Peritoneal Carcinomatosis: Pathophysiology, Prevention, and Treatment

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1 Peritoneal Carcinomatosis: Pathophysiology, Prevention, and Treatment Wim Ceelen, MD, PhD, FACS GI Surgery, UZ Gent KAGB 27/4/2013

2 Overview What is peritoneal carcinomatosis? Rationale for IP drug delivery and hyperthermic IP Chemoperfusion (HIPEC) Results

3 Primary Peritoneal Malignancy Malignant peritoneal mesothelioma Cystic mesothelioma Primary peritoneal carcinoma Desmoplastic round cell tumor (DRCT) Peritoneal sarcoma

4 Secundary Peritoneal Malignancy Extraabdominal tumours Lobular breast cancer Lung cancer Melanoma Intraabdominal tumours Ovarian cancer GI cancer: stomach, pancreas, colon, appendix Pseudomyxoma peritonei (PMP)

5 Steps in the peritoneal metastatic cascade 1. Liberation of cells from primary tumor 2. Transport throughout the peritoneal cavity 3. Adhesion and invasion 4. Systemic spread

6 Peritoneal shedding of tumor cells T4 or perforated tumors (colon) Iatrogenic spill Tumor tisue incision or biopsy Blood/lymph vessels section Bile duct section Elevated Interstitial Fluid Pressure (IFP)

7 Heldin Nat Rev Cancer 2004

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9 How do cancer cells move in the peritoneal cavity? Passive Gravity Respiratory movements Peritoneal recesses Active movement Predictable flow of cells

10 Yamazaki et al. Cancer Sci 2005

11 Adhesion of tumor cells in the To mesothelial cells peritoneal cavity To underlying ECM Special locations: greater omentum; diaphragm

12 Ceelen Lancet Oncol 2009

13 Nature Med 2011

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15 Invasion of submesothelial layers Areas of peritoneal discontinuity Specific anatomic locations Contraction of MC by inflammatory mediators (HGF) Induction of apoptosis of mesothelial cells Release of proteases, e.g. MMP-7

16 PC: Indications for extensive Tx Appendiceal neoplasm, PMP Colorectal cancer Ovarian cancer Epitheloid malignant peritoneal mesothelioma Other?

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18 A rose by any other name... Peritonitis myxomatosa chronica (Virchow) Maladie gélatineuse du péritoine (Péan) Pseudomyxoma peritonei (Werth, 1884) Richard Werth

19 Prevalence of PC in CRC Underestimated Registry data (Sweden; Norway; The Netherlands) Isolated Synchronous PC: 5% Metachronous PC: 4-12%

20 Risk factors for PC in CRC Honoré Ann Surg Oncol 2012

21 CRS + HIPEC Cytoreductive surgery (debulking) Peritonectomy Intraoperative chemoperfusion under hyperthermic conditions

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23 Philosoph Trans 1744

24 Postop IP Chemo in Ovarian Cancer

25 Rationale for Hyperthermic IP chemotherapy (HIPEC) IP Chemotherapy Pharmacokinetic argument: peritoneal plasma barrier higher dose feasible Maximal effect immediately after cytoreduction Limited systemic resorption / toxicity Hyperthermia Pharmacodynamic argument: increased drug penetration Selective cytotoxicity of hyperthermia Synergism with chemotherapy and radiotherapy

26 Peritoneal plasma barrier Flessner Am J Physiol Renal Physiol 288: F433-F442, 2005

27 De Lima Vaquez Cancer Chemother Pharmacol 2003

28 Ceelen Nat Rev Clin Oncol 2010

29 Ceelen Cancer Treat Rev 2007

30 Wiener klin Wochenschrift 1974

31 PMP; two procedures: Thiotepa 60 mg/m 2 and MTX 40 mg/m 2

32 Safety considerations Adequate personnel protection Adequate disposal of material and body fluids Coliseum technique: adequate vapor evacuation Adequate safety handbook/guidelines

33 Complications of HIPEC Prolonged ileus < hyperthermia Chemotherapy toxicity (bone marrow, renal, hepatic): rare Oxaliplatin: autoimmune thrombopenia; mild hepatic toxicity Cisplatin: nephrotoxicity; thiosulphate iv Increased risk of anastomotic leak Risk of the combined procedure mainly related to extent of surgery

34 Makrin J Surg Oncol 2005

35 Limitations of HIPEC Local toxicity Limited tissue penetration (3 mm) Limited contact time Only non cell cycle specific chemotherapy

36 Results: PMP Chua J Clin Oncol 2012

37 Results: CRC Elias J Clin Oncol 2009

38 Results: EOC Ceelen Ann Surg Oncol 2009

39 Ongoing Phase III Studies Colon cancer Prodige 7: CRS versus CRS+HIPEC ProphyloChip: mandatory 2nd look Ovarian cancer CHIPOR: relapsed OC, cytoreduction ± HIPEC (cisplatin 75 mg) NKI: secondary debulking surgery ± HIPEC

40 Unresolved issues Specific contribution of HIPEC (versus cytoreduction) Role of hyperthermia Standardization of hyperthermic drug delivery Role of (neo) adjuvant therapy Staging of PC; patient selection

41 Normo- versus hyperthermic chemoperfusion in PC from CRC (NCT )

42 Future Developments Data from Phase III trials awaited More efficient IP drug delivery: nanocarriers, hydrogels Multimodal strategies: postop repeated IP cycles

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