1. Joint Hospital Grand Round 20 th May 2006 Catherine Choi United Christian Hospital

2. Radio-Frequency Ablation of Liver Metastasis from Colorectal Carcinoma

3. most common site of metastasis from colorectal cancer more than 50% patient would develop colorectal metastasis at diagnosis and subsequently Liver Metastasis from colorectal carcinoma

4. Patients with unresected liver metastases median survival 15 - 21 months Colorectal liver metastases “ The natural history of untreated cancer is the standard against which the effectiveness of any treatment should be measured…..” Wagner JS Ann Surg 1984 Wood CB Clin Oncol 1976 Survival Median ( month ) Extent of liver involvement3yr5 yr Solitary metastasis21%3%21 Multiple but unilateral6%0%15 Widespread or bilobal4%2% Wagner JS Ann Surg 1984 Natural history of colorectal liver metastases

5. Surgical resection for liver metastases already well accepted as the standard treatment for colorectal liver metastases survival after liver resection for solitary liver metastasis Author No of patients Actuarial 5-year survivals Median survival (months) Hughes KS Surgery 1988 50937%- Rosen CB Ann Surg 1992 18530% Scheele J World J Surg 1995 18036%45 Taylor M Am J Surg 1997 7747%54 Fong Y J Clin Oncol 1997 24047% Overall 5-year survival 25 – 39% Fong Y. et al (1997) J Clin Oncol 15: 938-997 Colorectal liver metastases

6. Radio Frequency Ablation Current Indication Colorectal liver metastases Limited but inoperable liver disease Extent or distribution permits ablation but not resection In-operable due to co-morbidity In-operable due to inadequate residual functioning normal liver In combination with resection Downstage by chemotherapy, can be ablated but is in-operable

7. Radio Frequency Ablation Limitation Size  5 – 7 cm ablation zone  max diameter of tumor 5 cm ( with allowance for 1 cm resection margin )  overlapping technique Gerald D Dodd III, AJR Oct 2001 Number of tumors  5 or fewer ( rule of fives ) Poston GJ J Clin Oncol Mar 2005  maximum number not known  Risk  high failure rate with increased number  Laparotomy allowed more lesions to be ablated than percutaneous approach Location  adjacent to major vessel < 3 mm diameter  higher recurrence rate  risk of thermal damage to bile duct  risk of thermal damage to hollow viscus avoid with laparoscopic or laparotomy Colorectal liver metastases

8. Role of Radio Frequency Ablation in colorectal liver metastases Colorectal liver metastases As primary treatment modality resectable disease (curability) unresectable disease (additional benefit over modern chemotherapy)

9. RFA as primary treatment in resectable disease Results compared with hepatic resection No randomized control study French study started Poston GJ Journal of Clin Oncoloy Mar 2005  prospectively compared RFA vs surgical resection  ethical issue  slow recruitment Existing evidence case series for unresectable colorectal liver metastasis only excluded from surgery for  location precluded clear resection margin ( near major vessels or portas )  poor co-morbid  inadequate liver reserve  reluctant for resection Colorectal liver metastases

10. Tito Livraghi Percutaneous Radiofrequency ablation of liver metastases in Potential candidate for Resection - The “Test-of-Time” approach Cancer June 2003  88 patients with 134 colorectal liver metastases  < 3 lesions  ≦ 4 cm max diameter ; mean diameter 2.1 cm ( 0.6 – 4 )  80% received chemotherapy  median follow-up 28 months (18-75 mths)  complete ablation achieved in 53 / 88 (60% ) only  16 / 53 ( 30%) tumor-free  37 / 53 ( 70% ) developed new lesions  26 intrahepatic ( repeated RFA ; 7 tumor free )  4 extrahepatic  7 both intrahepatic + extrahepatic  Overall  23 / 88 ( 26% ) tumor-free with RFA  7 / 88 ( 8% ) tumor-free with additional hepatic resection (20 out of 35 with partial necrosis underwnet hepatectomy)  34% disease free in the study Colorectal liver metastases RFA as primary treatment in resectable disease

