Present and Future of
Hyperthermic intraperitoneal
chemo (HIPEC) in Colorectal
Peritoneal Metastases
Dominique ELIAS
Cancer Campus, Grand-Paris
Stages IV treated with Chemo: PC have a
poorer prognosis than other sites
From the phase III trials N9741 and N9841 (Folfox / Folfiri)
Without PC
Nb
Median OS
1731
17.6 months
p< 0.01
With PC
Conclusion:
364
12.7 months
- Shorter OS and DFS when PC
- 5-y survival with Folfox (all pts: 4%)
(Franko J et al. ASCO 2011)
Is it possible to obtain definitive
cure with CCRS + HIPEC ?
(Goéré et al. Ann Surg 2013, on line)
•Prospective study of our patients treated between January 1995
and December 2005 (n=93).
•Learning curve = worst results.
The Cure = no recurrence during a minimal
delay of 5 years



Median follow-up: 99 months
Median Survival : 34 months
Overall 5-year survival : 32%
1.00
0.90
0.80
0.70
0.60
0.50
0.40
0.30
0.20
0.10
0.00
Overall Survival
Disease-free
Survival
0
Absolute cure at 5
years:17/107 pts = 16%
12 24 36 48 60 72 84 96 108 120
Months
At risk
93
93
89
49
64
24
41
16
33
16
27
14
15
10
8
7
5
4
2
3
1
2
At 10 years:
102/612 pts =16,7%
At 5 years without rec.
24/148 pts =16%
At last……
1)
Hepatectomy for PM or HIPEC for PM:
overall survival and definitive cure rates are
the same.
2)
Peritoneum can be considered as an
organ, a site of metastasis, similarly to the
liver .
Current survival rate of 146 colorectal PC
treated with CCRS + HIPEC:
Prospective bi-centric study (Paris/ Montpellier)
Median survival:
41 months
5-year
survival:
48%
(Quenet, Elias et al, Ann Surg 2011; 254: 294-301)
Is there a benefit to use
surgery alone ?
Surgery versus No Surgery

Is there a trial comparing ?
Surgery
Similar patients
®
No Surgery

Answer is: NO
Complete resection alone of PC ?
Nb
Mulsow 2011
Selection
Median OS
5-Y Survival
31
IP <10
25 months
22%
57
+ SPIC*
25 months
18%
30
IP <10
30 months
25%
(Erlangen)
Cashin 2012
(Uppsala)
Evrard 2012
(Bordeaux)
*SPIC = Sequential postop. intraperitoneal chemo.
Retrospective comparative study
In the control group: 3.4 lines of chemo
Median survivals: 25 months vs 60 months
C H IP
D ifférence entre les
m oyennes de surv ie
restreinte
C him io
(Elias et al. J Clin Oncol 2009; 27:681-5)
Conclusion:



No clear difference between resection and no
resection.
When it is possible to easily resect the PC: probably
it is useful for the patient.
If you do it, median survival will be at least 25-30
months.
Who is it interesting to
resect, and how to resect ?
French registry: 523 colorectal PC treated with
cytoreductive surgery + intraperitoneal chemo
treated in 23 centres.






Multicentric retrospective study (15 years),
Including the leaning curves of all the centres = the
worst results
Complete cytoreductive surgery (CC0) in 85% of the
cases
Postoperative deaths: 3%
Morbidity (grade 3-4): 30%
Mean hospital staying: 22,5 days
(Elias et al. J Clin Oncol 2009; 27: 681-685)
Overall Survival of the 523 patients
Median survival: 30 months
5-years survival: 27%
Survival according to the Radicality
of the Surgery (p< 0.0001)
Look at the median survivals….
The Peritoneal carcinomatosis
Index (PCI)
(Ranging from 1 to 39)
Survival according to the Extent of the
Péritoneal Carcinomatosis (p< 0.0001)
PC with associated LM ?
IGR’series:
61 HIPEC alone vs 37 HIPEC + LM
(Maggiori L et al. Ann Surg 2013)

Retrospective study issued from a prospective data
base.
Selection of similar patients (61 and 37):
Age, Sex, Status of the primary, PCI (mean was 13),
radicality, systemic chemotherapy.


Except for LM
Mortality: 4%; Morbidity: 54%
Higher Survival rate (p=0.04) when
no LM
Overall Survivals according to the
extent of the disease
PCI<12 without LM : 76 months
PCI<12 + LM <3:
40 months
PCI≥12 or LM ≥3: 27 months
What patients to resect ?

Those with a PCI < 20

Those with a good general status

LM are not a contraindication if resectable
without major risk
Is it useful to add HIPEC ?
Principle of HIPEC:
A combined treatment
1.
2.

Surgery to treat the visible disease (> 1 mm)
HIPEC to treat the remaining non visible disease.
The strong belief of surgeons in the efficacy of
this « package » encourages them to devote a lot
of time and a lot of energy to resect all visible
disease (+++).
Impact of HIPEC alone:
experimental data
60 rats with colorectal PC were randomized in 3 arms.
Hipec: 90 min, close procedure, inflow temperature at 42°C.
CRS
Nb
R2
Med. Surv
P
20
6
43d
CRS + HIPEC
Mito 15 mg/m²
20
4
75d
0.003
CRS + HIPEC
Mito 35 mg/m²
20
4
97d
< 0.001
Conclusion: Efficacy of HIPEC and efficacy of increasing dosage.
(Klaver Y et al. Br J Surg 2010; 97: 1874-80)
Complete surgery (CS) alone
versus CS plus HIPEC ?

