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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.
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Peritoneal metastases fromcolorectal and gastric cancers
Glehen olivierSurgical Oncology
Hospices Civils de LyonCentre Hospitalier Lyon Sud
Colorectal carcinomatosis
Is There a Possibility of a Cure in Patients With Col orectal Peritoneal Carcinomatosis?Goere et al. Ann Surg 2012
107 patients treated with completecytoreductive surgery and Intraperitoneal Chemotherapy
Follow-up for all patients more than 5 years surgical procedures
16% of patients were considered curedwith 5-year or more of disease-freeinterval
YES
Cytoreductive surgery+ HIPEC (MMC)
+ 5FU-Leucovorin
N=48
� Colorectal PC5-FU-Leucovorin
N=44
43% (HIPEC)
� 2-year survival
16% (control roup)
Verwaal et al. J Clin Oncol 2003, Ann Surg Oncol 2008
COLORECTAL PCRandomized study
P=0.001
-Elias et al.J Clin Oncol 2008
Retrospective study.-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% (p<0,05)-Median survival of 62 months vs 24 months
Cytoreduction with HIPEC
PERITONEAL CARCINOMATOSIS from COLORECTAL CANCER
-Franko et al.Cancer 2010
Prospective study.-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
Cytoreduction with HIPEC
PERITONEAL CARCINOMATOSIS from COLORECTAL CANCER
2012 : Treatment of Peritoneal carcinomatosis :When and how to treat ? French national
recommandations
� Pseudomyxoma Peritonei.� Peritoneal Mesothelioma.
� PC from colorectal , smallbowel adenocarcinoma and appendiceal cancers.
Patient in good general statusWhen 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 recommendedUnder evaluation
Ongoing trial inclusion
Probably not ???
2 2 2 2 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
COLORECTAL CARCINOMATOSIS
Cytoreductive surgery and intraperitoneal chemotherapy
2 2 2 2 Registres: national and international
�Identification of 2 principal prognostic factors
�Completeness of cytoreductive surgery
�Extent of carcinomatosis
J Clin Oncol 2004 and 2010
COLORECTAL CARCINOMATOSIS
Cytoreductive surgery and intraperitoneal chemotherapy
Colorectal carcinomatosis
Completeness of cytoreductive surgery
J Clin Oncol 2010
CC-0
CC-1
CC-2 ou 3
CC-0
Quantitative toolPeritoneal Cancer Index (Sugarbaker) : PCI
PCI from 0 to 39
Consensus Milan 2006
CC-0
Colorectal carcinomatosis
Carcinomatosis ExtentCarcinomatosis ExtentCarcinomatosis ExtentCarcinomatosis Extent
Is synchronous liver
metastasis a
contraindication for
curative treatment of
carcinomatosis?
Questions
Survival according to the presence of associated Liver Metastases (n= 65) (p= NS)
� 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
Colorectal carcinomatosis and synchronous liver metastasis
What about systemic
chemotherapy?
Questions
Improved efficiency of systemic chemotherapyfor metastatic colorectal cancers
6
12 12
1415
18 18
21 21
24
0
5
10
15
20
25
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
PC from colorectal origin Palliative systemic chemotherapy
2095 patients
Median survival
•Patients with PC : 12.7 months
•Patients without PC : 17.6 months
French registry colorectal PCMultivariate 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
Peritoneal carcinomatosis has a different naturalhistory and response to systemic chemotherapy than
liver or lung metastasisBUT
50 to 75% of patient with peritonealcarcinomatosis will develop extra-peritoneal
diseaseRole of adjuvant systemic chemotherapy into registries
SYSTEMIC CHEMOTHERAPY
PERITONEAL CARCINOMATOSIS from COLORECTAL CANCER
Systemic chemotherapy should be consideredas one important tool in the multidisciplinary
management of PC
Systemic chemotherapy
should be used before,
after, both ?
Unresolved Questions
P = 0.042
Ann Surg 2012
120 patients
Patients with progressive but resectable disease had median survival more than 30 months
P = NSAnn Surg 2012
� 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 extraperitonealdisease
Colorectal carcinomatosis and neoadjuvant chemotherapy
Ann Surg 2012
What is the exact role of
HIPEC into therapeutic
management ?
Unresolved Questions
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 ?
