CRS and HIPEC for Colorectal Cancer. Rajesh Nair, MD UF Health Cancer Center-Orlando Health March 11, 2017

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1 CRS and HIPEC for Colorectal Cancer Rajesh Nair, MD UF Health Cancer Center-Orlando Health March 11, 2017

2 Peritoneal Carcinomatosis from CRC Historically, a devastating problem Extreme morbidity from disease and from treatment Obstruction Prior to modern chemotherapy, survival was very limited Zhu et al. J Gastrointest Oncol 2013; 4(1):

3 Colorectal Cancer True incidence of PC in CRC hard to estimate In various series, the peritoneal surface is the initial site of failure in 10%-20% of patients after curative colon resection It is also involved in 40%-70% of patients who present with advanced disease In ~ 5%-10% of all patients with colon cancer and in 10%-35% of all patients with recurrent disease, tumor recurrences are confined to the peritoneal surface only Khatri. J Clin Oncol 2010; 28(1): 5-7.

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5 Multi-step process The pathophysiology of PC is complex and incompletely defined Likely includes: Exfoliated tumor cells with direct communication to the peritoneal surface Exfoliated cells delivered by the lymphatic system into the peritoneal cavity and sub-mesothelial spaces Growth factors, angiogenic factors and implantation factors either embedded in mucin or secreted directly into the peritoneal cavity

6 Sugarbaker PH (ed): Peritoneal Carcinomatosis: Principles of Management. Kluwer: Boston, p79, 1996

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8 CRS and HIPEC Goal: Complete cytoreduction followed by perfusion Applications Appendiceal Mesothelioma Colorectal Small bowel

9 Why even consider HIPEC? Systemic chemotherapy for advanced colorectal cancer has improved with longer median survival times Recent trials in advanced colorectal cancer with intensified systemic chemotherapy (both oxaliplatin and irinotecan treatment) including a biologic monoclonal antibody have demonstrated 30+ month median OS and a 12+ month PFS Loupakis et al. N Engl J Med 2014; 371: pp

10 However, long-term survival is still poor with 5-year projected survival < 10% The complete response rate is ± 4.8% and systemic chemotherapy alone has in spite of the improvements, basically no curative potential Cashin et al. Eur J Cancer :

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12 The peritoneum Single layer of mesothelial cells overlying several layers of connective tissues Total thickness of 90 μm There are very few blood vessels within the peritoneum, and those that exist are 40 μm from the surface Flessner et al. American Journal of Physiology - Renal Physiology 2005; 288 (3).

13 The peritoneum The mesothelial cells play a major role in the secretion of lubricant solutions made of primarily phospholipids and glycosaminoglycans This ensures a smooth sliding surface between the visceral and parietal peritoneum which is important for gut motility Flessner et al. American Journal of Physiology - Renal Physiology 2005; 288 (3).

14 Something perhaps a little better High drug concentrations in contact with floating tumor cells and at-risk lining surfaces Limited drug absorption, thereby enhancing tumor drug exposure but limiting systemic toxicity With mitomycin C, peak IP concentrations about 50-fold higher than peak serum levels have been demonstrated

15 Intraperitoneal chemotherapy gives high response rates within the abdomen because the peritoneal space to plasma barrier provides dose intensive therapy (1). Figure 1 shows that large molecular weight substances, such as mitomycin C. are confined to the abdominal cavity for long time periods (2). This means that the exposure of peritoneal surfaces to pharmacologically active molecules can be increased considerably by giving the drugs via the intraperitoneal as opposed to intravenous route. Sugarbaker PH et al. Cancer Res 1990; 50:

16 Rationale for hyperthermia Heat has anti-tumor effects by itself Heat increases drug penetration into tissue Heat increases the cytotoxicity of selected chemotherapy agents Heat at the peritoneal surface causes increased cytotoxicity of systemic chemotherapy to small cancer nodules

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18 Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy A retrospective, multicenter cohort study performed in French-speaking institutions to evaluate toxicity and principal prognostic factors after CRS and HIPEC and/or early postoperative intraperitoneal chemotherapy (EPIC) for PC from nongynecologic malignancies Glehen et al. Cancer 2010; 116(24):

