1. Optimal Management of Peritoneal Carcinomatosis (Complete cytoreductive surgery plus HIPEC) Dominique Elias, Institut Gustave Roussy, Villejuif, France

2. A New Therapeutic Concept... To treat MACROscopic disease with complete surgical resection. To treat remaining MICROscopic disease with intraperitoneal chemotherapy, which is specific by Its timing: immediate Its concentration (20 to 400 times higher than I.V. route) (Sugarbaker PH et al. Seminars Oncol 1989; 16: 83-97)

3. Importance of a complete macroscopical resection as a first step DrugReferenceModelDepth penetration CisplatinBrincker (93)Mesothelioma1-2 mm Mc Vie (85)Ovarian1-3 mm Doxorub.Ozol (82)Ovarian4-6 layers of cells Methotr.West (80)Sarcoma3-7 layers of cells 5-FUNederman (81)Glioma0.2 mm Mitoxant.Los (90)Sarcoma5-6 layers of cells

4. 506 patients with colorectal PC 28 teams, between May 1987 and December 2002 With numerous different techniques (with and without hyperther.) Médian follow-up: 53 months Mortality: 4%, morbidity: 23% Residual Residual tumor 2.5 mm Median Survival 32.4 8.4 (months) p < 0.001 ( Glehen et al. J Clin Oncol 2004; 22; 3284-92)

5. Glehen, O. et al. J Clin Oncol; 22:3284-3292 2004 Actuarial survival of 506 patients who had cytoreductive surgery combined with perioperative intraperitoneal chemotherapy, according to the completeness of cytoreduction

6. Survival according to the Completness of the CRS (100 cases, colorectum) Sugarbaker P. Cancer Chemother Pharmacol 1999; 43 (suppl) S15-25)

7. Verwaal 2005: 117 patients avec CP d’origine Colorectale

11. To cure the millimetric and microscopic residual tumor disease: The « Chemical shock »

12. Hyperthermia potentiates the efficacy of Chemotherapy - At a Tissular level: - Decreases dramatically the intertitial pressure in tumors (from 13 to 0 mm Hg) - At a cellular level: - Increases the penetration of the drugs (+ 78% for mito) - Increases their effect (30 to 50% for mito). More high is the temperature, more efficient is the IPCH. The aim: to be as close as possible to possible 43°C (+++)

13. Relation between the level of Hyperthermia and dura- tion on tumor death. Meta-analysis of studies < 1940 Johnson HJ Amer J Cancer 1940; 38: 533-46 Straight line concerns in vivo results 42°C20 hours 40°C 50 hours 44°C 8 hours 46°C 1 hour

16. - Mitomycine - 40-41°C - 90 min - Coliseum Verwaal et al. Amsterdam J Clin Oncol 2003; 21: 3737

17. Cytoreduction Number no macroscopic tumour ( R1 )18 (38%) macroscopic tumour < 2.5 mm (R2 a )21 (43%) macroscopic tumour > 2.5 mm (R2 b )9 (19%)

18. Survival Log Rank p = 0.0013 At 3 years: 36% vs 10% (p< 0.01)

19. Retrospective comparative study In the control group: 3.4 lines of chemo Median survivals: 25 months vs 60 months (Elias et al. J Clin Oncol 2009; 27:681-5)

20. Trial «Chip 2-2» Survival rates of 30 colorectal patients Overall Disease free 2 years73% (59-88) 48% (32-66) 3 years53% (39-72) 41.5% (27-59) 5 years48.5% (31-66) 34% (19-52) (Elias et al. Gastroenterol Clin Biol 2006; 30: 1200-4)

21. Survival rates of 30 colorectal patients Median follow-up: 55 months (31-84)

24. At last…… After a complete cytoreductive surgery followed with HIPEC, overall survival rate (40-50%) is the same than those obtained after partial hepatectomy for liver metastases.

