O. Glehen - HIPEC Colorectal and Gastric
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Transcript of O. Glehen - HIPEC Colorectal and Gastric
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Peritoneal metastases fromcolorectal and gastric cancers
Glehen olivierSurgical Oncology
Hospices Civils de LyonCentre Hospitalier Lyon Sud
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Colorectal carcinomatosis
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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
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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
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-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
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-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
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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 ???
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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
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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
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Colorectal carcinomatosis
Completeness of cytoreductive surgery
J Clin Oncol 2010
CC-0
CC-1
CC-2 ou 3
CC-0
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Quantitative toolPeritoneal Cancer Index (Sugarbaker) : PCI
PCI from 0 to 39
Consensus Milan 2006
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CC-0
Colorectal carcinomatosis
Carcinomatosis ExtentCarcinomatosis ExtentCarcinomatosis ExtentCarcinomatosis Extent
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Is synchronous liver
metastasis a
contraindication for
curative treatment of
carcinomatosis?
Questions
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Survival according to the presence of associated Liver Metastases (n= 65) (p= NS)
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� 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
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What about systemic
chemotherapy?
Questions
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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
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PC from colorectal origin Palliative systemic chemotherapy
2095 patients
Median survival
•Patients with PC : 12.7 months
•Patients without PC : 17.6 months
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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
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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
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Systemic chemotherapy
should be used before,
after, both ?
Unresolved Questions
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P = 0.042
Ann Surg 2012
120 patients
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Patients with progressive but resectable disease had median survival more than 30 months
P = NSAnn Surg 2012
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� 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
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What is the exact role of
HIPEC into therapeutic
management ?
Unresolved Questions
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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 ?
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PRODIGE 7 (F Quenet)RANDOMIZED FRENCH STUDY
No HIPEC
Complete cytoreductive surgery
RANDOMIZATION
HIPEC oxaliplatin
Colorectal carcinomatosis
Perioperative systemic chemotherapy for 6 months
RANDOMIZATION
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Interest of 2nd look for
patients at risk of
carcinomatosis
development?
Prevention
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� 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
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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
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Gastric carcinomatosis
Results
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Overall survival according to etiology
Cancer 2010
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� Feb. 1989 – Aug. 2007
� 159 patients
� 15 centers
� M: 83 F: 76
� Mean age 53,4 ± 12,8
� PC Synchronous : 44%
� PC Metachronous : 66%
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� 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
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� 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
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Gastric carcinomatosisPrognostic factors
Institutions
P<0,001
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Gastric carcinomatosisPrognostic factors
Treatment with neoadjuvant systemic chemotherapy
P=0,018
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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
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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
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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
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PHASE III STUDY in Gastric CancerYang et al. Ann Surg Oncol 2011
HIPEC did not improve mortality and morbidity rates
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PHASE III STUDY in Gastric CancerYang et al. Ann Surg Oncol 2011
HIPEC improved survival (p=0.046)
Synchronous PC++
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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
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� 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
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Conclusions
� How to improve selection?
• Neoadjuvant systemic chemotherapy� Gold standard in Europe� Exclusion of patients with metastatic progression
• Neoadjuvant intraperitoneal chemotherapy
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Neoadjuvant intraperitoneal systemic chemotherapy (NIPS) Yonemura
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Neoadjuvant intraperitoneal systemic chemotherapy (NIPS) Yonemura
Increases the rate complete cytoreductive surgery by increasing downstaging
Phase I-II in Europe
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Conclusions� How to improve
selection?
• Laparoscopy as soon as possible +++++
� Exclusion of patients diffuse disease
� Diagnosis of limited PC
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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
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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
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Meta-analysis of postoperative intraperitoneal chemotherapy in gastric cancer
Yan et al Ann Sug Oncol 2007
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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
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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