19 Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy Included 1290 patients from 25 institutions who underwent 1344 procedures between February 1989 and December 2007 Overall morbidity rate: 33.6% Overall mortality rate: 4.1% Glehen et al. Cancer 2010; 116(24):

20 Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy Overall median survival: PMP: not reached Appendiceal adenoca: 77 months Mesothelioma: 41 months CRC: 30 months Gastric cancer: 9 months Glehen et al. Cancer 2010; 116(24):

21 Origin of Carcinomatosis in Patients Who Underwent Cytoreductive Surgery Combined With Perioperative Intraperitoneal Chemotherapy Etiology No. of Patients % Colorectal cancer Pseudomyxoma peritonei Gastric cancer Peritoneal mesothelioma Appendiceal adenocarcinoma Small bowel adenocarcinoma Primary peritoneal serous carcinoma Peritoneal sarcomatosis Others Glehen et al. Cancer 2010; 116(24):

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24 From Esquivel J. Sugarbaker PH: Elective surgery in recurrent colon cancer with peritoneal seeding: When to and when not to proceed. Cancer Therapeutics, Nov, l998.

25 Completeness of cytoreduction From Esquivel J. Sugarbaker PH: Elective surgery in recurrent colon cancer with peritoneal seeding: When to and when not to proceed. Cancer Therapeutics, Nov, l998.

26 In high-grade malignancy, complete cytoreduction may require a CC-0 score In less invasive malignancy such as pseudomyxoma peritonei, a complete cytoreduction may include CC-0 and CC-1 cytoreduction

27 Imaging Challenges Disease underestimation

28 Imaging Challenges

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31 Diagram highlighting the common 'blind spots' on conventional imaging owing to the low contrast of metastases against adjacent structures Kyriazi et al. Nature Reviews Clinical Oncology 2010; 7:

32 Steps/Areas of Inspection Abdominal incision Abdominal peritoneum Greater omentum Lesser omentum Right hemidiaphragm Left hemidiaphragm Liver surface Spleen Pancreas surface Stomach Small bowel Large bowel Right paracolic gutter Left paracolic gutter Right pelvic sidewall Left pelvic sidewall Bladder Vagina & internal genitalia Cul-de-sac of Douglas Retroperitoneum Kidneys

33 Assessment of the parietal peritoneum After the linea alba has been divided, a single entry into the peritoneal cavity in the upper portion of the incision (peritoneal window) allows the surgeon to assess the requirement for a complete parietal peritonectomy If cancer nodules are palpated on the parietal peritoneum, a decision regarding a complete parietal peritonectomy should occur Except for the small defect in the peritoneum required for this peritoneal exploration, the remainder of the peritoneum is maintained intact From De Lima Vazquez V, Sugarbaker PH: Total anterior parietal peritonectomy. J Surg Oncol 83: , 2003.

34 From Sugarbaker PH: Peritonectomy procedures. Surg Oncol Clin N Am 12: , 2003.

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40 All adhesions must be lysed to allow for even/complete drug distribution

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43 Major Complications (Grade 3/4 According to the National Cancer Institute Common Toxicity Criteria) Type of Complication No. of Patients % Grade 3-4 complications Reoperations Neutropenia Digestive fistula Pneumonia Postoperative bleeding Intra-abdominal abscess 90 7 Systemic sepsis Bowel obstruction Renal insufficiency 14 1 Glehen et al. Cancer 2010; 116(24):

44 Major Complications (Grade 3/4 According to the National Cancer Institute Common Toxicity Criteria) Type of Complication No. of Patients % Grade 3-4 complications Reoperations Neutropenia Digestive fistula Pneumonia Postoperative bleeding Intra-abdominal abscess 90 7 Systemic sepsis Bowel obstruction Renal insufficiency 14 1 Glehen et al. Cancer 2010; 116(24):