25. French on-going trial « Prodige 7 » Complete resection of PC Randomization HIPECNo HIPEC Any types of systemic chemotherapy are autorized…

26. The French Multicentric Database Official report of the 2008 AFC’s congress Each year, the French Association of Surgery (AFC) selects one subject as main topic for its congress. This topic is selected 3 years before the congress and comitted to 2-3 experts who are in charge to organize a national retrospective data base. After analysis, the results of this multicentric data base are presented during the first general session of the congress, and published in a specific book (AFC ‘s monography).

27. Colon-Rectum 523 patients treated in 23 centres (1990-2007) Mean age: 53 ± 12 years 7% came from rectum Complete cytoreductive surgery (CC0) in 85% of the cases With HIPEC: 86%, with EPIC: 14%

30. Morbi-mortality Postoperative deaths: 3% Morbidity (grade 3-4): 30% Mean hospital staying: 22,5 days Multivariate study: 1. The extent of the PC (Sugarbaker’index)(p< 0.0001) 2. The centre (p< 0.0001) 3. With a lower impact: - EPIC (more morbid than HIPEC) (p=0.03)

31. Overall Survival of the 523 patients Median survival: 30 months 5-years survival: 27%

32. Survival according to the Radicality of the Surgery (p< 0.0001)

33. Survival according to the Extent of the Péritoneal Carcinomatosis (p< 0.0001)

34. Survival according to the Lymph Node Involvement (n= 125) (p= 0.02)

35. Survival according to the presence of associated Liver Metastases (n= 65) (p= NS)

36. Survival according to the Grading (p=0.09)

37. Multivariate study Variable pRelative risk P. Index <0.0001 1.052 Each increasing of one point increases the risk of death of the rapport of risk, i.e. of 5.2%. CC-Status 0.05 1.398 In three classes: CCR-0, CCR-1, and CCR-2. To pass from one class to another increases of 39.% the risk of death. Lymph node 0.02 1.534 Adjuv. Chemo 0.002 0.578

38. Survival of the 416 patients of the CC0-Group Median survival: 33 months 5-years survival: 30%

39. Survival according to the Extent of the Peritoneal Carcinomatosis (p< 0.0001)

40. Survival according to the Centre (p= 0.003)

41. Survival according to the Type of I.P. Open / Close / EPIC (=NS)

42. HIPEC: for which patients ? 1) Physiologic aging  65 years. 2) No extraperitoneal localization (except 1-3 LM). 3) Moderate extent of the PC (operative report +++, rectal exam., CT-scan). 4) No occlusion in more than 1 site 5) No ascitis growing under chemo. 6) Chemosensitive patient (?).

43. Results of a Systematic Second- Look Surgery in Pts at High risk of developing Colorectal Peritoneal Carcinomatosis (Elias et al. Ann Surg 2008; 247: 445-450)

44. Rationnal HIPEC is all the more « light » and all the more efficient that the PC is minimal. But to detect early minimal PC is possible neither with clinic neither with imaging. It is the reason why it is logical to propose a systematic second-look to asymptomatic patients presenting high risks to develop a PC, with the aim to treat PC at an early stage. We chose the delay of 1 year…

45. Patients et Methods From 1999 to 2006, 29 patients with a high risk to develop a PC (without clinical, radiologic or biologic symptoms), underwent a second look, 12 months after their first surgery. Selected: 3 groups of patients: 16 who presented a minimal macroscopic PC synchronous to the primary (and which was completely resected during the same session) 4 who presented synchronous ovarian metastases, 9 who presented a perforation of their primary tumour. All these patients received the adjuvant standard treatment after the first surgery: 6 months of systemic chemotherapy (Folfox or Folfiri)

46. Patients et Methods (2) Careful exploration of the whole abdominal cavity Mean duration of surgery: 6 hours 29 patients 16 with PC13 without PC 16 Cytoreduc Surg + HIPEC Nb of positive areas: 5.6gp + initial PC: 6 HIPEC Mean peritoneal index: 10 (2-24) 7 others: No HIPEC

48. Results A macroscopic PC was found and treated in 16/29 (55%) patients, Respectively: In gp with a PC at the first look: 10 of 16 patients had PC (63%) In gp with ovarian metastasis: 3 of 4 had PC (75%) In gp with perforarion of the I, 3 of the 9 patients had PC (33%) No mortality (0%) Morbidity (grade III/IV) was 14%. Mean duration of hospital stay was 16 days (Elias D et al. Ann Surg 2008; 247: 445-450)

