Pr Olivier Glehen presents HIPEC in colorectal carcinomatosis in Slovenia 2013. Présentation de la CHIP dans la carcinose péritonéale d'origine colorectale.

1. HIPEC in colorectal carcinomatosis
Glehen olivier
Surgical Oncology
Hospices Civils de Lyon
Centre Hospitalier Lyon Sud

2. Management of peritoneal carcinomatosis:
EVOLUTION
Before 1980
PALLIATIVE TREATMENT
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EEEEPPPPIIIICCCC
1995-2000: Cytoreductive surgery,
phase II studies
2000-2011: Registration, randomized study,
Development of expert centers
CURATIVE TREATMENT OF PC

3. Strong rational for locoregional
treatment
Peritoneal PPPeeerrriiitttooonnneeeaaalll ccccaaaarrrrcccciiiinnnnoooommmmaaaattttoooossssiiiissss
LLLLooooccccoooorrrreeeeggggiiiioooonnnnaaaallll ddddiiiisssseeeeaaaasssseeee
Treatment of macroscopic disease
Cytoreductive surgery
Peritonectomy procedures
Treatment of microscopic disease
Intraperitoneal chemotherapy

4. Peritonectomy
procedures

5. Organ resections

6. Rational for Hyperthermic
Intraperitoneal Chemotherapy
1. Pharmacokinetic advantages of
Intraperitoneal Chemotherapy
2. - Cytotoxicity of hyperthermia
(42,5°C)
3. Synergistic effect « Hyperthermia -
chemotherapy »
4. Following surgical procedures
- Avoid « cancer cells entrapment »
- BUT « single shot » treatment

7. Improved efficiency of systemic chemotherapy
fro 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

8. METASTATIC COLORECTAL CANCER Systemic Chemotherapy
Author Year Journal IV Chemoregimen MFS
(mths)
Median
(mths)
Liver/Lung
metastase
PC
Moertel 1989 JCO 5FU LV 6,2 14,7 ?
DeGramont 2000 JCO 5FU LV
OXALIPLATINE
9,0 16,2 91% ?
Saltz 2000 NEJM 5FU LV IRINOTECAN 7,0 14,8 662/683 ?
Giachetti 2000 JCO 5FU chrono LV OXA 8,7 19,9 242/256 ?
Douillard 2000 Lancet 5FU IRINOTECAN 6,7 17,4 367/387 20 ?
Tournigand 2003 JCO FOLFIRI + FOLFOX 14,2 20,6 220/220 0
Kabbinavar 2003 JCO 5FU LV Avastin 9,0 21,5 35 ?
Hurwitz 2004 NEJM 5FU LV IRI
Bevacizumab
10,6 20,3 813 ?
Goldberg 2006 JCO 5FU LV IRINOTECAN 9,7 19,0 305/305 0
Masi 2006 Ann
Oncol
5FU LV OXA IRI 8,1 15,2 71/71 0
TOTAL >4000 < 20

9. PC from colorectal origin Palliative systemic
-Folprecht et al.
Cancer Treat Res, 2007.
chemotherapy
Retrospective study 3825 patients.
-12% of peritoneal carcinomatosis
-PC as strong prognostic factor
-Patients with PC: median survival 7 to 18 months
-Patients without PC: median survival 11 to 20 months

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

11. SYSTEMIC
CHEMOTHERAPY
PERITONEAL
CARCINOMATOSIS
from COLORECTAL CANCER
Peritoneal carcinomatosis = metastatic disease
BUT
Different natural history and response to systemic
chemotherapy from liver or lung metastasis
5 months < median survival of colorectal PC ?? < 24 months
Systemic chemotherapy should be considered
as one important tool for the treatment of PC

12. 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

13. 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

14. PERITONEAL
CARCINOMATOSIS
from COLORECTAL CANCER
-Franco 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

15. COLORECTAL
CARCINOMATOSIS
Cytoreductive surgery and
intraperitoneal chemotherapy
2222 Registres: 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

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

17. Colorectal carcinomatosis
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CC-0

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

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

20. Colorectal carcinomatosis
and synchronous liver
metastasis
Liver metastasis does not contitute 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

21. Unresolved Questions
Response to neoadjuvant
systemic chemotherapy
should be used for patient’s
selection ?

22. Survival according to the use of neoadjuvant
chemotherapy (n= 120 patients)
P = 0.042
Ann Surg 2012

23. Survival according to response to neoadjuvant
chemotherapy (n= 120) (p= NS)
P = NS Ann Surg 2012

24. Colorectal carcinomatosis and
neoadjuvant chemotherapy
Progression with neoadjuvant systemic
chemotherapy does not contitute 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. 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 ???