45 Morbidity and mortality after treatment for peritoneal surface malignancies N Morbidity Mortality Ref CRS, HIIC, and EPIC (19%) 7 (2%) Sugarbaker et al. Ann Surg Oncol CRS and DIC 14 5 (36%) 0 (0%) Sugarbaker et al. Dis Colon Rectum CRS and EPIC (17%) 4 (2%) Sugarbaker et al. Ann Surg CRS, HIIC, and EPIC (35%) 3 (5%) Jacquet et al. Cancer CRS, HIIC, and EPIC (27%) 4 (2%) Stephens et al. Ann Surg Oncol CRS and HIIC (55%) 6 (9%) Elias et al. Cancer CRS and EPIC 13 7 (54%) 1 (8%) Butterworth et al. Am J Surg CRS and HIIC (25%) 6 (3%) Glehen et al. Ann Surg Oncol CRS and HIIC (35%) 0 (0%) Pilati et al. Ann Surg Oncol CRS and HIIC (30%) 9 (12%) Shen et al. Ann Surg Oncol CRS and HIIC 33 9 (27%) 0 (0%) Ahmad et al. Ann Surg Oncol CRS and HIIC (35%) 8 (8%) Verwaal et al. J Surg Oncol CRS and HIIC (34%) 3 (4%) Schmidt et al. Eur J Surg Oncol CRS and HIIC (12%) 2 (1%) Kusamura et al. Ann Surg Oncol 2004.

46 Quality Metrics Mortality Morbidity Completeness of cytoreduction Survival Quality of life

47 Pre-2003 Nonrandomized Data on Patients With Peritoneal Carcinomatosis from CRC Treated by Cytoreduction and Intraoperative Hyperthermic Chemotherapy Study Year No. of Patients Median Survival (months) Survival Duration (years) % of Patients Shen et al Piso et al Elias et al Witkamp et al NA 2 45 Beaujard et al Cavaliere et al NR Loggie et al Rey et al NA 2 12 Sugarbaker and Chang NA 5 30 Fujimara et al Schneebaum et al NA Verwaal et al. J Clin Oncol 2003; 21(20):

48 Randomized Trial - The Netherlands Cancer Institute Initially published in 2003 and reviewed in 2008

49 . Verwaal V J et al. JCO 2003;21: by American Society of Clinical Oncology

50 Median survival in the standard arm was 12.6 months, compared with 22.4 months in the HIPEC arm (P =.032). Verwaal V J et al. JCO 2003;21: by American Society of Clinical Oncology

51 . Verwaal V J et al. JCO 2003;21: by American Society of Clinical Oncology

52 Follow-up at 8 years. DSS Disease-specific survival was 12.6 months in the standard arm and 22.2 months in the experimental arm (P = 0.028) Verwaal et al. Ann Surg Oncol 2008; 15(9):

53 PFS The progression-free survival was 7.7 months in the standard arm and 12.6 months in the experimental arm (P = 0.020) Verwaal et al. Ann Surg Oncol 2008; 15(9):

54 JCO 2004 Retrospective multiinstitutional study of 506 patients Variable No. of Patients Median Survival (months) P Sex Male Female Age, years < Location Right colon Sigmoid Left colon Rectum Transverse colon Lymph node involvement Positive Negative Tumor differentiation Well <.0001 Moderately Poor Unknown Glehen et al. J Clin Oncol 2004; 22(16):

55 JCO 2004 Retrospective multiinstitutional study of 506 patients Variable No. of Patients Median Survival (months) P Extent of carcinomatosis Limited <.0001 Extended Preoperative systemic chemotherapy Yes No Resection of concomitant liver metastasis Yes No Synchronous resection of primary tumor Yes No Completeness of cytoreduction CCR <.0001 CCR CCR Glehen et al. J Clin Oncol 2004; 22(16):

56 JCO 2004 Retrospective multiinstitutional study of 506 patients Variable No. of Patients Median Survival (months) P Perioperative intraperitoneal chemotherapy IPCH EPIC IPCH + EPIC Postoperative systemic chemotherapy Yes No Second procedure Yes <.001 No Glehen et al. J Clin Oncol 2004; 22(16):

57 With a median follow-up of 53 months (range, 5 to 192 months), the overall 1-year, 3-year, and 5- year actuarial survival rates were 72%, 39%, and 19%, respectively. The overall 1-year, 3-year, and 5-year disease-free survival rates were 40%, 16%, and 10%, respectively. Glehen O et al. JCO 2004;22: by American Society of Clinical Oncology