49. Survival (early results) After a mean follow-up of 27 months (6-96): For the 16 patients who underwent a resection of PC + HIPEC: - 8 (50%) are free of disease, - 4 (25%) recurred on peritoneum, - 4 (25%) recurred outside the peritoneum. For the 6 patients who underwent HIPEC, without detectable PC (prophylactic): - No recurrence (+++) For the 7 patients who did not undergo HIPEC: - 3 developped a PC (+++)

50. Future French randomized multicentric trial High-risk group after first surgery (information, signed consent, registration) 6 months of IV Folfox (then complete work-up: if no detectable recurrence:) Randomization [8 th month] NothingSurgery, with HIPEC « de principe »

51. Conclusion / Colon-rectum 1. Cytoreductive surgery + HIPEC has become the new therapeutical standard (when feasible) Dramatic impact of the completness of the cytoreductive surgery Less clear prognostic impact of HIPEC Low impact of associated liver metastases Two other important prognostic factors: - The extent of the PC (= confirmation) - The adjuvant systemic chemo (= new) 2. Possibly, in high-risk patients, prophylactic surgery + HIPEC could be benefit

52. Peritoneal Pseudomyxomas

55. Pseudomyxomas Origin: appendix, (> 90%) From benign to malign forms (Ronnett): Low grade=Diffuse peritoneal adenomucinosis Intremediate grade High grade =Mucinous peritoneal carcinomatosis But a benign disease is able to kill…..

65. Tumor nodule on stomach

66. Grade 0 ???

67. Grade 1: Bordure Unicellulaire

68. Grade 1: bordure unicellulaire, sans atypie

69. Grade 3: + présence de blocs tumoraux

70. Classical treatment: Iterative « optimal » cytoreductive surgery 1.Gough et Coll. 1995 (Mayo Cinic): 56 patients (1957-83) - 33% with complete surgery - 5-year survival: 53%, 10-year survival: 31% - 97% with recurrence 2.Miner et Coll. 2005 (Memorial SK): 97 patients - 53% with complete surgery - 31% received IP chemo - Mean of 2.2 laparotomy per patient - 10-year survival: 21% - 88% with recurrence at 5 years (Ann Surg 1994; 219: 112-9)(Ann Surg 2005; 241: 300-8)

72. Pseudomyxome: nettoyage du pédicule hépatique

74. Pseudomyxomas: Results of Incomplete Cytoreduction in 174 patients (Glehen, Sugarbaker Ann Surg 2004; 240: 278-85) ____________________________________________________ = 27% of the 645 operated patients 76 received EPIC, and 61 received IPCH Mortality: 0%, mortality 33% Survival rates: 3-y = 34%, 5-y = 15% Assesment by tumor histology (5-y survival rates): Grade 1 and grade 2: 20% Grade 3: 10% p=0.01 Conclusion: incomplete cytoreduction results in poor long-term survival.

75. Results / Survival Series Nb de Pts 5-y Survival Sugarbaker 200450172% Zoetmulder 200610360%* Loggie 2006 11050%* IGR 200710580% AFC 200830175% * Some incomplete surgery

76. AFC’s Report 2008: 301 patients 18 centres between mars 1993 and October 2007 Origin: appendix in 91% of the cases

77. Treatement Complete resection in only 73% I.P chemotherapy: - HIPEC in 90% with: * 80% with Coliseum technique * 62% with oxaliplatine - EPIC in 10% of pts

78. Morbi-Mortality Mortality: 4.4% Morbidity (grades 3-4): 41% with 18% of re-surgery. Impacting factors: (multivariate study): - Extent of the PC Sugarbaker’s index) (p= 0.002) - Histological grade 3 (p= 0.03)

