6 th International Workshop on Peritoneal Surface Malignancy

1. 6th International Workshop on Peritoneal Surface Malignancy • These notes were adapted from the slides shown at the presentations. Copyrights are owned by the authors. Please do not quote without their permission.

2. DAY (1)9h00-9h30 : Opening Lecture – PH Sugarbaker (Washington, USA):Moving from consensus to clinical integration with the help of intracavitary pharmacology

3. 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)

4. Moving from consensus to clinical integration with the help of the intracavitary pharmacology - PH Sugarbaker (USA) • 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 • What can be recommended when the CT markedly underestimates the extend of disease? Is a surgical complete response a worthy goal? • 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 • 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

5. 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 (log-kill hypothesis)

6. 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: • Evidence based medicine supports the use of CRS& HIPEC over systemic chemo and serial debulking. • It is very difficult to run phase III study and have patients choose to be randomized to the arm with less favorable prognosis. • 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. • By analogy, we need to declare CRS& HIPEC as standard of care without need for phase III study. • The problems we face are not scientific but are economic and skill related. • PC patients need to be informed of their options for treatment. • The next step is optimization of therapy using clinical and pharmacological data.

7. DAY (1)9h30-11h00: Indications and place of imaging. Role of radiologists. Chairmen: F Cotton (Lyon, France), DL Bartlett (Pittsburg, USA)9h30-9h50: Cytoreductivesurgery 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)

8. 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 • PCI<20 • no extra abdominal metastasis • Limited small bowel disease • Good performance status, WHO 1-2 Decision making: other factors • Lymph node metastasis • Response to systemic chemo • N-category primary tumor • Differentiation (signet cell) • Postoperative quality of life • Learning curve • 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.

9. 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) 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

10. 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 • Reasonable detection of extraperitoneal disease (complemented by PET/CT) • Identification of key features that preclude a complete cytoreduction • 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.

11. Imaging and peritoneal carcinomatosis: what should be preoperative exams? The radiologist’s point of view O. Pellet (Lyon, France) Imaging of peritoneal carcinomatosis PET/CT: negative points • Low spatial resolution of PET=5mm • Risk of false positives due to infection, inflammation and granulomatosis which also uptakes FDG (hypercellularity) • Limited equipment PET –emdCT Which means: Diagnostical use of CT :mdCT, Iodine contrast injection: e • 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.

12. 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. • 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. • 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. • The CT scans having a spatial resolution of 5mm are exceptional for anatomical imaging. • With CTs we can see: • ascites • Omental masses • Omentum lesions • Implants • Thickening • Nodules • Mesenteric carcinomatosis • With PET scans we have the advantage of knowing: • 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. • Unfortunately the correlation between the PCI score and the CT scan is really low making CT scans not sufficiently sensitive for Peritoneal Carcinomatosis Staging • The radiologist advices: Use NEGATIVE contrast (water), not POSITIVE (that lights things up in the imaging).

13. Conclusions of the whole session • 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)

14. 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 extentM. Valle (Roma, Italy)11h50-12h10: Recommendations to general surgeons for preoperative peritoneal carcinomatosis discoveryB. 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)

15. Place of laparoscopy for the evaluation of carcinomatosis extent - M. Valle (Italy) • Laparoscopy could become a diagnostic tool for disease staging. • 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. • 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: • 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: • Many were excited at the prospect of laparoscopic discovery but were usually put down by the instruction to limit incisions to midline. • Participants looked forward to further evidence on the safety of the procedure and the identification of a long-term follow up for tumor seeding.

16. Recommendations to general surgeons for preoperative peritoneal carcinomatosis discoveryB. Moran (Basingtoke, UK) Some variables must be noted by the general surgeons who assess the patients with PC: • Age (over 70) • liver involvement • whether patient is fit • neurological history • clinical aggressiveness • malnutrition • small bowl involvement (most determining factor to survival)

17. 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

18. DAY (1)14h30-15h45: Cytoreductive surgery. Technical aspects (Video-Photo)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)

19. Bowel and mesentery disease. Anastomoses, Stomy by O’Dwyer • 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.

20. Parietal disease. Parietal peritonectomy (gutters, cupula), scar removing by D. Bartlett Cytoreduction steps • 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

21. Parietal disease. Parietal peritonectomy (gutters, cupula), scar removing by D. Bartlett Specialized tools • 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

22. 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 • Pelvis • Ileoceacal • Omentum/colontransversum • Small bowel • Sub hepatic • Sub phrenic left • Sub phrenic right

23. 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 complicationsA. Gomez Portilla (Vitoria, Spain)17h20-17h40: Intraoperative parameters that could be markers of morbidityS. Kusamura (Milan, Italy)

24. Treatment of postoperative surgical complications by Portilla Carcinomatosis vs. conventional patients Conventional patients Cytoreductionpatients Previous surgeries 0 >1 Previous chemotherapy 0 >1 Parietal peritoneum present absent Greater and lesser omentum present/absent absent Parietal peritonectomies 0 >3 Visceral resections 1 >3 Bowel anastomosis 1 or 2 >2 Serosal tears unusual frequent HIIC + EPIC no Yes Empty cavity / dead space no Yes Severe sepsis or C.I.D. unusual frequent Abdominal compartment syndrome unusual frequent

25. Treatment of postoperative surgical complications by Portilla • 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.

