Transcript Moving from consensus to clinical integration with the

6th International Workshop on
Peritoneal Surface Malignancy
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These notes were adapted
from the slides shown at the
presentations. Copyrights are
owned by the authors. Please
do not quote without their
permission.
DAY (1)
9h00-9h30 : Opening Lecture – PH Sugarbaker
(Washington, USA):Moving from consensus to clinical
integration with the help of intracavitary pharmacology
Moving from consensus to clinical integration with the help of
the intracavitary pharmacology - PH Sugarbaker (USA)
Patients with colorectal cancer recommended for SECOND LOOK SURGERY
T3 or T4 tumor
Positive peritoneal cytology
Ovarian involvement
Peritoneal seeding on the serosal surface of the primary cancer
Adjacent organ involvement
Perforation of the primary tumor
Intraoperative
rupture of a necrotic tumor mass
Limited peritoneal seeding
Intraoperative tumor spill
Resected primary colon cancer with carcinomatosis or high risk for carcinomatosis:
if the lymph nodes are negative:
if the lymph nodes are positive:
3 months/physical conditioning
folfox for 6 months /physical conditioning.
second look surgery
No carcinomatosis:
carcinomatosis:
Omentectomy
CRS
Oophorectomy
HIPEC
HIPEC
Moving from consensus to clinical integration with the help of
the intracavitary pharmacology - PH Sugarbaker (USA)
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Questions to be addressed:
1.evidence-based medicine, systemic chemotherapy vs. CRS + HIPEC
2. Optimization (with clinical and pharmacologic data)
3. Treatment vs. prevention, role of second-look surgery for high risk patients
4. Palliation of carcinomatosis, open and close vs. palliative CC-1 cutoreduction and HIPEC
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What can be recommended when the CT markedly underestimates the extend of disease? Is a surgical
complete response a worthy goal?
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Adriamycin (generic name Doxorubicin) in HIPEC plus: it gets in the cancer nodules, it stays there
5-FU in HIPEC plus
Target Intra Vascular 5-FU to peritoneal surface tissues
In general: we should use drugs that are slowly metabolized in the tissues and quickly metabolized in the
rest of the body
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Technical improvements:
Lesser omentectomy and omental bursectomy
Access the peritoneum not from the midline
Perihepatic area, small bowel: sites at greatest risk for disease progression after CRS + HIPEC
Surgical decision making: selective second-look
Moving from consensus to clinical integration with the help of
the intracavitary pharmacology - PH Sugarbaker (USA)
Conclusions
1. In carcinomatosis evidence-based medicine supports the use of CRS+HIPEC over
FOLFOX + Avastin.
2. Optimization of CRS + HIPEC need clinical trials but further clinical and
pharmacologic studies will be of benefit
3. Second look surgery is indicated for patients at high risk for local-regional
recurrence.
4. If possible, a CC-1 cutoreduction is always indicated.
A. a proportion of the patients are cured
B. it provides palliation
C. it best prepares the patient for subsequent systemic chemotherapy (logkill hypothesis)
Moving from consensus to clinical integration with the help of
the intracavitary pharmacology - PH Sugarbaker (USA)
SUMMARY: Sugarbaker called for a multidisciplinary comprehensive care approach for
delivering CRS/HIPEC. This is his argument:
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Evidence based medicine supports the use of CRS& HIPEC over systemic chemo
and serial debulking.
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It is very difficult to run phase III study and have patients choose to be
randomized to the arm with less favorable prognosis.
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Liver metastasis resection is considered standard of care because is was found to
be effective. This was done without the need for phase III studies.
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By analogy, we need to declare CRS& HIPEC as standard of care without need for
phase III study.
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The problems we face are not scientific but are economic and skill related.
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PC patients need to be informed of their options for treatment.
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The next step is optimization of therapy using clinical and pharmacological data.
DAY (1)
9h30-11h00: Indications and place of imaging. Role of
radiologists.
Chairmen: F Cotton (Lyon, France), DL Bartlett (Pittsburg,
USA)
9h30-9h50: Cytoreductive surgery and intraperitonel
chemotherapy: which peritoneal surface malignancy should be
treated ? Recommendations.
P. Piso (Regensburg, Germany)
9h50-10h10: What should be expected from imaging before
cytoreduction for peritoneal carcinomatosis: the surgeon's
point of view.
S. Gonzales Moreno (Madrid, Spain)
10h10-10h30: Imaging and peritoneal carcinomatosis: what
should be preoperative exams? The radiologist's point of view.
O. Pellet (Lyon, France)
Cytoreductive surgery and intraperitoneal chemotherapy: which
peritoneal surface malignancy should be treated?
Recommendations - P. Piso (Germany)
Selection peritoneal surface oncology group
Consensus Conferences 2006
Colon/Appendix carcinoma
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PCI<20
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no extra abdominal metastasis
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Limited small bowel disease
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Good performance status, WHO 1-2
Decision making: other factors
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Lymph node metastasis
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Response to systemic chemo
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N-category primary tumor
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Differentiation (signet cell)
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Postoperative quality of life
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Learning curve
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Amsterdam >120 procedures
Basingstoke >90 procedures
Sydney >60 procedures
In a patient with DPAM we can perform laparoscopic HIPEC to treat recurrent ascites after CRS +
HIPEC.
What should be expected from imaging before cytoreduction for
peritoneal carcinomatosis: the surgeon’s point of view - S.
Gonzales Moreno (Madrid, Spain)
CT scan in peritoneal carcinomatosis
Patient selection in mucinous peritoneal carcinomatosis
Volume of disease: minimal <0.5 cm: sensitivity of CT scan : 28% (true positives), 72% false negative (79 =
number of observations)
Volume of disease : moderate 0.5cm to 5cm: sensitivity of CT scan : 72% (true positives), 28% false negatives
(192= number of observations)
Volume of disease: Gross >5cm: sensitivity of CT scan : 90% (true positives), 10% false negatives (492= number
of observations)
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CT scan in peritoneal carcinomatosis
Patient selection in colorectal and appendiceal peritoneal carcinomatosis
Detection of peritoneal carcinomatosis: 60% vs. 76%
Detection of peritoneal implants
• Size<1cm 9.1% vs. 24.3%
• Size>5cm 59.3 vs. 66.7
Significant interobserver differences
• Tumor size 1-5cm
• Detection of tumor on small bowel and mesentery
CT scan in peritoneal carcinomatosis
Patient selection in advanced ovarian cancer
Unresectable disease
Attachment of the omentum to the spleen
Or disease greater than 2 cm on the
diaphragm
Liver surface or parenchyma
Pleura
Mesentery
Gallbladder fossa
Suprarenal paraaortic nodes
What should be expected from imaging before cytoreduction for
peritoneal carcinomatosis: the surgeon’s point of view - S.
Gonzales Moreno (Madrid, Spain)
Conclusions
1. Enhanced CT of the thorax, abdomen and pelvis (oral, IV,
rectal) is the current imaging standard to evaluate peritoneal
surface malignancy patients for surgical exploration with the
