Pr Olivier Glehen (Lyon - France) presents HIPEC in treatment for colorectal and gastric carcinomatosis. La CHIP dans le traitement des carcinoses péritonéales d'origine colorectale et gastrique.

1. Peritoneal metastases from
colorectal and gastric cancers
Glehen olivier
Surgical Oncology
Hospices Civils de Lyon
Centre Hospitalier Lyon Sud

2. Colorectal
carcinomatosis

3. Is There a Possibility of a Cure in Patients With Colorectal
Peritoneal Carcinomatosis?
Goere et al. Ann Surg 2012
107 patients treated with complete
cytoreductive surgery and
Intraperitoneal Chemotherapy
Follow-up for all patients more than 5
years surgical procedures
16% of patients were considered cured
with 5-year or more of disease-free
interval
YES

4. COLORECTAL PC
Randomized study
Cytoreductive surgery+ HIPEC (MMC)
+ 5FU-Leucovorin
N=48
Colorectal PC
5-FU-Leucovorin
N=44
43% (HIPEC)
2-year survival
16% (control roup)
P=0.001
Verwaal et al. J Clin Oncol 2003, Ann Surg Oncol 2008

5. PERITONEAL
CARCINOMATOSIS
from COLORECTAL CANCER
-Elias et al.
J Clin Oncol 2008
Retrospective study.
Cytoreduction with HIPEC
-48 Cytoreductions + HIPEC (oxaliplatin) versus
48 « modern » systemic chemotherapy alone
-Median follow-up 63 months
-Better results for patients treated with HIPEC
-51% of 5 year survival vs 13% (p0,05)
-Median survival of 62 months vs 24 months

6. PERITONEAL
CARCINOMATOSIS
from COLORECTAL CANCER
-Franko et al.
Cancer 2010
Prospective study.
Cytoreduction with HIPEC
-67 Cytoreductions + HIPEC versus 38
« modern » systemic chemotherapy alone
-Some patients had liver metastasis
-Better results for patients treated with HIPEC
-Median survival of 35 months vs 17 months

7. 2012 : Treatment of Peritoneal carcinomatosis :
When and how to treat ? French national
recommandations
Pseudomyxoma Peritonei.
Peritoneal Mesothelioma.
PC from colorectal, small
bowel adenocarcinoma and
appendiceal cancers.
Patient in good general status
When optimal cytoreductive
surgery (R0 – R1) is achievable.
Strict patient selection.
Experienced multidisciplinary
center.
PC from gastric cancer.
PC from ovarian cancer.
PC from pancreas, bile duct,
gallblader, breast, ….
Highly recommended
Under evaluation
Ongoing trial inclusion
Probably not ???

8. COLORECTAL
CARCINOMATOSIS
Cytoreductive surgery and
intraperitoneal chemotherapy
2222 Registries: national and international
500 patients
1990 - 2007
75 to 86 % : HIPEC
54 to 85% de complete cytoreduction
Mortality: 3 to 4% Morbidity:25 to 30%
Median survival 30 months
5 year survival 30%
J Clin Oncol 2004 and 2010

9. COLORECTAL
CARCINOMATOSIS
2222 Registres: national and international
Identification of 2 principal
prognostic factors
Completeness of cytoreductive
surgery
Extent of carcinomatosis
J Clin Oncol 2004 and 2010
Cytoreductive surgery and
intraperitoneal chemotherapy

10. Colorectal carcinomatosis
Completeness of cytoreductive surgery
CC-0
CC-1
J Clin Oncol 2010
CC-2 ou 3
CC-0

11. Quantitative tool
Peritoneal Cancer Index (Sugarbaker) : PCI
Consensus
Milan 2006
PCI from 0 to 39

12. Colorectal carcinomatosis
CCCCaaaarrrrcccciiiinnnnoooommmmaaaattttoooossssiiiissss EEEExxxxtttteeeennnntttt
CC-0

13. Questions
Is synchronous liver
metastasis a
contraindication for
curative treatment of
carcinomatosis?

14. Survival according to the presence of associated
Liver Metastases (n= 65) (p= NS)

15. Colorectal carcinomatosis
and synchronous liver
metastasis
Liver metastasis does not constitute an
absolute contraindication for curative
approach of carcinomatosis
• Liver metastasis should be controlled by
systemic chemotherapy
• Extensive liver surgery combined to
extensive peritoneal surgery should be
avoided