26. Intraoperative parameters that could be markers of morbidity by Kusamura There are 4 markers of morbidity: • 1. systemic inflammatory response syndrome (SIRS) • 2. sepsis (bacteremia + SIRS) • 3. Severe sepsis • 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

27. 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 cancerF. Quenet (Montpellier, France)9h10-9h30: USA ongoing trials in the treatment of peritoneal carcinomatosis from colorectal cancerJ. Esquivel (Washington, USA)9h30-9h50: Long term of randomized study in colorectal carcinomatosisV. Verwaal (Amsterdam, Netherlands)

28. 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. • Survival according to liver metastases: Liver metastases has a negative impact. • Survival according to HIPEC drugs: Oxaliplatin doesn’t show a significant impact compared to Mitomycin C Analysis of disease-free survival Prognostic parameters: • Completeness of cytoreduction • Peritoneal index • Lymph node status • Postoperative systemic chemo Conclusion / colon –rectum • HIPEC has become the new therapeutic standard • Dramatic impact of the completeness of the cytoreductive surgery • The prognostic impact of HIPEC is less clear • Low impact of associated liver metastases There are 2 other important prognostic factors: • The extent of the PCI • The adjuvant systemic chemo Conclusion / Appendix cancer • Good results of HIPEC • The prognosis is better in women Survival / complications: • Lower than those of all pseudomyxomas, but close to those of grade 3 pseudomyxoma • Far better than those of colon – rectum • 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: • The high-risk patient group should have 6 months of FOLFOX, then a second-look surgery • 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.

29. French ongoing trials in the treatment of peritoneal carcinomatosis from colorectal cancer by Quenet Drug: Mitomycin C : The Dutch trial 1998-2001 105 patients • The median survival was approximately 21 months • The 3 and 5 year survival rates were 28% and 19% • Complete cytoreduction : median survival 42.9 months. • Minimal residual disease: median survival 17.4 months • When a gross macroscopic tumor was left behind the median survival was 5 months. • After an 8 years follow up: the 5-year survival was 45% for those patients in whom a R1 resection was achieved. Oxaliplatin-Retrospective study • 2 groups of patients retrospectively selected • 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.

30. 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. • The hypothesis is that HIPEC increases survival from 30% to 48%. Trial is conducted in the following way: • Pool of patients: respectable PC • Everyone gets CC (R1/R2) which is <1mm. • Patients are then randomized to an arm with HIPEC and an arm without HIPEC. • Both arms receive systemic chemo after surgery. • Trial is still at the early stages. Findings so far support the hypothesis. The second trial is about a systematic second look surgery. • This trial is conducted for patients with a high risk of developing PC at 12 months. • Patient pool includes those with minimal micro PC, synchronous ovarian cancer, and those with perforations. • Finding so far corroborate the hypothesis that high risk population might benefit from systematic second look surgery. Discussion focused on the following: • Clear distinction between the concept of systematic second look and serial debulking. The latter involving CCR. • The difficulties involved in second surgery following a CCR.

31. USA ongoing trials in the treatment of peritoneal carcinomatosis from colorectal cancer by Esquivel • 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. • 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. • 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.

32. Long term of randomized study in colorectal carcinomatosisV. Verwaal (Amsterdam, Netherlands) • 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.

33. DAY (2)10h30-12h40: Rare Peritoneal Surface Malignancies and Place of PathologistChairmen: 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 pathologyS. Bruin (Netherlands)11h10-11h30: New prognostics factors for peritoneal mesotheliomeM. 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)

34. 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

35. 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 : 1. Disseminated Peritoneal Adeno Mucinosis 2. Peritoneal Mucinous Carcinomatosis Non-mucinous : Peritoneal Carcinomatosis (PCA)

36. The renewal of pseudomyxoma peritonei pathology by Bruin Non-mucinous Mucinous DPAM PMCA PMCA-I PCA

37. The renewal of pseudomyxoma peritonei pathology by Bruin Primary tumor location and type of PSM: 71%: DPAM6% : PMCA-I14%: PMCA9% : PCAPSM from primary colon tumors: 37% mucinousDPAM most frequently from a primary appendix tumor29% of primary appendix tumors: non-DPAMSurvival analysisSignificant factors multivariate analysis Histological classification Gender Number of regions Result of cytoreduction HIPEC as first treatment on PSM Tumor locationA nomogram score (predictor of survival for individual patients) was created based on the theoretical assumptions of this studySummary:PSM is often mucinousDPAM carried better survival than PMCA and PMCA better than PCAFemale patients have better survival than male in mucinous PSMNon-mucinous tumors have worse survivalHistological classification of colorectal and appendiceal PSM give prognostic informationPSM should be classified by a standardized protocolHIPEC nomogram provides a tool for individual patient risk assessment.

38. 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.

39. 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

40. DAY (2)14h30-15h45: Gastric Cancer. Chairmen : P. Shen (WinstonSalem, 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)

41. 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: StagePeritoneal carcinomatosis description Stage 0No macroscopic disease Stage 1Malignant implants less than 5 mm in diameter Localized in one part of the abdomen Stage 2Diffuse to the whole abdomen Stage 3Malignant implants 5 mm to 2 cm Stage 4Large 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.

42. 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.

43. 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.

44. 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)

45. 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.

46. DAY (2)17h30-18h45: FREE PAPER SESSION n°1Chairmen: 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 treatmentSpeakers: Marian Gutowski, MDTuesday 18h10-18h18: Peritonectomy with high voltage electrocautery generates higher levels of ultrafine smoke particlesSpeakers: 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.

47. 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: • Histological variant (PMCA, ID vs. DPAM) • PCI (<20 vs. >20) • Preoperative serum (CEA, CA125, CA19-9, CA15.3) • 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 • 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.

48. 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

49. 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.

50. 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.