intent to perform complete cytoreductive surgery and HIPEC
2. We can expect:
A good sensitivity for the detection of peritoneal
carcinomatosis but an underestimation of peritoneal
disease extent
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Reasonable detection of extraperitoneal disease
(complemented by PET/CT)
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Identification of key features that preclude a
complete cytoreduction
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Help in planning surgical procedure
3. Gadolimium-enhanced, fat-suppressed MRI is a good
imaging complement to CT scan for the detection of
subtle peritoneal, mesenteric or bowel surface
disease, but its actual clinical integration in
peritoneal surface malignancy practices is yet to
occur
4. The role of PET/CT is limited to the detection of
extraperitoneal disease. Its role in the evaluation of
peritoneal disease extent is marginal.
Exam
Fundamental
Useful, not
fundamental
useless
Thin slice CT
scan (with
IV, oral,
rectal
contrast)
96.77
3.23
0
PET total
body
19.35
64.52
16.13
MRI
12.90
70.97
16.13
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Imaging and peritoneal carcinomatosis: what should be preoperative
exams? The radiologist’s point of view O. Pellet (Lyon, France)
Imaging of peritoneal carcinomatosis
Peritoneal
carcinomatosis
Sensitivity
CT
42%
PET
57%
PET/CT: negative points
PET/CT
78%
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Low spatial resolution of PET=5mm
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Risk of false positives due to infection, inflammation and granulomatosis which also uptakes
FDG (hypercellularity)
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Limited equipment
PET –emdCT
Which means: Diagnostical use of CT :mdCT, Iodine contrast injection: e
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Combination of the high performances of PET and CT
Avoids needless and superfluous exams
Is consequently more efficient and cost effective
Conclusions
PET-CT on its optimal use, PET –emdCT, should be the best imaging technique
for the exploration of PC lesions combining morphological and functional
data and providing a whole body acquisition.
Peritoneal carcinomatosis imaging requires a perfect coordination between
radiological and surgical staffs.
Imaging and peritoneal carcinomatosis: what should be preoperative
exams? The radiologist’s point of view O. Pellet (Lyon, France)
It is very important in imaging to be able to determine the completeness of score.
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PET/CT scan:
PET scan: mucinous tumors often do not light up therefore we have false negatives (but we have true positives as well)
The CT sensitivity on small bowel implants is 26%, it is 0% when using a PET scan.
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MRIs
The spatial resolution is better when using a CT scan but MRIs really depict soft tissue exceptionally. So they are worth
exploring as an addition to CT scans. The MRIs are also precise for the detection of mesenteric retraction.
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The CT scans having a spatial resolution of 5mm are exceptional for anatomical imaging.
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With CTs we can see:
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ascites
Omental masses
Omentum lesions
Implants
Thickening
Nodules
Mesenteric carcinomatosis
With PET scans we have the advantage of knowing:
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Tumoral metabolism (malignant tumors have an intense FDG uptake)
PET/CT scans:
Since the PET scan provides the metabolic map and the CT provides the anatomic map, combining the two should
provide us with greater sensitivity than any of them alone.
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Unfortunately the correlation between the PCI score and the CT scan is really low making CT scans not sufficiently
sensitive for Peritoneal Carcinomatosis Staging
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The radiologist advices: Use NEGATIVE contrast (water), not POSITIVE (that lights things up in the imaging).
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Conclusions of the whole session
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Radiologists must be able to assess possibility of a complete
Cytoreduction. (patient selection role)
Current correlations between radiological assessments and surgical
findings reveal the following:
CT: moderate (.53), PET-CT: low (.12), MRI superior to CT in
assessment of soft tissue.
The session revealed that the sensitivity of the radiological studies
can be improved by combining Ct with PET in a new machine that
runs both tests simultaneously and increases sensitivity of Ct from
42% to 78%.
There is a learning curve for radiologists and this must be taken
into account in reading results.
We will begin to see the fruits of targeted imaging in the next 5-10
years (targeting the tumor cells)
DAY (1)
11h30-13h00: How to improve patient selection. Role of general
surgeons.
Chairmen: V. Verwaal (Amsterdam, Netherland), H. Mahteme
(Uppsala, Sweden)
11h30-11h50: Place of laparoscopy for the evaluation of
carcinomatosis extent
M. Valle (Roma, Italy)
11h50-12h10: Recommendations to general surgeons for
preoperative peritoneal carcinomatosis discovery
B. Moran (Basingtoke, UK) \
12h10-12h30: Selection of patients with colorectal
carcinomatosis for a procedure combining perioperative
intraperitoneal chemotherapy. Proposition of guidelines.
M. Pocard (Paris, France)
Place of laparoscopy for the evaluation of carcinomatosis
extent - M. Valle (Italy)
Laparoscopy could become a diagnostic tool for disease staging.
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It is a very precise procedure, the speaker stated that there were no neoplasms
found at the trocar, it is a half an hour procedure with minimal hospitalization stay
of one day.
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It is suggested that during a laparoscopy all the ports should be put in the midline
because lateral ports could risk a metastasis. However this is difficult when a
patient had previous laparotomy.
Conclusions:
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Presenter basically claimed 'good' results with laparoscopic evaluation of PC.
Incisions were not made at midline as is the general recommendation in the
Sugarbaker manual and consensus so far. Presenter claims no tumor seeding existed
at the laparoscopic incisions at follow up. We do not know the time frame for follow
up.
Discussion:
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Many were excited at the prospect of laparoscopic discovery but were usually put
down by the instruction to limit incisions to midline.
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Participants looked forward to further evidence on the safety of the procedure and
the identification of a long-term follow up for tumor seeding.
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Recommendations to general surgeons for preoperative
peritoneal carcinomatosis discovery
B. Moran (Basingtoke, UK)
Some variables must be noted by the general surgeons who assess the
patients with PC:
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Age (over 70)
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liver involvement
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whether patient is fit
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neurological history
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clinical aggressiveness
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malnutrition
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small bowl involvement (most determining factor to survival)
Selection of patients with colorectal carcinomatosis for a procedure
combining perioperative intraperitoneal chemotherapy. Proposition of
guidelines - M. Pocard (France).
Major criteria (for exclusion)
1. Age over 70 years
2. Liver metastases multiple bilobular
3. OMS 2 or more
4. Serious medical histories (especially neurological or renal)
5. Clinical aggravation with systemic chemotherapy