26. PERITONEAL
CARCINOMATOSIS
RECOMMENDATIONS TO
GENERAL SURGEONS
AND ONCOLOGISTS

27. For current practice
1ST Message
Curative treatment of peritoneal
carcinomatosis must be
considered at the time of
diagnosis
Not after failure of palliative treatment (surgery –
systemic chemotherapy)

28. How to select patients for
treatment with curative intent?
Which PATIENTS ??
AN AGGRESSIVE THERAPEUTIC
APPROACH
Mortality 4%
Morbidity 34%
Evaluation of general status

29. How to manage patients for treatment
with curative intent?
Cytoreductive surgery and perioperative
intraperitoneal chemotherapy should be
performed in expert centers in peritoneal
surface malignancy
Complex, costly, long procedures
Better patients selection
Lower complications rates
Higher rate of complete cytoreduction
Smeenk, Br J Surg 2007
AFC 2008
WHERE ???
Expert center should be contacted at the time of
diagnosis

30. How to select patients for
treatment with curative intent?
WHICH carcinomatosis ???
Indications
• Patients with no extraabdominal disease
Body-scan
Pet-scan
• POSSIBILITY of COMPLETE CYTOREDUCTIVE
SURGERY +++
Preoperative assessment: CT-scan, MRI
Peroperative assessment ++++
• Laparoscopy
• Detailed operative report

31. For current practice
SECOND Message
Precise description of
carcinomatosis distribution and
extension must be performed

32. How to manage patients for
treatment with curative intent?
IN ALL CASES
• POSSIBILITY of COMPLETE
CYTOREDUCTIVE SURGERY +++
• PRECISE ASSESSMENT OF
CARCINOMATOSIS EXTENT ++++
Description of small bowel, hepatic pedicula,
bladder involvement
Photos or films
Help expert centers for selection
Avoid useless explorative laparotomy

33. Precise description during laparotomy or laparoscopy
of carcinomatosis that are not evaluable on
morphologic exams
Mesenteric retraction Diffuse small tumoral nodules

34. For current practice
THIRD Message
Respect peritoneum !!
Respect parietal wall!!

35. Respect peritoneum and
parietal wall
Peritoneum is the first-line of defense
“Cancer cells entrapment”
Curative procedure more complex and less
efficient
No extensive peritonectomies or cytoreductive surgery
without perioperative intraperitoneal chemotherapy

36. Respect peritoneum and
parietal wall
Clinical situations: carcinomatosis suspected on
preoperative exams
• Explorative laparoscopy (trocarts on middle line)
• Diagnostic biopsy

37. Respect peritoneum and
parietal wall

38. Respect peritoneum and
parietal wall
Clinical situations: Carcinomatosis is
discovered peroperatively
No resection of primary tumor
• Rectosigmoïd tumors (ureters)
Stomia for occlusive tumor
Exception for hemorrhagi tumors
Avoiding drainage into flank
The prognosis depend on the treatment of the metastatic
disease and not on the primary tumor

39. Respect peritoneum and
parietal wall
What should we do with scars or
intraperitoneal nodules or anastomoses
following previous surgery?
More extensive will be previous
surgery, more difficult, extensive and
less curative will be the curative
treatment

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

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

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

43. Patients et Methods (1)
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:
• 28 who presented a minimal macroscopic PC synchronous to the
primary (and which was completely resected during the same session)
• 8 who presented synchronous ovarian metastases,
• 11 who presented a 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)

44. Patients et Methods (2)
Careful exploration of the whole abdominal cavity
Mean duration of surgery: 6 hours
47 patients
23 with PC (49%) 24 without PC (51%)
23 Cytoreduc Surg + HIPEC
Mean peritoneal index: 7 No HIPEC = 6 (PC- H-)
(PC+ H+) HIPEC = 18 (PC- H+)

45. Follow-up: 45 months (mean)
Nb Recurrence IP recurrence Died
PC+ H+ 23 12 (52%) 6 3 (13%)
PC - H + 18 2 (11%) 1 0
PC – H - 6 4 (75%) 3 3 (50%)
Only one prognostic factor: HIPEC (p = 0.02)
Among the 41 pts with HIPEC: only 7 (17%)
presented a peritoneal recurrence

46. Conclusion (1)
A second-look, performed 1 year after the resection of the primary,
in a selected high-risk group of patients, allowed to found and treat
an early and minimal PC in 50% of the patients.
This new therapeutical approach seems benefit for the patients
who initialy presented a minimal PC or ovarian metastasis.
These encouraging preliminary results lead to initiate a prospective
randomized trial, with the aim to definitely prove this benefit.

47. 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