16. Questions
What about systemic
chemotherapy?

17. Improved efficiency of systemic chemotherapy
for metastatic colorectal cancers
6
12 12
14
15
18 18
21 21
24
25
20
15
10
5
0
BSC Bolus
5FU-LV
Xeloda LV5FU2 IFL Folfox Folfiri Folfox
puis IRI
Folfiri
puis oxali
Bevaciz +
sequentiel
5FU alone Sequentiel
treatment
Combined
treatment
Targeted therapy
Median survival
(months)
0
%
23
%
21
%
36-
59%
34-
56%
60-
72%
45-
72%
Objective
response

18. PC from colorectal origin Palliative systemic
chemotherapy
2095 patients
Median survival
•Patients with PC : 12.7 months
•Patients without PC : 17.6 months

19. French registry colorectal PC
Multivariate analysis
Variable p Relative risk
PCI 0.0001 1.052
CC-Score 0.05 1.398
Lymph node + 0.02 1.534
Adjuvant Chemotherapy 0.002 0.578

20. SYSTEMIC
CHEMOTHERAPY
PERITONEAL
CARCINOMATOSIS
from COLORECTAL CANCER
Peritoneal carcinomatosis has a different natural
history and response to systemic chemotherapy than
liver or lung metastasis
BUT
50 to 75% of patient with peritoneal
carcinomatosis will develop extra-peritoneal
disease
Role of adjuvant systemic chemotherapy into registries
Systemic chemotherapy should be considered
as one important tool in the multidisciplinary
management of PC

21. Unresolved Questions
Systemic chemotherapy
should be used before,
after, both ?

22. P = 0.042
Ann Surg 2012
120 patients

23. Patients with progressive but resectable disease
had median survival more than 30 months
P = NS
Ann Surg 2012

24. Colorectal carcinomatosis and
neoadjuvant chemotherapy
Progression with neoadjuvant systemic
chemotherapy does not constitute an
absolute contraindication for curative
approach of carcinomatosis
• Median survival more of 30 months may be
obtained
The use of neoadjuvant systemic
chemotherapy is important to exclude
patients who will develop extraperitoneal
disease
Ann Surg 2012

25. Unresolved Questions
What is the exact role of
HIPEC into therapeutic
management ?

26. There was not significant difference
between:
Median OS ox alone 41 months,
(95%CI 29–61)
Median OS ox-iri 47 months, (95%CI
32-61)
(p=0.94)
What is the specific role of HIPEC ?

27. PRODIGE 7 (F Quenet)
RANDOMIZED FRENCH STUDY
Colorectal carcinomatosis
Complete cytoreductive
No HIPEC
surgery
RANDOMIZATION
HIPEC oxaliplatin
Perioperative systemic
chemotherapy for 6 months
RANDOMIZATION

28. Prevention
Interest of 2nd look for
patients at risk of
carcinomatosis
development?

29. From 1999 to 2009, 47 patients with a high risk to develop a PC
(without clinical, radiologic or biologic symptoms), underwent a
second look, 12 months after their first surgery.
Selected: 3 groups of high-risk patients:
• Minimal macroscopic PC completely resected
• Ovarian metastases,
• Perforation of primary tumour.
All these patients received the adjuvant standard treatment after the
first surgery: 6 months of systemic chemotherapy (Folfox or Folfiri)
50% of patients had carcinomatosis
HIPEC was an the only independant
prognostic factor

30. French randomized multicentric study
(Prophylochip)
Patients at risk of carcinomatosis
development
(Perforated tumors, localized carcinomatosis
removed, isolated ovarian metastasis)
Adjuvant FOLFOX (6 months)
or systemic chemotherapy
(Negative workshop)
Randomization 8 months
Follow-up
2nd look and
prophylactic HIPEC

31. Gastric
carcinomatosis
Results

32. Overall survival according to etiology
Cancer 2010

33. Feb. 1989 – Aug. 2007
159 patients
15 centers
M: 83 F: 76
Mean age 53,4 ± 12,8
PC Synchronous : 44%
PC Metachronous : 66%

34. Gastric carcinomatosis AFC
Intraperitoneal chemotherapy
HIPEC : 154 cases (94%)
• Closed abdomen :
142 cases (54%)
• Open abdomen : 46%
EPIC : 12 cases (7,5%)
Mitomycin C : 83%

35. Gastric carcinomatosis AFC
Mortality-Morbidity
Mortality: 10 cases (6,5%)
Morbidity grade 3-4: 38 cases
(27,8%)
• Digestive fistula : 16%
• Reoperation: 14%
• Mean post-operative stay :
24,2±19 days
1344 procedures
Mortality : 4,1%
Morbidity gr. 3-4:
33,8%
• Dig. fistula : 9,6%
• Reoperation: 14%
• Mean post-operative
stay :
24,1±18 days