6. Malnutrition
7. Lung metastases
Minor criteria
1. No drop markers with adjuvant chemotherapy
2. Being overweight (BMI>40)
3. History of pelvic irradiation
4. Carcinomatosis extended at the scanner or clinically significant
5. More than 4 surgical procedures
6. Occlusion
7. Associated metastases not resected – except ovary
Guidelines contraindication criteria
No criterion: indication for HIPEC – send the patient
One minor criterion: possible indication – contact a specialist
One major criterion or 2 minor criteria: not yet – back in 3 months
More than one major criterion or 3 minor criteria: no
DAY (1)
14h30-15h45: Cytoreductive surgery. Technical aspects (VideoPhoto)
Chairmen: DM Kecmanovic (Belgrade, Serbia), P. Sugarbaker
(Washington, USA)
14h45-15h00: Bowel and mesentery disease. Anastomoses,
Stomy – S. O’Dwyer (UK)
15h00-15h15: Parietal disease. Parietal peritonectomy (gutters,
cupula), scar removing – D. Bartlett (USA)
15h15-15h30: Sus-mesocolic disease. Omental bursa, lesser
omentum, cholecyctectomy and gastrectomy – V. Verwaal
(Netherlands)
Bowel and mesentery disease. Anastomoses, Stomy by O’Dwyer
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O’ Dwyer uses a low voltage diathermia technique for nodules on the small
bowel. Dr Sugarbaker does scissor dissection for nodules on the small bowel.
Can multiple small bowel anastomoses prevent small bowel syndrome? O’
Dwyer has done a maximum number of 4 on a single patient.
Parietal disease. Parietal peritonectomy (gutters, cupula), scar
removing by D. Bartlett
Cytoreduction steps
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Midline laparotomy
Complete omentectomy with en bloc splenectomy (if involved)
Run small bowel from ligament of treitz to ileocecal valve, removing all tumor from
mesentery and bowel surface.
Run large bowel from cecum to rectum, removing all tumor from mesentery
Resect abdominal wall peritoneum if diffusely involved including gutters
Pelvic dissection
Peel peritoneum and trace uterers to insertion into bladder
Pelvic peritonectomy if diffusely involved
Left subdiaphragmatic peritonectomy if diffusely involved
Resect falciform ligament
Resect gastrohepatic ligament
Resect peritoneum over crus and rest of lesser sac
Resect disease to left of retrohepatic cava
Mobilize liver from peritoneal attachments
Right subdiaphragmatic peritonectomy if diffusely involved
Strip port hepatis
Parietal disease. Parietal peritonectomy (gutters, cupula), scar
removing by D. Bartlett
Specialized tools
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High energy cautery
Sponge clamps/ring forceps
Ligasure device
Staplers
Argon beam coagulator
Scar removal, abdominal wall and gutters
Routine vs. selective scar and umbilicus removal
Open vs. closed technique for abdominal wall peritoneum
Routine complete peritonectomy vs. selective peritonectomy for
tumor involvement
Ball tip vs. sharp tip cautery
Sus-mesocolic disease. Omental bursa, lesser omentum,
cholecyctectomy and gastrectomy by Verwaal
Context
 Most HIPEC surgeons are lower GI surgeons
 The upper abdomen is an interesting place with hidden corners and caves and
too important structures to damage.
7 region system
1. Pelvis
2. Ileoceacal
3. Omentum/colontransversum
4. Small bowel
5. Sub hepatic
6. Sub phrenic left
7. Sub phrenic right
DAY (1)
16h00-18h20: Peritoneal Surface Malignancy. A multidisciplinary
approach. Role of Anesthesiologists, Nutritionists, Nurses,
Perfusionists.
Chairmen: KH Link (Wiesbaden, Belgium), AC Beaujard (Lyon,
France)
16h20-16h40: Treatment of postoperative surgical complications
A. Gomez Portilla (Vitoria, Spain)
17h20-17h40: Intraoperative parameters that could be markers
of morbidity
S. Kusamura (Milan, Italy)
Treatment of postoperative surgical complications
by Portilla
Cytoreductive surgery +HIIC +EPIC
Sugarbaker protocol
Intra-operative
drugs
Elias protocol
Primary tumor
Mitomycin C
Pseudomyxoma
Colorectal
gastric
Cisplatin Adriamycin
Ovary
Mesothelioma
Sarcomatosis
90 minutes
42 degrees C
Previous surgeries
Previous chemotherapy
Parietal peritoneum
Greater and lesser omentum
Parietal peritonectomies
Visceral resections
Bowel anastomosis
Serosal tears
HIIC + EPIC
Empty cavity / dead space
Severe sepsis or C.I.D.
Abdominal compartment syndrome
Intra-operative
drugs
Oxaliplatin
Primary tumor
Pseudomyxoma
Colorectal
gastric
30 minutes
43 degrees C
Carcinomatosis vs. conventional patients
Conventional patients
0
0
present
present/absent
0
1
1 or 2
unusual
no
no
unusual
unusual
Cytoreduction patients
>1
>1
absent
absent
>3
>3
>2
frequent
Yes
Yes
frequent
frequent
Treatment of postoperative surgical complications
by Portilla
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Unnoticed serosal tears are a major issue when performing CRS. They lead to
diffused peritonitis (which leads the surgeons to temporary abdominal closure, open
vacuum abdomen). It usually becomes noticeable on the second week of the
hospitalization when the patient becomes septic and we see intestinal contest in his
bags.
Conclusions
The open vacuum abdomen is an optimal technique useful for temporary closure of
the abdominal cavity in patients suffering abdominal complications after
cytoreductive surgery.
A primary fascial closure was possible in 2/3 of the cases, 1 patient died, 2
developed enteric fistula.
All but one patient were discharged alive from the hospital.
Preventive measures
Right diaphragmatic peritonectomy with glisectomy FIRST.
Avoid cytoreductions of more than 10 hours duration.
Although a colo-anal anastomoses is always performed, opt for an excluding
derivative ostomy from the outset in case of more than 2 anastomoses.
Prompt reintervention when fistulas or the dehiscence of sutures are suspected or
reveal themselves, and even in unidentified septic processes.
Intraoperative parameters that could be markers of
morbidity by Kusamura
There are 4 markers of morbidity:
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1. systemic inflammatory response syndrome (SIRS)
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2. sepsis (bacteremia + SIRS)
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3. Severe sepsis
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4. Septic shock that leads to death
80% of the patients develop SIRS.
Prevention by methylprednisolone (MPS) of increased circulating TNF-a levels (Tumor
Necrosis factor –a levels) and lung injury associated with SIRS due to intraperitoneal
Hyperthermia
Objective
To investigate whether pretreatment with MPS may modulate serum TNF-a and lung injury in patients
undergoing HIPEC.
Conclusions II
CDDP dosage influenced the rates of post op complications
CDDP dose decreasing advisable if concurrent risk factors
Sepsis: the most frequent complication before death
Inflammatory/infective aspects
promising future research
DAY (2)
8h30-10h00: Colorectal Cancers. Chairmen: F. Antos (Prague,
CZH), F. Cavaliere (Roma, Italy)
8h30-8h50: Cytoreductive surgery and perioperative
intraperitoneal chemotherapy for colorectal carcinomatosis.
Results of the French multicentric database.
D. Elias (Villejuif, France)
8h50-9h10: French ongoing trials in the treatment of peritoneal
carcinomatosis from colorectal cancer
F. Quenet (Montpellier, France)
9h10-9h30: USA ongoing trials in the treatment of peritoneal
carcinomatosis from colorectal cancer
J. Esquivel (Washington, USA)
9h30-9h50: Long term of randomized study in colorectal
carcinomatosis
V. Verwaal (Amsterdam, Netherlands)
Cytoreductive surgery and perioperative intraperitoneal chemotherapy
for colorectal carcinomatosis. Results of the French multicentric
database by Elias
Survival according to the extent of peritoneal carcinomatosis: The PCI score is of utmost importance. The extent of
carcinomatosis is an important survival factor.
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Survival according to liver metastases: Liver metastases has a negative impact.
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Survival according to HIPEC drugs: Oxaliplatin doesn’t show a significant impact compared to Mitomycin C
Analysis of disease-free survival
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Prognostic parameters:
1.
Completeness of cytoreduction
2.
Peritoneal index
3.
Lymph node status
4.
Postoperative systemic chemo
Conclusion / colon –rectum
1.
HIPEC has become the new therapeutic standard
2.
Dramatic impact of the completeness of the cytoreductive surgery
3.
The prognostic impact of HIPEC is less clear
4.
Low impact of associated liver metastases
There are 2 other important prognostic factors:
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The extent of the PCI
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The adjuvant systemic chemo
Conclusion / Appendix cancer
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Good results of HIPEC
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The prognosis is better in women
Survival / complications:
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Lower than those of all pseudomyxomas, but close to those of grade 3 pseudomyxoma
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Far better than those of colon – rectum
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Open abdomen technique (coliseum)/closed abdomen/ EPIC : they almost give the same results
Adenocarcinoma of the small bowel carries a 33% survival rate over 5 years. So does colon adenocarcinoma
We need a Phase III trial on HIPEC. We only have the Dutch trial on the Mitomycin C
HIPEC drugs: Mitomycin C or Oxaliplatin + Camptosar or Oxaliplatin
The tolerance of HIPEC is better when the cytoreduction is minimal
Trial on second-look surgery by Dr Elias:
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The high-risk patient group should have 6 months of FOLFOX, then a second-look surgery
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Second-look: absence of PC = exploratory laparotomy with prophylactic HIPEC. Presence of PC = CRS + HIPEC
Conclusion: Radicality of surgery is the most important prognostic factor.
French ongoing trials in the treatment of peritoneal carcinomatosis
from colorectal cancer by Quenet
Drug: Mitomycin C : The Dutch trial
1998-2001 105 patients
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The median survival was approximately 21 months
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The 3 and 5 year survival rates were 28% and 19%
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Complete cytoreduction : median survival 42.9 months.
Minimal residual disease: median survival 17.4 months
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When a gross macroscopic tumor was left behind the median survival was 5 months.
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After an 8 years follow up: the 5-year survival was 45% for those patients in whom a
R1 resection was achieved.
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Oxaliplatin-Retrospective study
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2 groups of patients retrospectively selected
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Half underwent complete cytoreductive surgery + HIPEC with Oxaliplatin. The rest had
only the standard treatment of systemic chemotherapy: The result was that the group
that had CRS + HIPEC had a significant median survival benefit compared to the group
with the standard treatment.
French ongoing trials in the treatment of peritoneal carcinomatosis
from colorectal cancer by Quenet
The first trial presented is relevant to PC from colorectal origin and whether HIPEC rather
than CCR increases survival rate.
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The hypothesis is that HIPEC increases survival from 30% to 48%.
Trial is conducted in the following way:
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Pool of patients: respectable PC
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Everyone gets CC (R1/R2) which is <1mm.
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Patients are then randomized to an arm with HIPEC and an arm without HIPEC.
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Both arms receive systemic chemo after surgery.
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Trial is still at the early stages. Findings so far support the hypothesis.
The second trial is about a systematic second look surgery.
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This trial is conducted for patients with a high risk of developing PC at 12 months.
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Patient pool includes those with minimal micro PC, synchronous ovarian cancer, and
those with perforations.
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Finding so far corroborate the hypothesis that high risk population might benefit
from systematic second look surgery.
Discussion focused on the following:
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Clear distinction between the concept of systematic second look and serial
debulking. The latter involving CCR.
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The difficulties involved in second surgery following a CCR.
USA ongoing trials in the treatment of peritoneal carcinomatosis from
colorectal cancer by Esquivel
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Less than 1% of patients with PC and colorectal cancer ever get to the specialists.
There is more enthusiasm than data to support CRS&HIPEC as standard of care. Data
should be a result of phase III trial conducted in the following way:
Pool of patients with limited PSM from colorectal origin with no prior CRS.
Patients will be stratified into two classes: those who have had prior chemo and those
who did not.
Patients will then be randomized to an arm receiving best systemic chemo and another
arm receiving CRS&HIPEC.
Outcomes that will be measured are: peritoneal progression free survival, overall
survival, toxicity, QOL, CTC during Rx.
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Approval of trial required modifications of the model in the following way:
Pool of patients with limited PSM from colorectal origin with no prior CRS.
Patients will be stratified into synchronous vs. metastatic disease, and into those with
measurable vs. non-measurable Perf status, and into groups according to cytotoxic
biologics.
Patients will then be randomized to an arm receiving best systemic chemo and another
arm receiving CRS&HIPEC & Best systemic chemo.
Outcomes that will be measured are: overall survival, toxicity, QOL, CTC during Rx.
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The approval of the trial is still underway.
This situation requires establishment of American Society of Peritoneal Surface Malignancy.
Currently in progress. Website: www.americansoceitypsm.com
There is also a need for an open access journal of PSM.
Long term of randomized study in colorectal carcinomatosis
V. Verwaal (Amsterdam, Netherlands)
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Confirming their previous findings Verwaal and colleagues ended follow up
to 94 months.
2 patients were crossed over (censored at cross over).
The study shows increased effectiveness of the treatment, lower mortality
and morbidity rates and confirms the need to follow their earlier conclusion
about the learning curve for the combined treatment.
Important note: Netherlands group is working on accreditation system
for HIPEC centers.
DAY (2)
10h30-12h40: Rare Peritoneal Surface Malignancies and Place
of Pathologist
Chairmen: B. Moran (Basingstoke, UK), PJ Valette (Lyon,
France), JC Sabourin (Rouen, France)
10h30-10h50: Cytoreductive surgery and perioperative
intraperitoneal chemotherapy for rare peritoneal disease.
Results of the French multicentric database.
O. Glehen (Lyon, France)
0h50-11h10: The renewal of pseudomyxoma peritonei pathology
S. Bruin (Netherlands)
11h10-11h30: New prognostics factors for peritoneal
mesotheliome
M. Deraco (Milan, Italy)
11h30-11h50: French National Organization for the treatment of
rare peritoneal disease:RENAPE. From a national to an
international cooperation.
FN Gilly (Lyon, France)
The renewal of pseudomyxoma
peritonei pathology by Bruin
Begins with presentation of current variety of definitions and pathological categories for PMP.
HIPEC literature reports