58 Morbidity and Mortality Type of Complication No. % Digestive fistula Hematologic toxicity Systemic sepsis 10 2 Postoperative bleeding Intra-abdominal abscess Respiratory distress Pneumonia Urinary fistula 5 1 Line sepsis 5 1 Bowel obstruction 5 1 Pulmonary embolism Peritonitis Other Combined morbidity Mortality 20 4 Glehen et al. J Clin Oncol 2004; 22(16):

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60 Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial (Swedish Peritoneal Trial) Four expert institutions 1:1 allocation Study closed early due to poor accrual as patients increasingly opted for HIPEC Open-label study with no masking Randomisation was performed by telefax to an external secretariat The random sequence was computer generated and stratified on primary tumour colon/rectum versus appendix Cashin et al. Eur J Cancer :

61 Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial (Swedish Peritoneal Trial) Exclusion criteria were: Extra-abdominal or liver metastases Para-aortic or other non-resectable lymph-node metastases Need of emergency surgery (obstruction, bleeding or peritonitis) Prior treatment with systemic chemotherapy except adjuvant therapy ending at least 6 months prior to evaluation or previous cytoreductive surgery with intraperitoneal chemotherapy Clinical or histological appearance of pseudomyxoma peritonei Age >80 years Ongoing infection Cashin et al. Eur J Cancer :

62 Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial (Swedish Peritoneal Trial) Cashin et al. Eur J Cancer :

63 Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial (Swedish Peritoneal Trial) Surgical Arm After surgery, the patients received intraperitoneal chemotherapy within 3 h after completion of surgery through an abdominal porta-cath and continued daily for a total of six infusions (6 days) Systemic Arm Patients in the systemic chemotherapy arm received FOLFOX-6 If oxaliplatin was contraindicated, irinotecan was administered Treatment was given every fortnight for a planned number of 12 cycles or for about 6 months Cashin et al. Eur J Cancer :

64 Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial (Swedish Peritoneal Trial) Surgical Arm The regimen consisted of 5- fluorouracil via the port-acath combined with IV leucovorin given as a bolus dose 1 h after start of the intraperitoneal infusion Systemic Arm Patients in the systemic chemotherapy arm received FOLFOX-6 If oxaliplatin was contraindicated, irinotecan was administered Treatment was given every fortnight for a planned number of 12 cycles or for about 6 months Cashin et al. Eur J Cancer :

65 Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial (Swedish Peritoneal Trial) Surgical Arm Further 6-day infusion series was administered with the same dosage every 4 5 weeks for a total of 6 treatments spanning over a 6-month postoperative period These patients did not receive any systemic chemotherapy Systemic Arm Patients in the systemic chemotherapy arm received FOLFOX-6 If oxaliplatin was contraindicated, irinotecan was administered Treatment was given every fortnight for a planned number of 12 cycles or for about 6 months Cashin et al. Eur J Cancer :

66 Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial (Swedish Peritoneal Trial) The completion rates for chemotherapy cycles in both arms were low, 33% (intraperitoneal chemotherapy) versus 58% (systemic chemotherapy) Cashin et al. Eur J Cancer :

67 Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial (Swedish Peritoneal Trial) Actuarial OS after 2 years was 54% in the surgery arm compared to 38% in the systemic chemotherapy arm (p = 0.04) OS after 5 years was 33% (n = 8) and 4% (n = 1), respectively (p = 0.02) Cashin et al. Eur J Cancer :

68 Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial (Swedish Peritoneal Trial) Median OS in the surgery arm was 25 months versus 18 months for the systemic chemotherapy arm with a hazard ratio between the arms of 0.51 (95% CI: , p = 0.04) Cashin et al. Eur J Cancer :

69 Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial (Swedish Peritoneal Trial) Actuarial PFS in the surgery arm was 12 months versus 11 months in the systemic chemotherapy arm ( p = 0.16) Despite this, curves demonstrate that a curative potential exists with the surgical approach but not for systemic chemotherapy only Cashin et al. Eur J Cancer :

70 Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial (Swedish Peritoneal Trial) 20 patients were labelled resectable 18/24 were resectable at surgical exploration as well as 2/13 who crossed over from the chemotherapy arm Patients with resectable disease had 40% 5-year OS with 40 months median OS In multivariate analysis, it was demonstrated that surgical resectability was the main independent determinant of OS Cashin et al. Eur J Cancer :

