
8. Bleeding cancer
9. p
pT3 mucinous cancer and pT3
p signet
g
ring
g cell cancer
10.Positive cytology either before or after cancer resection
Honoré et al. Ann Surg Oncol 2012
Patients at high risk of PC
1. Peritoneal carcinomatosis synchronous to primary
> 30%
2. Ovarian
O
metastasis
3. Perforated cancer
4. pT4 tumors
5. Obstructed cancer
6. Positive lateral margins of excision
7. Adjacent organ involvement or cancer-induced fistula
8. Bleeding cancer
9. p
pT3 mucinous cancer and pT3
p signet
g
ring
g cell cancer
10.Positive cytology either before or after cancer resection
Honoré et al. Ann Surg Oncol 2012
2nd look Surgery
Resection R0 of the primary « at high risk »
Adjuvant chemotherapy for 6 months
No evidence of recurrence
•Symptoms
•Serosal tumoral markers
•Imaging
2nd look surgery 6 months after
Complete exploration of all the abdomen
Followed by systematic HIPEC
open technique 42-44°C, 30 minutes
Oxaliplatine + irinotecan IP
5-FU + Folinic acid IV
Elias, Goéré et al. Ann Surg 2011
High risk and 2nd look Surgery
1999 and 2009
41 patients
Systematic second-look surgery
Diagnosis of PC : 56%
Mean PCI : 8 ± 6
Total
N= 41
Minime PC
resected with
primary
(n=25)
Ovarian mets
(n=8)
Perforated
tumor (n=8)
PC at 2nd look
23 (56%)
15 (60%)
5 (62%)
3 (37%)
Mean PCI
8±6
9±6
7±5
5±2
Elias et al. Ann Surg 2011
2nd look Strategy
•Mortality
Mortality : 2% (1/41)
•Morbidity (grade > 2) : 9,7% (4/41)
•Peritoneal recurrence : 7 p
patients (17%)
(
)
-6 (26%) pts in the group of with PC at 2nd look, associated
to recurrence elsewhere in 5/6 pts
-1 in the group without PC at 2nd look (6%), p= 0.006
2nd look Strategy
Median follow-up : 30 [9-109] months
Median Survival : not attained
1,00
0,90
0,80
0,70
0,60
0,50
0,40
0,30
0,20
0 10
0,10
0,00
5-y 90%
OS 90%
5-y
44%
DFS 44%
Overall survival
Disease free survival
0
10
20
30
41
31
34
50
60
70
M onths
Patients at risk
41
40
24
15
19
11
18
8
12
6
11
9
4
4
2nd look Strategy
Selection criteria for high-risk patients :
• Peritoneal carcinomatosis synchronous to primary
•
Ovarian metastasis
• Perforated cancer
appear to be accurate.
In these patients, the second-look strategy treated peritoneal
carcinomatosis preventively or at an early stage, yielding
promising results.
results
y has allowed us to design
g a multicentric randomized
This study
trial (comparing the second-look + HIPEC approach to
standard follow-up alone) which is actually opened.
ProphyloCHIP Trial (NCT01226394)
•Every
E
3 months
th for
f
2y
•Then every 6 months
phase III, multicentric
1st EP : 3y RFS
130 pts
t
•Minimal PC resected
•Ovarian Metastases
•Perforated
Adjuvant Chemo
•Folfox ou xelox
•± targeted
therapies
No sign of
recurrence
Ran
ndomisattion
High risk patients
Monitoring alone
•No symptom
•Seroral timor marker Neg
•CTscan Neg
Surgery + HIPEC
•Every 3 months for
2y
•Then every
y 6 months
Surgery for Primary
6 months
< 1 month 2 months max
Conclusion
Results
R
l off complete
l
cytoreductive
d i surgery plus
l
HIPEC used to treat colorectal peritoneal carcinomatosis
are the same as those obtained with hepatectomy for
liver metastases in selected patients; with an overall 5
year survival rate approximating 40%.
Therefore, complete surgery plus HIPEC should be
considered as the standard treatment of colorectal
peritoneal carcinomatosis.
Cytoreductive
C
t
d ti Surgery
S
plus
l
HIPEC in the treatment of
P
Pseudomyxoma
d
Peritonei
P it
i
Peritoneal pseudomyxoma
Incidence : 1 to 2 /million/year
y
From appendix in most of the cases
Result of the appendicular
perforation (full of mucus) and of the
seeding
di
off tumor
t
cells
ll
Diffuse intra-abdominal gelatinous
collections with mucinous implants
on peritoneal surfaces (« jellybelly »)
Pathological Classification
Pathological classification OMS 2010
•Low grade
•High grade
Transition from benign disease to malignacy
Low g
grade : dessiminated adenomucinosis (DPAM)
(
)
Mucin Without cellular atypia
Pathological Classification
High
Hi
h grade
d : peritoneal
it
l mucinous
i
carcinomatosis
i
t i (PMCA)
Mucus and Cellular atypia
adenocarcinoma
Sub diaphragmatic resection
Survival after « debulking » surgery
55 patients
1957-1983
Macroscopic complete
resection : 34%
Tumor progression 76%
5 year survival 53%
5-year
10-year survival 32%
Gough et al. Ann Surg 2001
Survival after complete surgery + HIPEC
2298 patients
From 16 specialized units
Chua et al. J Clin Oncol 2012
Survival after complete surgery + HIPEC
Cytoreductive surgery + intraperitoneal chemotherapy
CC0/1 : 83%
HIPEC : 89%
Postoperative mortality 2%
Major complications 24%
Chua et al. J Clin Oncol 2012
Survival after complete surgery + HIPEC
Median survival : 98 months (8.2 years)
10 and 15 y survivals : 63% and 59%
Chua et al. J Clin Oncol 2012
Conclusion HIPEC and Pseudomyxoma
Complete cytoreductive surgery plus HIPEC to treat
pseudomyxoma leads to prolong survival, far much
than after debulking surgery.
Therefore, complete surgery plus HIPEC should be
considered as the standard treatment of pseudomyxoma
p
y
in selected patients.
Thank you