1. Present and Future of Hyperthermic intraperitoneal chemo (HIPEC) in Colorectal Peritoneal Metastases Dominique ELIAS Cancer Campus, Grand-Paris

2. Stages IV treated with Chemo: PC have a poorer prognosis than other sites From the phase III trials N9741 and N9841 (Folfox / Folfiri) NbMedian OS Without PC173117.6 months p< 0.01 p< 0.01 With PC36412.7 months Conclusion: - Shorter OS and DFS when PC - 5-y survival with Folfox (all pts: 4%) (Franko J et al. ASCO 2011)

3. Is it possible to obtain definitive cure with CCRS + HIPEC ? Prospective study of our patients treated between January 1995 and December 2005 (n=93). Learning curve = worst results. The Cure = no recurrence during a minimal delay of 5 years (Goéré et al. Ann Surg 2013, on line)

4. Median follow-up: 99 months Median follow-up: 99 months Median Survival : 34 months Median Survival : 34 months Overall 5-year survival : 32% Overall 5-year survival : 32% Absolute cure at 5 years:17/107 pts = 16%

5. At 10 years: 102/612 pts =16,7% At 5 years without rec. 24/148 pts =16%

6. At last…… 1) 1) Hepatectomy for PM or HIPEC for PM: overall survival and definitive cure rates are the same. 2) 2) Peritoneum can be considered as an organ, a site of metastasis, similarly to the liver.

7. Current survival rate of 146 colorectal PC treated with CCRS + HIPEC: Prospective bi-centric study (Paris/ Montpellier) (Quenet, Elias et al, Ann Surg 2011; 254: 294-301) Median survival: 41 months 5-year survival: 48%

8. Is there a benefit to use surgery alone ?

9. Surgery versus No Surgery Surgery versus No Surgery Is there a trial comparing ? Is there a trial comparing ?Surgery Similar patients ® No Surgery Answer is: NO Answer is: NO

10. Complete resection alone of PC ? NbSelection Median OS 5-Y Survival NbSelection Median OS 5-Y Survival Mulsow 201131IP <10 25 months22% (Erlangen) Cashin 201257+ SPIC* 25 months18% (Uppsala) (Uppsala) Evrard 201230IP <10 30 months25% (Bordeaux) *SPIC = Sequential postop. intraperitoneal chemo.

11. 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)

12. Conclusion: Conclusion: No clear difference between resection and no resection. When it is possible to easily resect the PC: probably it is useful for the patient. If you do it, median survival will be at least 25-30 months.

13. Who is it interesting to resect, and how to resect ?

14. Multicentric retrospective study (15 years), Multicentric retrospective study (15 years), Including the leaning curves of all the centres = the worst results Complete cytoreductive surgery (CC0) in 85% of the cases Complete cytoreductive surgery (CC0) in 85% of the cases Postoperative deaths: 3% Postoperative deaths: 3% Morbidity (grade 3-4): 30% Morbidity (grade 3-4): 30% Mean hospital staying: 22,5 days Mean hospital staying: 22,5 days (Elias et al. J Clin Oncol 2009; 27: 681-685) French registry: 523 colorectal PC treated with cytoreductive surgery + intraperitoneal chemo treated in 23 centres.

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

16. Survival according to the Radicality of the Surgery (p< 0.0001) Look at the median survivals….

20. The Peritoneal carcinomatosis Index (PCI) (Ranging from 1 to 39)

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

22. PC with associated LM ? IGR’series: 61 HIPEC alone vs 37 HIPEC + LM Retrospective study issued from a prospective data base. Retrospective study issued from a prospective data base. Selection of similar patients (61 and 37): Selection of similar patients (61 and 37): Age, Sex, Status of the primary, PCI (mean was 13), radicality, systemic chemotherapy. Age, Sex, Status of the primary, PCI (mean was 13), radicality, systemic chemotherapy. Except for LM Except for LM Mortality: 4%; Morbidity: 54% Mortality: 4%; Morbidity: 54% (Maggiori L et al. Ann Surg 2013)

23. Higher Survival rate (p=0.04) when no LM

24. PCI<12 without LM : 76 months PCI<12 + LM <3: 40 months PCI≥12 or LM ≥3: 27 months Overall Survivals according to the extent of the disease

25. What patients to resect ? Those with a PCI < 20 Those with a PCI < 20 Those with a good general status Those with a good general status LM are not a contraindication if resectable without major risk LM are not a contraindication if resectable without major risk

26. Is it useful to add HIPEC ?

27. Principle of HIPEC: A combined treatment 1. Surgery to treat the visible disease (> 1 mm) 2. HIPEC to treat the remaining non visible disease. The strong belief of surgeons in the efficacy of this « package » encourages them to devote a lot of time and a lot of energy to resect all visible disease (+++). The strong belief of surgeons in the efficacy of this « package » encourages them to devote a lot of time and a lot of energy to resect all visible disease (+++).