71 HIPEC timing Prolonged systemic chemotherapy prior to surgery and intraperitoneal chemotherapy is of uncertain benefit In this study, the proportion of patients with resectable disease was clearly smaller after 6 months of chemotherapy (patients that crossed over) compared with those undergoing up-front surgery (15% versus 79%, p < 0.001), albeit not based upon randomisation Cashin et al. Eur J Cancer :

72 Overall survival of group receiving cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), and systemic treatment versus those receiving standard treatment. Elias D et al. JCO 2009;27: by American Society of Clinical Oncology

73 The American Society of Peritoneal Surface Malignancies evaluation of HIPEC with Mitomycin C versus Oxaliplatin in 539 patients with colon cancer undergoing a complete cytoreductive surgery Median overall survival (OS) of 539 patients with complete cytoreduction was 32.6 months 32.7 months for the MMC group vs months for the Oxaliplatin group (P = 0.925) However, when stratified by PSDSS, median OS rates in PSDSS I/II patients were 54.3 months in those receiving MMC vs months in those receiving oxaliplatin (P = 0.012) In PSDSS III/IV patients, median OS rates were 19.4 months in those receiving MMC vs months in those receiving Oxaliplatin (P = 0.427) Prada-Villaverde et al. J. Surg. Oncol., 110:

74 Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in the Management of Peritoneal Surface Malignancies of Colonic Origin: A Consensus Statement J. Esquivel1, R. Sticca2, P. Sugarbaker3, E. Levine4, T. D. Yan3, R. Alexander5, D. Baratti6, D. Bartlett7, R. Barone8, P. Barrios9, S. Bieligk10, P. Bretcha-Boix11, C. K. Chang12, F. Chu13, Q. Chu14, S. Daniel13, E. de Bree15, M. Deraco6, L. Dominguez-Parra16, D. Elias17, R. Flynn10, J. Foster18, A. Garofalo19, F. N. Gilly20, O. Glehen20, A. Gomez-Portilla21, L. Gonzalez-Bayon22, S. Gonzalez-Moreno23, M. Goodman24, V. Gushchin25, N. Hanna5, J. Hartmann26, L. Harrison27, R. Hoefer28, J. Kane29, D. Kecmanovic30, S. Kelley31, J. Kuhn32, J. LaMont32, J. Lange33, B. Li14, B. Loggie18, H. Mahteme34, G. Mann35, R. Martin36, R. A. Misih37, B. Moran38, D. Morris13, L. Onate-Ocana39, N. Petrelli37, G. Philippe40, J. Pingpank41, A. Pitroff1, P. Piso42, M. Quinones43, L. Riley44, L. Rutstein45, S. Saha46, S. Alrawi29, A. Sardi25, S. Schneebaum47, P. Shen4, D. Shibata31, J. Spellman48, A. Stojadinovic49, J. Stewart4, J. Torres-Melero50, T. Tuttle51, V. Verwaal52, J. Villar53, N. Wilkinson54, R. Younan6, H. Zeh7, F. Zoetmulder52 and G. Sebbag55 Reasonable expectation of achieving a complete removal of all tumor greater than 2.5 mm and: (1) ECOG performance status two or less (2) no evidence of extra-abdominal disease (3) up to 3 small, resectable parenchymal hepatic metastases (4) no evidence of biliary obstruction (5) no evidence of ureteral obstruction (6) no evidence of intestinal obstruction at more than one site (7) small bowel involvement: no evidence of gross disease in the mesentery with several segmental sites of partial obstruction (8) small volume disease in the gastro-hepatic ligament Ann Surg Oncol 2007;14(1):

75 USMCI 8214 / Z6091 Phase III Randomized Pilot Study of Standard Systemic Therapy With Versus Without Cytoreduction Surgery and Hyperthermic Intraperitoneal Mitomycin C in Patients With Advanced Limited Peritoneal Dissemination of Colon Adenocarcinoma Expected Enrollment: 340 Primary Outcome(s) Overall survival (OS) Secondary Outcome(s) Progression-free survival (PFS) Quality of life Toxicity burden Circulating tumor cells