79. Overall Survival - 75% at 5 years - 55% at 10 years After a CC0 surgery: - 84% at 5 years - 61% at 10 years

80. Survival according the completness of surgery (p < 0.0001)

81. Survival according to Sex (p= 0.02)

82. Survival according to the extent of the PC (p< 0.0001)

83. Survival according to the Grading (Ronnett) (p =0.03)

84. Survival according to the technique of I.P. Chemo. (p= 0.001)

85. Multivariate study of pronostic factors 1. The extent of the PC (p= 0.002), strongly correlated with incomplete resection rate. 2. Histological grading and presence of invaded lymph nodes (p=0.02) 3. The technique of IP chemotherapy (p= 0.005)

86. Analysis of the 220 CC0-patients

87. The Extent of the PC (p=0.004)

88. Experience of the centre (P < 0.01)

89. But the grading losts its impact (+++)

90. Conclusion PMP are rare but deadly. There is different forms of PMP, but prognosis is almost similar if the resection is complete. The gold standard treatment is complete cytoreductive surgery plus HIPEC, when feasible.

91. Peritoneal Mesotheliomas

92. Mesotheliomas Abdominal pain Increasing of the abdominal volume Alteration of the general status Ascitis Coelioscopy: biopsy and meticulous description of all the lesions (+++)

93. A rare pathology 200 cases /year in France Numerous differential diagnosis Diagnosis possible only histology: It must be a constant thought….

94. Histo. Diagnosis is difficult: Immunohistochimy (+++) MPM AdénoKEpiderm Calrétinine +90% 10% WT1 + (T. Wilms) 70% 0% 0% Ber-Ep4 -85% ovary: 0% B72-3 -90% 20% ACE -90% 10%

95. Numerous histological types High grades: Sarcomatoid Biphasique Many epithelioid (the more frequent) Low grades: Papillairy forms of epithelioid Multikystiques

96. Typical MPM

97. Papillary Mesothelioma

98. Epithelioid Mesothelioma

99. MPM (girl of 14 years)

100. Kystique Mesothelioma (1)

102. Kystique Mesothelioma (2)

103. Classical treatment Systemic chemo : Alimta* (premetexed) + Platine Gem-ox Tom-ox Navelbine + Platine Median survival : 12-15 months (5-years survival : 15-25%)

104. Survival with classical treatement AuthorsYearNb Pts Median /months Markman 1992199 Neumann19997412 Eltabbali19991512.5

105. IGR : Pts treated with CCRS + HIPEC (1996-2004; mean follow-up: 55 months) 26 patients 1 postop. Death (4%) Morbidity: 54% Median de survival > 100 months Overall 5-year syrvival: 63% Low grades >> High grades

107. Results of HIPEC for MPM AuthorYear No PtsMédiane Survie 5 ans Sugarbaker 8 2006 1005246% Alexander 9 2003 499259% Deraco 10 2006 49NA57% Glehen 11 2003 153629% Loggie 12 2001 123433% IGR2006 26 10063% AFC2008 834544% 7 gps (Yan)2009 4055347%

108. Conclusion / Mesotheliomas Different pathological types with different prognosis. When feasible the gold-standard treatment is the complete cytoreductive surgery plus HIPEC.

109. Other results and indications of Complete cytoreductive surgery plus HIPEC

110. AFC’s Report 2008 Origin Nb PtsSurvival rate Stomach 159 3-y: 12% K. Appendix 49 5-y: 56% Small Bowel455-y: 33% Serous primitive 33 5-y: 58% Sarcomatosis 283-y: 27%

111. What about Ovarian cancer ? Gynecologists are late……. Results are very poor as « salvage » treatment. High probability of efficacy if early proposed (even at the first-look, even at the « intervalle surgery », possibly at a second-look). Modality of HIPEC must be defined… Conclusion: only in prospective trials.

112. Thank-you !

113. Multivariate Study for the CC0 Group Variable p Relative risk Perit. Index <0.00011.054 Adjuv. Chemo 0.030.719 Experience <6y 0.011.841 Synchr. LM 0.011.623

114. Criteria of Exclusion Major criterias: Age > 70 years, OMS status  2, Extra-abdominal localizations LM (except if  3 and peripheric) Progression under chemo Minor criterias: Extended PC on clinic or CT-scan Occlusion Other intra-abdominal metastase (except liver or ovary)