28. Impact of HIPEC alone: experimental data 60 rats with colorectal PC were randomized in 3 arms. Hipec: 90 min, close procedure, inflow temperature at 42°C. CRS CRS + HIPEC CRS + HIPEC Mito 15 mg/m²Mito 35 mg/m² Nb 2020 20 R2 64 4 Med. Surv 43d75d 97d P 0.003 < 0.001 Conclusion: Efficacy of HIPEC and efficacy of increasing dosage. (Klaver Y et al. Br J Surg 2010; 97: 1874-80)

32. Complete surgery (CS) alone versus CS plus HIPEC ? We have not yet the answer We have not yet the answer French Prodige 7 trial is on going French Prodige 7 trial is on going Complete cytoreductive surgery ® HIPECNo HIPEC Oxali, 30 min, 43°C +5-FU and Leuco IV Already 250 randomized patients among the 280…

33. Equivalence between LM and PM 287 hepatectomy 287 hepatectomy 119 CCRS+HIPEC 119 CCRS+HIPEC Exclusion of [Hepatec + CCRS-HIPEC] (n=37) Exclusion of [Hepatec + CCRS-HIPEC] (n=37) Subgroups according to the global tumor load: Subgroups according to the global tumor load: –LM in 2 groups: ≤ 10 LM, and > 10 LM –PM in 3 groups: PCI 1-5, 6-15, > 15

34. Same overall global survival

35. Overall survival for the 2 gps of LM

36. Overall Survival for the 3 gps of PM

37. Equivalence of prognosis between LM and PM

38. Application and extension of this therapeutical concept: Introduction to the concept of a Second- Look Surgery in patients at high risk of developing colorectal peritoneal metas. at the moment of the resection of the primary Introduction to the concept of a Second- Look Surgery in patients at high risk of developing colorectal peritoneal metas. at the moment of the resection of the primary (Elias et al. Ann Surg 2008; 247: 445-450)

39. Rational of the second-look 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. 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.

40. Definition of High-risk patients Review of the literature (6522 articles) Review of the literature (6522 articles) No real high-risk: –Occlusive tumors –Bleeding tumors –T4 –Positive cytology –Positive lymph nodes –Rignet-cell tumors –Mucinous tumors Real high-risk: -Perforated tumors -Peritoneal metastases -Ovarian metastases (Honoré C. et al. Ann Surg Oncol 2013; 20: 183) Risk between 35% and 80%Risk ≤ 20%

41. Patients et Methods Patients with a high risk to develop a PC: we selected 3 gps: – (which was completely resected during surgery) –With minimal macroscopic PC (which was completely resected during surgery) – –With ovarian metastases – of their primary tumour –With 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), 12 months after their first surgery, if a complete work-up was negative, we proposed a second look + HIPEC (Elias et al. Ann surg 2011; 254: 289-293)

42. Results (1) Between 1999 and 2009 – –41 patients included – –Median follow-up: 30 months [range: 9-109] Macroscopic PC at « 2 nd look » : (23/41) (mean PCI 8 + 6) Macroscopic PC at « 2 nd look » : 56% (23/41) (mean PCI 8 + 6) 100% HIPEC Mortality : 2% (1/41) Morbidity : 9,7% (4/41)

43. Results (2) Minimal synchronous PC resected with the primary tumour Minimal synchronous PC resected with the primary tumour –Peritoneal recurrence rate 60% (15/25) –Mean PCI : 9±6 Synchronous ovarian metastases resected with the primary tumour Synchronous ovarian metastases resected with the primary tumour –Peritoneal recurrence rate 62% (5/8) –Mean PCI : 7±5 Perforated primary tumour Perforated primary tumour –Peritoneal recurrence rate 37% (3/8) –Mean PCI : 5±2

44. Results (3) Results (3) Peritoneal recurrence : 17% (7/41) 6 after PC at 2 nd look (26%) 1 after no PC at 2 nd look (6%) 5-y overall survival 90% 5-y disease free survival 44% PC at 2 nd look = risk factor for Peritoneal recurrence

45. « ProphyloCHIP » trial (Prodige 15) Nb of patients = 130 Nb of patients = 130 (75 patients already randomized) 1 st endpoint : 3-y Disease Free Survival 1 st endpoint : 3-y Disease Free Survival « high risk » patients Standard arm Experimental arm 6 months IV Folfox IV Surveillance Systematic 2 nd look plus HIPEC Randomization Negative work-up

46. Dans la vraie vie: que faire quand vous découvrez fortuitement une CP ? L’idéal L’idéal L’acceptable L’acceptable L’innaceptable L’innaceptable

47. Conclusion The treatment of PC has dramatically changed during the last 10 years. The treatment of PC has dramatically changed during the last 10 years. Now it is possible to definitely cure some PC (like liver metastasis) Now it is possible to definitely cure some PC (like liver metastasis) The impact of a complete surgery is major (+++). The impact of a complete surgery is major (+++). The impact of HIPEC is not clear enough. The impact of HIPEC is not clear enough. The second-look + HIPEC approach is promising as early treatment of early peritoneal metastases for high-risk patients. The second-look + HIPEC approach is promising as early treatment of early peritoneal metastases for high-risk patients. To progress more rapidly: please, include your patients in trials ! To progress more rapidly: please, include your patients in trials !

48. Thank you Thank you

49. Cox regression analysis Overall Survival Odds-Ratio (95%) p PCI ≥ 12 PCI ≥ 12 4.6 (2.5-8.5) <0.001 pN+ primary tumour 3.3 (1.3-8.9) 0.016 no postoperative chemotherapy 3.0 (1.5-6.2) 0.002 synchronous resection of PC & LM 2.0 (1.1-3.7) 0.022 Independent factors for poor overall survival :

50. Cox regression analysis Disease-free Survival Odds-Ratio (95%) p PCI ≥ 12 PCI ≥ 12 1.6 (1.01-2.7) 0.048 synchronous resection of PC & LM 1.9 (1.2-3.2) 0.007 Independent factors for poor disease-free survival