O. Glehen - HIPEC in colorectal carcinomatosis
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HIPEC in colorectal carcinomatosis
Glehen olivierSurgical Oncology
Hospices Civils de LyonCentre Hospitalier Lyon Sud
Management of peritoneal carcinomatosis: EVOLUTION
Before 1980PALLIATIVE TREATMENT
1980198019801980----95: HIPEC, 95: HIPEC, 95: HIPEC, 95: HIPEC, EPICEPICEPICEPIC
1995-2000: Cytoreductive surgery, phase II studies
2000-2011: Registration, randomized study, Development of expert centers
CURATIVE TREATMENT OF PC
Peritoneal carcinomatosis Peritoneal carcinomatosis Peritoneal carcinomatosis Peritoneal carcinomatosis
Locoregional diseaseLocoregional diseaseLocoregional diseaseLocoregional disease
Treatment of macroscopic disease
Cytoreductive surgery
Peritonectomy procedures
Treatment of microscopic disease
Intraperitoneal chemotherapy
Strong rational for locoregional treatment
Peritonectomy procedures
Organ resections
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
Improved efficiency of systemic chemotherapyfro 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
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
METASTATIC COLORECTAL CANCER Systemic Chemotherapy
-Folprecht et al.Cancer Treat Res, 2007.
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
PC from colorectal origin Palliative systemic chemotherapy
PC from colorectal origin Palliative systemic chemotherapy
2095 patients
Median survival
•Patients with PC : 12.7 months
•Patients without PC : 17.6 months
Peritoneal carcinomatosis = metastatic diseaseBUT
Different natural history and response to systemic chemotherapy from liver or lung metastasis
5 months < median survival of colorectal PC ??< 24months
SYSTEMIC CHEMOTHERAPY
PERITONEAL CARCINOMATOSIS from COLORECTAL CANCER
Systemic chemotherapy should be considered as one important tool for the treatment of PC
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
-Franco 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
2 2 2 2 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
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
CC-0
Colorectal carcinomatosis
Carcinomatosis ExtentCarcinomatosis ExtentCarcinomatosis ExtentCarcinomatosis Extent
Is synchronous liver
metastasis a
contraindication for
curative treatment of
carcinomatosis?
Unresolved Questions
Survival according to the presence of associated Liver Metastases (n= 65) (p= NS)
� 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
Colorectal carcinomatosis and synchronous liver metastasis
Response to neoadjuvant
systemic chemotherapy
should be used for patient’s
selection ?
Unresolved Questions
Survival according to the use of neoadjuvant chemotherapy (n= 120 patients)
P = 0.042
Ann Surg 2012
Survival according to response to neoadjuvant chemotherapy (n= 120) (p= NS)
P = NSAnn Surg 2012
� 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
Colorectal carcinomatosis and neoadjuvant chemotherapy
Ann Surg 2012
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 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 ???
PERITONEAL CARCINOMATOSIS
RECOMMENDATIONS TO GENERAL SURGEONS AND ONCOLOGISTS
For current practice
Curative treatment of peritoneal
carcinomatosis must be
considered at the time of
diagnosis
1ST Message
Not after failure of palliative treatment (surgery –systemic chemotherapy)
AN AGGRESSIVE THERAPEUTIC
APPROACH
Mortality 4%Morbidity 34%
Evaluation of general status
How to select patients for treatment with curative intent?
Which PATIENTS ??
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
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
How to select patients for treatment with curative intent?
WHICH carcinomatosis ???
For current practice
Precise description of
carcinomatosis distribution and
extension must be performed
SECOND Message
• POSSIBILITY of COMPLETE CYTOREDUCTIVE SURGERY +++
• PRECISE ASSESSMENT OF CARCINOMATOSIS EXTENT ++++
�Description of small bowel, hepatic pedicula, bladder involvement
�Photos or films
How to manage patients for treatment with curative intent?
IN ALL CASES
Help expert centers for selection
Avoid useless explorative laparotomy
Precise description during laparotomy or laparoscop y of carcinomatosis that are not evaluable on
morphologic exams
Mesenteric retraction Diffuse small tumoral nodules
For current practice
Respect peritoneum !!
Respect parietal wall!!
THIRD Message
�Peritoneum is the first-line of defense
� “Cancer cells entrapment”
�Curative procedure more complex and less efficient
Respect peritoneum and parietal wall
No extensive peritonectomies or cytoreductive surgery without perioperative intraperitoneal chemotherapy
Clinical situations: carcinomatosis suspected on
preoperative exams
• Explorative laparoscopy (trocarts on middle line)
• Diagnostic biopsy
Respect peritoneum and parietal wall
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
Respect peritoneum and parietal wall
The prognosis depend on the treatment of the metastatic disease and not on the primary tumor
� 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
Respect peritoneum and parietal wall
What is the exact role of
HIPEC into therapeutic
management ?
Unresolved Questions
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
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 asecond 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 thefirst surgery: 6 months of systemic chemotherapy (Folfox or Folfiri)
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 + HIPECMean peritoneal index: 7 No HIPEC = 6 (PC- H-)
(PC+ H+) HIPEC = 18 (PC- H+)
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
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 treatan early and minimal PC in 50% of the patients.
� This new therapeutical approach seems benefit for the patientswho initialy presented a minimal PC or ovarian metastasis.
� These encouraging preliminary results lead to initiate a prospectiverandomized trial, with the aim to definitely prove this benefit.
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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