Primary lesion
Appendiceal
Colorectal
Appendiceal and Colorectal

Pseudomyxoma Peritonei
Colonic Carcinomatosis?




Appendiceal neoplasms associated with mucinous peritoneal disease:

Adenoma

Cystadenoma

Appendiceal mucinous tumor of uncertain malignant potential

Cystadenocarcinoma

Mucinous adenocarcinoma

Signet ring cell carcinoma

Goblet cell carcinoma
Histopathology
Grading of mucinous peritoneal lesions according to different authors



Ronnett : DPAM, PMCA-i, PMCA
Cariker, Gough, Loungnarrath: Grade1, 2, and 3.
Bradly, Miner, Butterworth, Murphy: Low grade, High grade.
Survival predictors for PMP

Completeness of cytoreduction

Number of affected lesions

Histological characteristics
The renewal of pseudomyxoma
peritonei pathology by Bruin




The study is based on the histopathological review of 269 patients with appendiceal
and colonic tumors treated with HIPEC.
Studies evaluated the following features:
Extracellular Mucin
Mitotic activity
Cellularity
Cytologic atypia
Histological classification of peritoneal surface malignancy:
Mucinous :
Non-mucinous :
1. Disseminated Peritoneal Adeno Mucinosis
2. Peritoneal Mucinous Carcinomatosis
Peritoneal Carcinomatosis (PCA)
The renewal of pseudomyxoma
peritonei pathology by Bruin
Cellularity
Extra cel.
mucuc
None
1-50%
50-90
mitosis
few
many
Nuclear atypia
Nuclear atypia
none
little
lots
none
little
lots
None
Sporadic
9
Abundant
60
None
1
Sporadic
4
Abundant
20
None
Sporadic
1
Abundant
2
15
None
20
38
3
Sporadic
43
13
Abundant
6
13
Non-mucinous
DPAM
PMCA-I
Mucinous
PMCA
PCA
1
3
17
The renewal of pseudomyxoma
peritonei pathology by Bruin
Primary tumor location and type of PSM:
71%: DPAM
6% : PMCA-I
14%: PMCA
9% : PCA
PSM from primary colon tumors: 37% mucinous
DPAM most frequently from a primary appendix tumor
29% of primary appendix tumors: non-DPAM
Survival analysis
Significant factors multivariate analysis
Histological classification
Gender
Number of regions
Result of cytoreduction
HIPEC as first treatment on PSM
Tumor location
A nomogram score (predictor of survival for individual patients) was created based on the theoretical assumptions of this
study
Summary:
PSM is often mucinous
DPAM carried better survival than PMCA and PMCA better than PCA
Female patients have better survival than male in mucinous PSM
Non-mucinous tumors have worse survival
Histological classification of colorectal and appendiceal PSM give prognostic information
PSM should be classified by a standardized protocol
HIPEC nomogram provides a tool for individual patient risk assessment.
French National Organization for the treatment of rare
peritoneal disease: RENAPE. From a national to an
international cooperation by FN Gilly
Dr. Gilly presented the French experience in creating a unified framework for the diagnosis and treatment of rare peritoneal
disease. These include:

PMP

Mesothelioma

Primary Peritoneal Serous carcinoma

Desmoplastic tumor

Psammocarcinoma
The aims of this national organization called RENAPE are :

CARE: Provide best treatment for patients

TEACHING: Teaching and transfer of knowledge

RESEARCH: Fostering cutting edge research

STRUCTURING:
The steps to be taken are as follows:

Creating a national registry of rare peritoneal tumors

Creation of a frozen tissue bank

Creation of a blood sample bank

The evaluation of the practice by real incidence of the disease, the efficiency of best treatments, the differential in
outcomes between expert centers and new ones.
Discussion:

This experience could be globalized to maximize the benefits delivered to the patient, expedite research and
validate findings from different centers

In the absence of a universal health system in the USA it is very difficult to establish this national program.
Cytoreductive surgery and perioperative intraperitoneal
chemotherapy for rare peritoneal disease. Results of the
French multicentric dtabase by Glehen.
New prognostic factors for peritoneal mesothelioma by
Deraco

The completeness of cytoreduction and the experience of the institution are the most important
factors to increase survival to mesothelioma patients.