36. Gastric carcinomatosis
Prognostic factors
Institutions
P0,001

37. Gastric carcinomatosis
Prognostic factors
Treatment with neoadjuvant systemic
chemotherapy
P=0,018

38. Gastric carcinomatosis
Prognostic factors
Completeness of cytoreductive surgery
Patients CC-0:
•Median 15 months
•5 year
survival:25%
Patients CC-2 or 3
•Median 4 months
•2 years
survival:0%
P0,001

39. Gastric carcinomatosis
Prognostic factors
Influence of disease extension in patients
treated by complete cytoreductive surgery
No patient alive at
2 years for PCI
13
No patient alive at
1 year for PCI 19
P=0,038

40. PHASE III STUDY in Gastric Cancer
Yang et al. Ann Surg Oncol 2011
Gastric Carcinomatosis
Cytoreductive
surgery
RANDOMISATION
Cytoreductive surgery
+ HIPEC with CDDP
and MMC
Systemic chemotherapy ??
Perioperative or adjuvant??
RANDOMISATION

41. PHASE III STUDY in Gastric Cancer
Yang et al. Ann Surg Oncol 2011
HIPEC did not improve mortality and
morbidity rates

42. PHASE III STUDY in Gastric Cancer
Yang et al. Ann Surg Oncol 2011
HIPEC improved survival (p=0.046)
Synchronous PC++

43. Conclusions
Cytoreductive surgery and HIPEC are the only
way to obtain long-term survivors
5-year survival rates of 20% may be obtained
into expert centers
Strict selection necessary

44. Conclusions
Which patients?
• Patients with perfect general status ( 70
years)
High Mortality et Morbidity rates
Quality of life ++++
• Complete cytoreductive surgery
Strongest prognotic factor
• Limited PC (PCI 19 ou 12)
LIMITED NUMBER OF PATIENTS

45. Conclusions
How to improve selection?
• Neoadjuvant systemic chemotherapy
Gold standard in Europe
Exclusion of patients with metastatic progression
• Neoadjuvant intraperitoneal chemotherapy

46. Neoadjuvant intraperitoneal systemic
chemotherapy (NIPS) Yonemura

47. Neoadjuvant intraperitoneal systemic
chemotherapy (NIPS) Yonemura
Increases the rate complete cytoreductive surgery by increasing downstaging
Phase I-II in Europe

48. Conclusions
How to improve
selection?
• Laparoscopy as soon as
possible +++++
Exclusion of patients diffuse
disease
Diagnosis of limited PC

49. Gastric cancers and preventive
management
Recurrences following curative
treatment
Recurrences 50%
• 1/3 of peritoneal carcinomatosis
• 1/3 of locoregional recurrence
CANCER that HAVE THE MOST IMPORTANT
RATE of LOCOREGIONAL RELAPSE
Yoo Br J Surg 2000

50. Peritoneal recurrence and
gastric cancer
Factors associated with peritoneal
recurrence
• Linitis or poorly differentiated tumors
(independant cancer cells)
• Lymph node involvement
• Serosal involvement
• Positive cytology+++
Maehara Br J surg 2000
Ceelen Br J Surg 2000
Bonenkamp N Engl J Med 1999
Honore Eur J Surg Oncol 2013

51. Meta-analysis of postoperative intraperitoneal
chemotherapy in gastric cancer
Yan et al Ann Sug Oncol 2007

52. GASTRICHIP (PHRC 2012)
Randomized multicentric phase III
Gastric adenocarcinoma T3-T4 and/or
N+ and/or cyto + (laparoscopy and ultrasound
Peroperative systemic
chemotherapy recommended
Curative gastrectomy
Peroperative
RANDOMIZATION
endoscopy)
Curative gastrectomy +
HIPEC oxaliplatin
Postoperative adjuvant treatment
Peroperative
RANDOMIZATION
Indication of curative gastrectomy
Inform consent

53. Take Home Messages
•Cytoreduction and HIPEC should be considered for many colorectal
PC and some gastric PC
•The 2 most important prognostic factors are
COMPLETENESS OF CYTOREDUCTIVE SURGERY
PCI
•Multidisciplinary management including systemic chemotherapy is
very important and should be more evaluated
•HIPEC for prevention and prophylactic approach should be
considered