76 USMCI 8214 / Z6091 Closed due to poor accrual

77 Controversies Timing: Intraop vs. Periop vs. both No differences in outcomes Spratt et al. Cancer Res 1980; 40: Sugarbaker et al. Cancer Res 1990; 50: Sugarbaker et al. Ann Surg Oncol 1999; 6: Yan et al. Ann Surg Oncol 2007; 14: Yan et al. J Clin Oncol 2009; 27: Elias et al. J Clin Oncol 2010; 28: da Silva et al. J Am Coll Surg 2006; 203: Elias et al. Int J Surg Invest 2000; 1: Verwaal et al. Ann Surg Oncol 2005; 12: Quenet et al. Ann Surg (in press).

78 Controversies Open vs. Closed No differences in outcome Spratt et al. Cancer Res 1980; 40: Sugarbaker et al. Cancer Res 1990; 50: Sugarbaker et al. Ann Surg Oncol 1999; 6: Yan et al. Ann Surg Oncol 2007; 14: Yan et al. J Clin Oncol 2009; 27: Elias et al. J Clin Oncol 2010; 28: da Silva et al. J Am Coll Surg 2006; 203: Elias et al. Int J Surg Invest 2000; 1: Verwaal et al. Ann Surg Oncol 2005; 12: Quenet et al. Ann Surg (in press).

79 Controversies Different drug regimens: e.g. Oxaliplatin vs. MMC vs. Bidirectional No differences in outcome Spratt et al. Cancer Res 1980; 40: Sugarbaker et al. Cancer Res 1990; 50: Sugarbaker et al. Ann Surg Oncol 1999; 6: Yan et al. Ann Surg Oncol 2007; 14: Yan et al. J Clin Oncol 2009; 27: Elias et al. J Clin Oncol 2010; 28: da Silva et al. J Am Coll Surg 2006; 203: Elias et al. Int J Surg Invest 2000; 1: Verwaal et al. Ann Surg Oncol 2005; 12: Quenet et al. Ann Surg (in press).

80 Controversies Different temperatures, durations and carrier solutions: No differences in outcome Spratt et al. Cancer Res 1980; 40: Sugarbaker et al. Cancer Res 1990; 50: Sugarbaker et al. Ann Surg Oncol 1999; 6: Yan et al. Ann Surg Oncol 2007; 14: Yan et al. J Clin Oncol 2009; 27: Elias et al. J Clin Oncol 2010; 28: da Silva et al. J Am Coll Surg 2006; 203: Elias et al. Int J Surg Invest 2000; 1: Verwaal et al. Ann Surg Oncol 2005; 12: Quenet et al. Ann Surg (in press).

81 Does chemo really add anything to complete CRS? The main conclusion that can be drawn from these data is that perhaps IP chemotherapy is bereft of efficacy because the results are identical whatever the modalities used Randomized multicenter trial in humans comparing HIPEC versus no HIPEC after CCRS is ongoing in France (Prodige 7) and has already randomized more than half of the 260 patients planned for accrual

82 Peritoneal and organ mets

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84 Better imaging

85 PCI and location for PC from CRC Elias et al. Eur J Surg Oncol Nov;40(11):

86 Elias et al. Eur J Surg Oncol Nov;40(11):

87 Better delineation of timing

88 Optimal regimens Drugs Bidirectional Carriers Timing

89 American Society of Peritoneal Surface Malignancies standardized HIPEC delivery in patients with colorectal cancer with peritoneal dissemination A survey was conducted of all cancer centers performing HIPEC in the United States Attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters Turaga et al. Ann Surg Oncol (2014) 21: 1501.

90 American Society of Peritoneal Surface Malignancies standardized HIPEC delivery in patients with colorectal cancer with peritoneal dissemination HIPEC method Closed Drug Mitomycin C Dosage 40 mg Timing of drug delivery 30 mg at time 0; 10 mg at 60 min Volume of perfusate 3 L Inflow temperature 42 C Duration of perfusion 90 min Turaga et al. Ann Surg Oncol (2014) 21: 1501.

91 Future Uses for prophylaxis/second Look Operations

92 Ascites mitigation

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