Management of Peritoneal Carcinomatosis in Colorectal Cancer

1. Management of Peritoneal Carcinomatosis in Colorectal Cancer Dr. Chan Kwan Kit Queen Mary Hospital

2. Colorectal Cancer (CRC) • High incidence with significant morbidity and mortality • Metastasis on presentation or as recurrent disease commonly encountered • Liver and peritoneal surface are the most frequent sites of metastasis • Treatment of colorectal liver metastases well established

3. Peritoneal Carcinomatosis (PC) • “Death sentence” • Median survival: 6 – 9 months • Treatment of palliative intent • systemic chemotherapy • symptomatic relief • emergency operation for complications e.g. intestinal obstruction/ perforation Chu DZ et al. Cancer 1989;63:364–7 Sadeghi B et al. Cancer 2000; 88: 358-63 Jayne DG et al.British Journal of Surgery 2002;89:1545–50

4. Pathophysiology of PC • Consequence of full thickness invasion of bowel wall by invasive carcinoma • “Iatrogenic” during primary surgery • dissected lymphatics/ bowel lumen • blood spillage from the surgical field

5. Breakthrough? • Jayne et al.: 58% of all patients with synchronous PC had no other systemic metastasis • Sugarbaker et al.: peritoneal cavity is the only metastatic site in 25% of patients with recurrent CRC Hypothesis: PC as a locoregional disease still susceptible to treatment of curative intent

6. Dr Paul H Sugarbaker • Washington Hospital Centre • Pioneer of the combined treatment • “Sugarbaker’s protocol” • Cytoreductive surgery • Perioperative intraperitoneal chemotherapy

7. Cytoreductive Surgery • Removal of macroscopic tumour on visceral and parietal peritoneum • Significant involvement of visceral peritoneum may necessitate organ resections • Significant involvement of parietal peritoneum may necessitate formal peritonectomy procedures

8. Cytoreductive Surgery • Prognostic indicators: • Prior Surgical Score (PSS) • Peritoneal Cancer Index (PCI) • Completeness of cytoreduction score (CCS)

9. Prior Surgical Score • PSS-0: biopsy only • PSS-1: 1 region • PSS-2: 2-5 regions • PSS-3: >5 regions Higher PSS associated with reduced survival

10. Peritoneal Cancer Index (PCI) • Summary of lesion size and distribution of lesions • Correlates with outcome for peritoneal metastases in CRC

11. Sugarbaker et al. Cancer therapeutics 1998; 1: 213-325 0-39

12. Peritoneal Cancer Index • Sugarbaker in 1999: • PCI < 10: 50% five-year survival • PCI 11-20: 20% five-year survival • PCI > 20: 0% five-year survival Pestieau SR, Sugerbaker PH. Dis Colon Rectum 2000; 43:1341–1348 • Not applicable when tumour deposit at crucial anatomical site not amenable for resection

13. Completeness of Cytoreduction Score • Size of persisting tumour after cytoreduction • CCS-0: no visible tumour • CCS-1: tumours <2.5mm • CCS-2: tumours 2.5mm - 2.5cm • CCS-3: tumours >2.5cm Principle prognostic indicator – helps intraoperative decision making

14. Role of diagnostic laparoscopy • Allows more accurate “staging” with minimal surgical trauma • Reliable prediction of cytoreduction index

15. Perioperative Intraperitoneal Chemotherapy • Hyperthermic intraperitoneal chemotherapy (HIPEC) • Intraoperative/ early postoperative – no standard protocol as yet • Aim: eradication of microscopic residual disease for curative intent

16. HIPEC - advantages • Intraperitoneal • Increases exposure of tumour to pharmacologically active molecules • Hyperthermia • enhances cytotoxicity • improves drug penetration • heat has anti-tumour effect itself

17. HIPEC - advantages • Large volume removes tissue debris and blood products • Diminishes the promotion of tumour growth associated with wound healing process through elimination of platelets/ neutrophils/ monocytes

19. Surgeon manipulates all viscera to minimize adherence of peritoneal surfaces and allow uniform distribution of drugs

20. Duration: 30-90 minutes • Continuous irrigation • Temperature monitoring at inflow catheters and within peritoneal cavity - maintained at 42.5ºC