We have not yet the answer

French Prodige 7 trial is on going
Complete cytoreductive surgery
®
HIPEC
Oxali, 30 min, 43°C
+5-FU and Leuco IV
No HIPEC
Already 250 randomized patients among the 280…
Equivalence between LM
and PM

287 hepatectomy
119 CCRS+HIPEC
Exclusion of [Hepatec + CCRS-HIPEC] (n=37)

Subgroups according to the global tumor load:


– LM in 2 groups: ≤ 10 LM, and > 10 LM
– PM in 3 groups: PCI 1-5, 6-15, > 15
Same overall global
survival
Overall survival for the 2
gps of LM
Overall Survival for the 3
gps of PM
Equivalence of prognosis
between LM and PM
Application and extension of this therapeutical
concept:
Introduction to the concept of a SecondLook Surgery in patients at high risk of
developing colorectal peritoneal metas. at
the moment of the resection of the primary
(Elias et al. Ann Surg 2008; 247: 445-450)
Rational of the second-look

HIPEC is all the more « light » and all the more
efficient that the PC is minimal. But to detect early
minimal PC is possible neither with clinic neither with imaging.

It is the reason why it is logical to propose a
systematic second-look to asymptomatic patients
presenting high risks to develop a PC, with the aim
to treat PC at an early stage.
Definition of High-risk patients
(Honoré C. et al. Ann Surg Oncol 2013; 20: 183)


Review of the literature
(6522 articles)
No real high-risk:
–
–
–
–
–
–
–
Occlusive tumors
Bleeding tumors
T4
Positive cytology
Positive lymph nodes
Rignet-cell tumors
Mucinous tumors
Risk ≤ 20%

Real high-risk:
- Perforated tumors
- Peritoneal metastases
- Ovarian metastases
Risk between 35% and 80%
Patients et Methods

Patients with a high risk to develop a PC: we selected 3 gps:
– With minimal macroscopic PC (which was completely resected during
surgery)
– With ovarian metastases
– With perforation of their primary tumour


All these patients received the adjuvant standard treatment after the
first surgery: 6 months of systemic chemotherapy (Folfox or Folfiri)
12 months after their first surgery, if a complete work-up
was negative, we proposed a second look + HIPEC
(Elias et al. Ann surg 2011; 254: 289-293)
Results (1)



Between 1999 and 2009
– 41 patients included
– Median follow-up: 30 months
[range: 9-109]
Macroscopic PC at « 2nd look » : 56%
(23/41) (mean PCI 8 + 6)
100% HIPEC
Mortality : 2% (1/41)
Morbidity : 9,7% (4/41)
Results (2)

Minimal synchronous PC resected with the primary tumour
– Peritoneal recurrence rate 60% (15/25)
– Mean PCI : 9±6

Synchronous ovarian metastases resected with the primary
tumour
– Peritoneal recurrence rate 62% (5/8)
– Mean PCI : 7±5

Perforated primary tumour
– Peritoneal recurrence rate 37% (3/8)
– Mean PCI : 5±2
Results (3)
5-y overall survival 90%
1 ,00
0 ,90
0 ,80
0 ,70
0 ,60
5-y disease free survival
44%
0 ,50
0 ,40
0 ,30
O ve rall su rviva l
0 ,20
D ise a se free su rvival
0 ,10
0 ,00
0
10
20
30
40
50
60
70
M o n th s
P a tie n ts a t ris k
41
31
24
19
18
12
11
9
41
34
15
11
8
6
4
4
Peritoneal recurrence : 17% (7/41)
6 after PC at 2nd look (26%)
1 after no PC at 2nd look (6%)
PC at 2nd look = risk factor for Peritoneal recurrence
« ProphyloCHIP » trial (Prodige 15)
« high risk » patients
6 months IV Folfox IV
Negative work-up
Randomization
Standard
arm
Surveillance


Experimental arm
Systematic 2nd
look plus HIPEC
Nb of patients = 130 (75 patients already randomized)
1st endpoint : 3-y Disease Free Survival
Dans la vraie vie: que faire quand vous
découvrez fortuitement une CP ?



L’idéal
L’acceptable
L’innaceptable
Conclusion

The treatment of PC has dramatically changed during the last 10
years.

Now it is possible to definitely cure some PC (like liver metastasis)

The impact of a complete surgery is major (+++).

The impact of HIPEC is not clear enough.

The second-look + HIPEC approach is promising as early treatment
of early peritoneal metastases for high-risk patients.

To progress more rapidly: please, include your patients in trials !
Thank you
Cox regression analysis
Independent factors for poor overall survival :
Overall Survival
Odds-Ratio (95%)
p
4.6 (2.5-8.5)
<0.001
pN+ primary tumour
3.3 (1.3-8.9)
0.016
no postoperative chemotherapy
3.0 (1.5-6.2)
0.002
synchronous resection of PC &
LM
2.0 (1.1-3.7)
0.022
PCI ≥ 12
Cox regression analysis
Independent factors for poor disease-free survival
Disease-free Survival
PCI ≥ 12
synchronous resection of PC &
LM
Odds-Ratio (95%)
p
1.6 (1.01-2.7)
0.048
1.9 (1.2-3.2)
0.007