Mutations in the Tyrosine Kinase Domain of the EGFR are predictors of optimal resectability in
malignant mesothelioma
DAY (2)
14h30-15h45: Gastric Cancer. Chairmen : P. Shen (Winston
Salem, USA), TD Yan (Sydney, Australia)
14h30-14h50: Place of hyperthermic intraperitoneal
chemotherapy for the treatment of peritoneal carcinomatosis
from gastric cancer. Results of French multicentric database.
C. Arvieux (Grenoble, France)
14h50-15h10: Neoadjuvant intrapertoneal chemotherapy in
advanced gastric cancer.
Y. Yonemura (Japan)
15h10-15h30: Prevention of peritoneal carcinomatosis in gastric
cancer.
A. Garofalo (Roma, Italy)
Place of hyperthermic intraperitoneal chemotherapy for the treatment
of peritoneal carcinomatosis from gastric cancer. Results of French
multicentric database by Arvieux


Patients that had complete tumor resection but their PCI score was more than 19 didn’t
live for more than a year.
Hope of cure: R0 patients, Gilly 1 patients, patients with PCI <10.
Gilly staging:
Stage
Stage 0
Stage 1
Stage 2
Stage 3
Stage 4
Peritoneal carcinomatosis description
No macroscopic disease
Malignant implants less than 5 mm in diameter
Localized in one part of the abdomen
Diffuse to the whole abdomen
Malignant implants 5 mm to 2 cm
Large malignant nodules (more than 2 cm)
Conclusion:

Post operative mortality is high for patients treated for carcinomatosis of gastric origin,
especially for patients aged 60 and more.

The treatment of carcinomatosis from gastric cancer by peritonectomy and HIPEC has
worse long term results than the treatment of carcinomatosis from other causes

Long survival after peritonectomy and HIPEC for carcinomatosis arising from gastric
cancer are possible if the extension of the carcinosis is low and the resection R0.
Neoadjuvant intraperitoneal chemo in
advanced gastric cancer by Yonemura
Bidirectional chemotherapy: Neoadjuvant IntraPeritoneal – Systemic Chemotherapy
(NIPS)
The study aims to shows that NIPS (Neoadjuvant Intrapeitoneal Systemic chemotherapy)
delivers good results in:

the eradication of peritoneal free cancer cells.

The reduction of peritoneal dissemination

increase the incidence of compete Cytoreduction

preserve uninvolved peritoneum

Peritoneal cavity: IP chemo: Docetaxel + CDDP

Systemic chemo: TS -1

Delivery of treatment: (3 weeks of 60mg/m2 TS1 intravenously + simultaneous IP
injection from port 3 times containing CDDP 40mg, Taxotere 40mg, Saline500ml)

Conclusion:
 NIPS increased CC-0 from 40% to 60%
 Peritoneal zones with rich lymphatic networks tend to be involved by PFCC
 PFCC may invade through mesothelial holes on mocula cribrifolmis and into
submesothelial lymphatics
 These zones should be meticulously checked during operation or laparoscopy
 Correlation of PCI and CC in gastric cancer: PCI=<10 is an indicator for CC-0
 preoperative diagnosis of PCI is not correct because the size of PC small
 NIPS is safe and effective therapy to eradicate PFCC
 CC score and cytological status after NIPS are independent prognostic factors.
 NIPS can downstage large volume peritoneal dissemination of gastric cancer.
When combined with gastrectomy including peritonectomy and a complete
surgical resection is possible, the results show prolonged survival. This combined
intraperitoneal and systemic chemotherapy for PC from gastric cancer is worthy
of consideration.
Prevention of peritoneal carcinomatosis
in gastric cancer by Garofalo



Radical Resection : D2
Value of D2 dissection is controversial but today its strong
rationale is widely shared.
D2 is considered an appropriate option:



When the surgeons can show low operative mortality.
In gastric cancer stage II and III.
When the removal of pancreas and spleen is avoided.
DAY (2)
15h45-17h30: Hyperthermic Intraperitoneal Chemotherapy:
Unusual Indications.
Chairmen: D. Elias (Villejuif, France), M. Gutman (Tel Aviv,
Israel)
16h05-16h25: Place of hyperthermic intraperitoneal
chemotherapy as palliative treatment (ascites)
S. Miska (Paris, France)
Laparoscopic HIPEC
Laparoscopic HIPEC: methods

Midline ports

Aspiration of ascites

Limited adhesion lysis

Inflow + outflow catheters

Temperature probes

Pressure probes

Chemoperitoneum 15 Hg

Cisplatin, Doxorubicin, Melphalan, Mitomycin C
Laparoscopic HIPEC: results

Technical failure : 0

Complications : 2 minor wound infections, 1 DVT

Hospital mortality : 0

Median hospital stay 2-3 days

Ascites resolved at 1 month (ultrasound/CT): 49/52

No readmissions for ascites (*1)

Median survival : 96 days (range 21 -796)

Longest survival in patients with breast cancer (796, 725, 455. 212)
Laparoscopic HIPEC : Conclusions

Malignant ascites is a debilitating condition with low quality of life

No efficient conventional therapies

Laparoscopic HIPEC is a safe and feasible procedure

Pharmacokinetic rationale

Ascites resolved in 49-52 patients

No readmissions for ascites

Finding: increases survival rate, alleviates debilitating symptoms.
DAY (2)
17h30-18h45: FREE PAPER SESSION n°1
Chairmen: S. Gonzales Moreno (Madrid, Spain), F. Quenet (Montpellier,
France)
Tuesday 17h46-17h54: Biological features are the dominant prognostics
determinants for patients affected by pmp. Speakers: Dario Baratti, MD.
Tuesday 17h54-18h02: Intraoperative Immunophotodetection: a new
imaging technique to improve peritoneal surface malignancy diagnosis
and treatment
Speakers: Marian Gutowski, MD
Tuesday 18h10-18h18: Peritonectomy with high voltage electrocautery
generates higher levels of ultrafine smoke particles
Speakers: S. Naslund Andreasson, MD.
Tuesday 18h18-18h26: Morbidity of intraperitoneal chemotherapy:
effectiveness of eperidural anaesthesia / analgesia : a comparative study
Speakers: G. Lorimier, MD,PhD.
Tuesday 18h34-18h42: A phase II study evaluating the use of concurrent
mitomycin C and capecitabine in patients with advanced unresectable
pmp
Speakers: Farquharson AL, MD.
Biological features are the dominant prognostics
determinants for patients affected by pseudomyxoma.
Speakers: Dario Baratti, MD.
This paper presents a multivariate analysis of PMP patients at 4 specialised centers (Washington, Wake
Forest, Amsterdam, Milan).