21. Chemotherapeutic agent Varies with centres e.g. mitomycin C, oxaliplatin Mitomycin C being the commonest choice – large molecular weight substance confining to peritoneal cavity for long time periods

22. Results – the risks • Mortality 2-10% and morbidity 25-45%, predominantly determined by surgery-related factors • extent of surgery • number of anastomoses • volume of blood loss

23. Results – the risks • Common complication: • bowel perforation • anastomotic leakage • prolonged ileus/ bowel fistulation/ intraabdominal bleeding/ pancreatitis/ haematological toxicity

24. Results - survival benefit? • Glehen et al.: • multi-institutional retrospective study • median survival 19.2 months, irrespective of cytoreduction extent • 19% 5-year survival Glehen et al. J Clin Oncol 2004; 22: 3284-92 • Elias et al. & Verwaal VJ et al.: • the only two randomized, prospective studies • Elias: 60% survival at two years • Verwaal: median survival 22.2 months Elias et al. Ann Surg Oncol 2004; 11: 518-21 Verwaal VJ et al. Ann Surg Oncol 2005; 12: 65-71

25. Results - survival benefit? • With complete macroscopic cytoreduction (CCS-0) • average survival from 32.4 – 60 months Glehen et al. J Clin Oncol 2004; 22: 3284-92 Elias et al. Ann Surg Oncol 2004; 11: 518-21 Verwaal VJ et al. Ann Surg Oncol 2005; 12: 65-71 Sugarbaker PH. Tech Coloproctol 2005; 9: 95-103

26. Gomez Patilla A. et al. Rev Esp Enferm Dig 2009Feb;101(2):97-102, 103-6

27. Patient selection • No survival benefit for patients with synchronous metastases to other organs • Aggressive treatment of large volume, high grade cancer is unlikely to translate into long-term benefit

28. Prognostic factors • Peritoneal cancer index • Completeness of cytoreduction • Presence of lymph node involvement • Age and performance status

29. Validation? • Reported trials are of significant heterogeneity • No standard protocol e.g. timing of chemotherapy/ use of hyperthermia • Only two randomized trials published – relatively small scale

30. Conclusion • Peritoneal carcinomatosis from colorectal origin carries dismal prognosis with conventional treatment • “Combined treatment” - cytoreductive surgery with intraperitoneal chemotherapy may represent a new option of care in peritoneal-only metastatic disease

31. Conclusion • Significant procedural morbidity/ mortality mandates careful selection • Large scale, randomized, prospective studies needed for clarification of the role of this aggressive approach

33. HIPEC • Disadvantages • Removal of white cells due to chemotherapy and heat leaves the patient vulnerable to intra- abdominal infection • limited tissue penetration 3-5mm

34. Postoperative care • Expected prolonged bowel rest • prolonged ileus due to extensive surgery • allowing more time for healing • total parenteral nutrition

35. Peritonectomy • Peritoneum divided into 6 parts • greater omentectomy and splenectomy • left upper quadrant peritonectomy • right upper quadrant peritonectomy • lesser omentectomy and cholecystectomy • pelvic peritonectomy and resection of rectosigmoid colon • antrectomy/ gastrectomy

36. Hyperthermic intraperitoneal chemotherapy (HIPEC) • Setting up: • After completion of cytoreductive surgery • Catheters are inserted to dependent positions • Temperatures at the inflow/ outflow/ intraperitoneal cavity continuously monitored • Temporary abdominal skin closure • Intraperitoneal temperature maintained 42.5℃

37. Intraoperative chemotherapy • Reconstructive part of surgery follows • No anastomosis is constructed until after the intraoperative chemotherapy perfusion is completed

38. Early postoperative intraperitoneal chemotherapy • 5-fluorouracil is utilized usually • Commenced on day 1 after operation • Infusion via Tenckhoff catheter • Chemotherapy agent dwells in the abdomen for 23 hours and drain for 1 hour • Duration: 4-5 days

39. Counter-argument • Peritoneal carcinomatosis with low PCI and CCS may represent more favourable tumour biology • Opinions vary widely and no consensus could be reached • Genetics study? Molecular features of tumour?