1. Management of colorectal cancer with liver metastasis Dr. Vivian Lee Department of Surgery, UCH

2. Incidence UP to 70 % of patients with colorectal cancer develop liver metastasis during the course of their disease 50% are isolated liver metastasis 25% are synchronous 5-10% resectable Cady B, et al. Arch Surg 1992

3. Natural history Untreated patient open-and-close cases Median survival 6-12 months Bengmark S, et al. Cancer, 1969

4. Treatment Direct lesional approach Surgical Local ablative therapy Systemic approach Systemic chemotherapy Vascular approach Intraarterial infusion of chemotherapy

5. Surgical treatment is the gold standard for isolated liver metastasis !

6. Surgical treatment Prerequisites: Medical fittness for major surgery No sign on preoperative imaging of disseminated disease Tumors anatomically confined within liver such that adequate liver parenchyma could be preserved.

7. Surgical treatment 122 cases (74 metachronous lesions) over 8 years postoperative complication: 20 % pneumonia, pleural effusion hepatic insufficiency bile leak and biliary fistula Schlag P, et al. Eur J Surg Oncol, 1990

8. Operative mortality personal series 247 cases over 12 years operative mortality: < 5% Fortner JG, et al. Ann Surg. 1984

9. Surgical resection – early experience Multi-institutional review 859 patients of 24 centers 5-year survival 33% 5-year disease-free survival 21% Surgery 1998; 103: 278-288.

10. Major contraindications Positive perihepatic lymph nodes Presence of resectable extrahepatic metastasis Presence of 4 or more metastasis Surgery 1988; 103: 278-288.

11. Conditions with poor survival Margin of resection < 1 cm Positive mesenteric LN in primary tumor specimen Disease-free survival < 1 year NB. Presence of any one of these factors is not contraindication for surgery. Surgery 1988; 103: 278-288.

12. Survival rate nowadays surgicalsurvival StudyNmortality1y%3y%5y%10y% Butler6210_503421 Nordlinger8055412516 Scheele2196__3921 Scheele4694_453823 Jamison280484462720 Fong, 991001389573722 overall211135.6%21.6%

13. Predictors of poor long-term outcome 1001 consecutive cases from 1985 to 1998 multivariate analysis positive margin node-positive primary extrahepatic disease disease-free interval from primary to metastasis < 12 month number of hepatic tumor > 1 largest hepatic tumor > 5 cm CEA level > 200 ng/ml Fong Y, et al. Ann Surg, 1999

14. Recurrence after hepatectomy 50% develop another liver metastasis Half of them develop extrahepatic metastasis How could this be treated?

15. Repeat liver resection for recurrence ? 130 patients with 143 repeat liver resections (14 had both liver and extra-hepatic) Operative mortality 0.9% 3-year survival 33% 12 patients had the 3 rd liver resection → mean survival 12.5 months Nordlinger B, et al. J Clin Oncol 1994.

16. How can we prevent recurrence after surgery?

17. Hepatic artery chemotherapy implantable pump connected to intra-arterial catheter, GDA Complications Hepatic toxicity Peptic ulcer

18. Hepatic artery chemotherapy

19. HAI after hepatectomy Memorial Sloan- Kettering Cancer Center Trial Intrahepatic chemotherapy verse systemic chemotherapy after surgery 2 years survival : 86% vs 72%(p=0.03) Hepatic 2 years disease free survival: 90% vs 60 %( p<0.001)

20. HAI after hepatectomy Southwest Oncology Group study Surgery vs HAI after surgery 4-yr hepatic disease-free survival 43% vs 66.9% ( p=0.03) 4-yr overall disease-free survival 25.2% vs 45.7% ( p=0.04) 4-yr overall survival 52.7% vs 61.5% ( p=0.06)

21. Radiofrequency ablation Several advantages over cryotherapy Can be performed percutaneously Evenly distributed heat, unlike the ice ball formation Local Ablative Therapy

22. RFA Disadvantage Limited by the size, up to 3 or 4cm only Complete ablation rate HCC: 86% Metastasis:11% T Kaneko, et al. HBP, 2003

23. Radiofrequency ablation Prospective non randomized trial 123 patient HCC:39.1% Colorectal liver metastasis:49.6% Only 1 patient with local recurrence Curley SA, Ann Surgery. 1999

24. Is RFA with HAI feasible?

25. RFA and HAI Prospective non randomized study 50 patient treated with RFA and HAI with or without resesction Follow up: 20 months 32% patient remained disease free 30% developed new liver metastasis 48% developed extrahepatic disease Curley SA, Ann Surg Oncol. 2003

26. How can we treat systemic spread after surgery?

27. Systemic Chemotherpy Treat the entire patient Low response rates with short duration of response

28. Treated with chemotherapy 64 cases I.A. or I.V. 5-fluorodeoxyuridine Median survival 12-18 months Chang AE, et al. Ann Surg, 1987

29. Chemotherapy for metastatic colorectal carcinoma

30. First line chemotherapy 5FU + Leucovorin meta-analysis: response rate 23% vs 11% for 5FU alone no impact on overall survival

31. Second line chemotherapy Irinotecan (CPT 11) inhibit topoisomerase I just completed phase II study tumor growth control: 60% Gil-Delgado MA, American Journal of Clinical Oncology, 2001

32. Summary Surgical resection is the gold standard. Survival improves by post-operative hepatic arterial chemotherapy. Post-operative systemic chemotherapy is needed to cover micro-metastasis.