The following are the prognostic features the study investigates:




Markers of cell differentiation: CDX-2, CK-7, CK-20



CK20 expression is more common in low grade than in high grade colorectal carcinoma
Weak CDX-2 has been associated with poor prognosis in gastric, billiary and colon cancer
Markers of mucin production: MUC-2, MUC-5AC


Histological variant (PMCA, ID vs. DPAM)
PCI (<20 vs. >20)
Preoperative serum (CEA, CA125, CA19-9, CA15.3)
PMP is a disease of MUC-2 producing goblet cells. MUC-2 may be a tumor suppressor and may account for
the minimally invasive behavior of the disease. MUC2 expression is a potential molecular target
Markers of cell adhesion: CD-44s


CD44s is a cell surface glycoprotein involved in tumour peritoneal adhesion mechanisms.
Its increased expression correlates with a high risk of liver metastasis
Findings:

Low grade histology & negative CT may correlate with overall survival

Histology, negative CT and CA125 <35 may correlate with progression free survival.

Pathological and biological features may correlate to outcome following CCR & HIPEC

CK20, CDX-2 and MUC-2 expression may have a prognostic value related to the peculiar clinical
behavior of PMP

New standardized pathological classification and further molecular and cellular level investigations are
warranted.
Intraoperative Immunophotodetection: a new imaging
technique to improve peritoneal surface malignanc
Speakers: Marian Gutowski, MD.



This paper presented a technique whereby a cancer antigen antibody solution is
placed in the abdominal cavity causing tumor cells to stain with minimal uptake in
normal tissue. This will help the surgeon visualize small tumor nodules that would
have been otherwise missed. The study reports no side effects. Trials in humans
to be carried out soon.
General concept:
Target: specific tumor antigen = CEA
 Cell surface
 High density
 Low expression in nornal tissues
 Available Mab
 Physiology
 No cross-reaction with other treatments
 Low circulating fraction
Peritonectomy with high voltage electrocautery
generates higher levels of ultrafine smoke particles
Speakers: S. Naslund Andreasson, MD.

Ultra fine smoke particles are detected in the operating rooms using high voltage
electrocautery . The study reports 1 gm of tissue equals the smoke generated from
6 cigarettes. Surgeons and staff must take precautions (filtered masks) during
such procedures.
Morbidity of intraperitoneal chemotherapy: effectiveness
of eperidural anaesthesia / analgesia : a comparative study
Speakers: G. Lorimier, MD,PhD.

Conclusion: There is a higher morbidity rate associated with the combination of
HIPEC and Anesthesia. The effect is higher in the closed method. HIPEC centers
must employ anesthesiologists experienced in the combined effect of HIPEC and
anesthesia to minimize associated morbidity.
A phase II study evaluating the use of concurrent
mitomycin C and capecitabine in patients with advanced
unresectable pmp
Speakers: Farquharson AL, MD


Study conducted on 40 patients with advanced/inoperable pmp:
15/40 had radiological benefit from the treatment with Mitomycin C and Xeloda(38%)



23 patients had progressive disease at baseline
17 patients had stable disease at baseline
From the group of the 23 patients with disease progression:
•
•

From the group of the 17 patients with stable disease:
•

40 patients
9 became stable
3 had tumor reduction
Progressive disease at baseline
N=23
Stable disease at baseline
N=17
3 had tumor reduction
2 patients had cytoreductive surgery
Tumor stable
N=9
Tumor reduction
N=3
Tumor reduction
N=3
DAY (3)
Wednesday, November 19th
8h30-10h30: Pharmacokinetics and Biological Session
Chairmen: F. Mohamed (Basingstoke, UK), B. Tranchand (Lyon,
France)
8h30-8h45: Pharmacokinetics of intraperitoneal cisplatinium
E. Cotte (Lyon, France)
8h45-9h00: Effect of intraperitoneal pressure and adrenalin in
pharmacokinetics of intraperitoneal drugs
B. Chauffert (Dijon, France)
9h20-9h40: New targeted therapy: Application for loco-regional
therapy
JF Pingpank (Bethesda, USA)
9h40-10h00: Chemotherapy, environmental and juridic aspects.
AC Sayag-Beaujard (Lyon, Frace)
Pharmacokinetics of intraperitoneal cisplatinium
E. Cotte (Lyon, France)
Effect of intraperitoneal pressure and adrenalin in pharmacokinetics of
intraperitoneal drugs
B. Chauffert (Dijon, France)
Cisplatin:
There are 2 barriers for the distribution of chemotherapy:

Peritoneo-tumor barrier

Anatomical barrier
There is not only the histological barrier to drug diffusion but also the drug draining
through peritoneal and tumor vessels. The barrier is partially broken by
epinephrine, an adregenic vasocontricting drug.
Therefore the platinum accumulation increases by IP and addition of epinephrine.
In microscopic PC there is no need of epinephrine. Epinephrine is important in
millimetric PC and doesn’t play a role for advanced PC.
The abdominal pressure is another way to break the peritoneo-tumor barrier.
Intraperitoneal pressure
A 25mm Hg IP pressure for 2 hours is well tolerated in 50-60 kg pigs and it gives good
staining of the peritoneum and mesentery.
There is also the possibility to increase the cytotoxicity by altering the osmolarity to
increase the platinum accumulation in tumor nodules.
How to optimize IP protocols when tumor residues: pressure, osmolarity
New drugs: Gemzar appears to be very promising in vitro.
New targeted therapy: Application for loco-regional therapy
JF Pingpank (Bethesda, USA)
Chemotherapy, environmental and juridic aspects.
AC Sayag-Beaujard (Lyon, France)