PRODIGE 7 (F Quenet)RANDOMIZED FRENCH STUDY
No HIPEC
Complete cytoreductive surgery
RANDOMIZATION
HIPEC oxaliplatin
Colorectal carcinomatosis
Perioperative systemic chemotherapy for 6 months
RANDOMIZATION
Interest of 2nd look for
patients at risk of
carcinomatosis
development?
Prevention
� From 1999 to 2009, 47 patients with a high risk to develop a PC(without clinical, radiologic or biologic symptoms) , underwent asecond 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 thefirst surgery: 6 months of systemic chemotherapy (Folfox or Folfiri)
50% of patients had carcinomatosis
HIPEC was an the only independantprognostic factor
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-up2nd look and
prophylactic HIPEC
Gastric carcinomatosis
Results
Overall survival according to etiology
Cancer 2010
� Feb. 1989 – Aug. 2007
� 159 patients
� 15 centers
� M: 83 F: 76
� Mean age 53,4 ± 12,8
� PC Synchronous : 44%
� PC Metachronous : 66%
� HIPEC : 154 cases (94%)
• Closed abdomen :
142 cases (54%)
• Open abdomen : 46%
� EPIC : 12 cases (7,5%)
� Mitomycin C : 83%
Intraperitoneal chemotherapy
Gastric carcinomatosis AFC
� 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
Mortality-Morbidity1344 procedures
� Mortality : 4,1%
� Morbidity gr. 3-4:
33,8%
• Dig. fistula : 9,6%
• Reoperation: 14%
• Mean post-
operative stay :
24,1±18 days
Gastric carcinomatosis AFC
Gastric carcinomatosisPrognostic factors
Institutions
P<0,001
Gastric carcinomatosisPrognostic factors
Treatment with neoadjuvant systemic chemotherapy
P=0,018
Gastric carcinomatosisPrognostic 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%
P<0,001
Gastric carcinomatosisPrognostic factors
Influence of disease extension in patients treated by complete cytoreductive surgery
No patient alive at 2 years for PCI > 13
P=0,038
No patient alive at 1 year for PCI > 19
PHASE III STUDY in Gastric CancerYang et al. Ann Surg Oncol 2011
Cytoreductive surgery
RANDOMISATION
Cytoreductive surgery + HIPEC with CDDP
and MMC
Gastric Carcinomatosis
Systemic chemotherapy ?? Perioperative or adjuvant??
RANDOMISATION
PHASE III STUDY in Gastric CancerYang et al. Ann Surg Oncol 2011
HIPEC did not improve mortality and morbidity rates
PHASE III STUDY in Gastric CancerYang et al. Ann Surg Oncol 2011
HIPEC improved survival (p=0.046)
Synchronous PC++
Conclusions
� Cytoreductive surgery and HIPEC are the onlyway to obtain long-term survivors
� 5-year survival rates of 20% may be obtainedinto expert centers
� Strict selection necessary
� 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
Conclusions
Conclusions
� How to improve selection?
• Neoadjuvant systemic chemotherapy� Gold standard in Europe� Exclusion of patients with metastatic progression
• Neoadjuvant intraperitoneal chemotherapy
Neoadjuvant intraperitoneal systemic chemotherapy (NIPS) Yonemura
Neoadjuvant intraperitoneal systemic chemotherapy (NIPS) Yonemura
Increases the rate complete cytoreductive surgery by increasing downstaging
Phase I-II in Europe
Conclusions� How to improve
selection?
• Laparoscopy as soon as possible +++++
� Exclusion of patients diffuse disease
� Diagnosis of limited PC
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
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
Meta-analysis of postoperative intraperitoneal chemotherapy in gastric cancer
Yan et al Ann Sug Oncol 2007
GASTRICHIP (PHRC 2012)Randomized multicentric phase III
Curative gastrectomy
Peroperative systemic chemotherapy recommended
Peroperative
RANDOMIZATION
Curative gastrectomy + HIPEC oxaliplatin
Gastric adenocarcinoma T3-T4 and/or N+ and/or cyto + (laparoscopy and ultrasound
endoscopy)
Postoperative adjuvant treatment
Peroperative
RANDOMIZATION
Indication of curative gastrectomy
Inform consent
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 isvery important and should be more evaluated
•HIPEC for prevention and prophylactic approach should beconsidered