The first paper presented the value of molecular profiling for the purpose
of delivering individualized therapy during HIPEC.
The second paper discussed the precautions that must be taken by the
medical staff during CRS and HIPEC.
DAY (3)
Wednesday, November 19th
11h00-12h00: FREE PAPER SESSION n°2
Speeches:
Wednesday 11h08-11h16: Health related Quality of Life in
patients with peritoneal carcinomatosis after cytoreductive
surgery
Wednesday 11h16-11h24: Preoperative FDG-PET-CT correlates
with intraoperative findings in patients with peritoneal
carcinomatosis
Wednesday 11h24-11h32: HIPEC can influence the Malignant
Ascites Production
Wednesday 11h32-11h40: Preliminary results of pancreatic
cancer treated with surgical resection and HIPEC
Wednesday 11h40-11h48: A pharmacologic analysis of
perioperative administration of 5-Fluorouracil.
Wednesday 11h48-11h56: Is neoadjuvant FOLFOX
chemotherapy effective in patients with mucinous peritoneal
carcinomatosis of appendiceal origin?
Wednesday 11h56-12h04: Abdominal hyper-pressure in HIPEC
Health related Quality of Life in patients with peritoneal
carcinomatosis after cytoreductive surgery
Speakers: Johan Hansson, MD.


Paper claims that the global quality of life is not affected for patients who
undergo CRS.
The procedure seems to be well tolerated and improves emotional functioning
although it increases some symptoms and affects physical and social
functioning.
Preoperative FDG-PET-CT correlates with intraoperative findings in
patients with peritoneal carcinomatosis.
Speaker: Ingmar Konigsrainer, MD






Findings:
Small lesions <1cm detectable in more than 70%
High sensitivity and specificity in estimation of total PCI
Good sensitivity and specifying for the 'black box‘ of the small bowel
= region 9-12
Significant correlation of pre-op and intra-op score.
18F-FDG – PET/CT is best option in selection of patients for
CRS/HIPEC and exclusion for those with high PCI
HIPEC can influence the Malignant Ascites Production
Speakers: Frantisek Antos , MD, PhD.
Preliminary results of pancreatic cancer treated with surgical resection and HIPEC
Speakers: Antonios Apostolos K.Tentes , MD.
Antos:
How do we know that ascites is really malignant?
Ascites: HIPEC + debulking:
With HIPEC 60% of the patients will not produce malignant ascites until
their death. In 40% of the cases the ascites will form again but in the
limited amount and without the need of punctures.
Tentes:
Pancreatic cancer:
Median survival : 10 – 18 months
Gemzar is a potent cytostatic drug
HIPEC with Gemzar: 60 minute perfusion at a dose of 1000 mg/square
meter
IV administration of Gemzar in case of infiltrated lymph nodes or for
recurrent disease. The result of the treatment was that even in case of
recurrence all the failure sites were distant and not loco-regional (liver
metastases)
A pharmacologic analysis of perioperative administration of
5-Fluorouracil.
Speakers: K. Van der Speeten, MD.
5-FU is an inhibitor of thymidylate syntetase. It has a low molecular weight so theoretically
it shouldn’t be the ideal choice for HIPEC. However, 5-FU largely stays in the peritoneal
cavity and it is rapidly metabolized which is a compensation for its low molecular
weight. The fact that it is rapidly metabolized practically means that it has a very high
concentration immediately after use, only 7 minutes after instillation. So it has a rapid
distribution to all body compartments and its metabolisation is restricted to the plasma
compartment.
Rapidly transponded to all compartments and to some degree to the tumor nodules = true
pharmacological end point.
Is neoadjuvant FOLFOX chemotherapy effective in patients
with mucinous peritoneal carcinomatosis of
appendiceal origin? Speakers: Dal Yoo, MD.





















This study excludes patients with DPAM.
32 patients with mucinous peritoneal carcinomatosis of appendiceal origin stratified as follows:
Gender: 16 males, 16 females
Age: median = 47, range= 28-64
Pathology: 19 (PMCA), 8 (PMCA with signet ring morphology), 6 (adenocarcinoid with neuroendocrin component)
Positive lymph nodes: 11
patients received 6 cycles of neoadjuvant chemotherapy: Folfox(29), Xelox (3), Bevacizumab (21) followed by
Evaluation and Clinical CT
11 patients were approved for CRS and HIPEC and 21 patients received an additional 6 cycles of neoadjuvant
chemotherapy.
After evaluation and CT, the latter 21 patients underwent CRS&HIPEC and were re-evaluated then.
Findings:
None of these patients had a complete response to chemo when evaluated intraoperatively.
17 patients had disease progression when evaluated intraoperatively.
9 patients were stable.
Only 6 patients had partial response (solid vs mucinous) intraoperatively
On histological examination. No criteria of progression were evident, 25 patients had no change in histology, 5 patients
had partial response (2 patients from PMCA to fibrosis, 3 patients from PMCA to DPAM)
Conclusion:
By serial histology only 7 out of 32 patients (22%) had a partial response to neoadjuvant FOLFOX. (5 patients with
partial mucinous carcinoma to diffuse fibrosis transition and 2 patients with complete response whose pathology was
changed from PMCA to DPAM).
Clinical and CT assessments were found to be of little value over this short period.
The surgeon's intraoperative findings must be interpreted with caution
The new standard for response assessment for these patients may be serial histological evaluations.
To those patients with PMCA invasive peritoneal lesions were noticed and abundant epithelium.
Progression
Stable
Partial
Complete
7
22
3
0
Clinical exam.
7
20
5
0
CT scan
17
9
6
0
Operative findings
0
25
5
2
Histology
DAY (3)
Wednesday, November 19th
13h30-15h30: Ovarian Cancer
Chairmen: G. Freyer (Lyon, France), AA Tentes (Didimotichon,
Greece)
14h30-14h40: Perspectives in clinical research for the treatment
of peritoneal carcinomatosis in ovarian cancer
M. Deraco (Milan, Italy)
Perspectives in clinical research for the treatment of peritoneal
carcinomatosis in ovarian cancer
M. Deraco (Milan, Italy)




The optimal residual disease for gynecologists is less than 1 cm.
The PSM group disagrees and states that it should be: residual disease<2.5mm
(huge difference)
To come to an agreement Deraco proposes that optimal cytoreduction would be when
the residual disease would be less than 5 mm.
Therefore, he proposes: for stage III/IV ovarian cancer with cytoreducable disease
according to the CT scan findings: patients to undergo cytoreduction with RD<5mm
and HIPEC.