11. Case control series compared with resection Oshowo et al Comparison of resection and radiofrequency ablation for treatment of solitary colorectal liver metastases British Journal of Surgery 2003 45 solitary colorectal liver metastases 25 percutaneous RF ablation  resection contraindicated for near major vessels (9 ) co-morbidity ( 9 ) stable extrahepatic disease ( 7 ) 20 liver resections in same period Colorectal liver metastases

12. RFA as primary treatment in resectable disease Major Case series Survival rate (%) median survival ( months ) StudyyearNo of patient 1 year3 year5 year Solbiati 1997 29 94 --- Lencioni 1998 29 93 --- Gillams 2000 69 90 34-- Solbiati 2001 117 93 46-36 Solbiati 2003 166 96 4522 Oshowo 2003 25 100 52-37 Abdalla 2004 57 92 37-- Lencioni 2004 423 86 4724- Gillams 2004 167 71 211422 Berber 2004 135 - --28.9 Colorectal liver metastases Reference data from surgical series Overall 5 years survival in liver resection series 25 – 39% 5 year survival of small solitary colorectal liver metastasis 50% ( Nuzzo et al Hepato-gstroenterology 1997 )

13. RFA as primary treatment in resectable disease Problems heterogeneous data inclusion of various metastatic tumors in large series various mode of approach for RFA different instruments used and difficult algorithm lapsed over long period with improvement in electrode design report of survival data incomplete / lacking presence of extrahepatic disease group in treated patient cohort  Conclusion of radio frequency ablation better / as effective as surgery is impossible from present data Colorectal liver metastases

14. RFA as primary treatment in resectable disease Local Recurrence Surgical resection DeMatteo et al J Gastrointest Surg 2000 compromised margin ( < 1 cm tumor free resection margin ) 2% for anatomic resection 16% for wedge resection Series Curle y Ann Surg 1999 de Baere AJR 2000 Siperstein Ann Surg Oncol 2000 Solbiati Radiology 2001 Bowles Arch Surg 2001 Bleicher Ann Surg Oncol 2003 Elias J Surg Oncol 2005 No of patient 12368661177615363 No of RFA 169121250170329447154 % colorectal met 5085351005139100 Route of RFA Percutaneous 2569010057520 Surgery 7531003433100 Laparoscopic 0010008150 mean FU ( months ) 151413.96 - 59151127.7 RFA site local recurrence 1.8%9%12%39%9%21%7.1% Colorectal liver metastases

15. Meta-analysis on local recurrence 95 independent RFA series minimal follow-up 6 months / mean follow-up 12 months Pooled 5224 treated liver tumors ( primary and secondary tumors ) 647 local recurrence  12.4% favorable factors to reduce local recurrence small tumor < 3 cm diameter surgical ( laparotomy / laparoscopic ) approach local recurrence rate similar for HCC and colorectal metastases Drawback  follow-up duration too short  local recurrence up to 18 months underestimates local recurrence rate Colorectal liver metastases Stefaan Mulier et at Ann Surg Aug 2005

16. RFA as primary treatment in unresectable colorectal liver metastases Classical criteria for unresectability  presence of extrahepatic metastases  resection margin < 10 mm  large number of metastatic tumors  inadequate residual liver volume Adjunct to hepatectomy

17. RFA in unresectable colorectal liver metastases Systemic chemotherapy with modern regimen  2 yr survival 22 – 27%  median survival 14 – 21 months Question  Any additional survival benefit with RFA over modern systemic chemotherapy ?  existing data  Yes 3yr survival 21 – 52% 5 yr survival 14 – 22% median survival 22 – 37 months EORTC trial ( European Organization for Research and Treatment of Cancer intergroup study 40004 ) Chemotherapy vs Chemotherapy + local ablation primary end point – overall survival open in Europe in late 2003 sample size 400 patients recruited about 70 patients in > 12 months period Colorectal liver metastases RFA series

18. Role of Radio Frequency Ablation in colorectal liver metastases Colorectal liver metastases As treatment option in intrahepatic recurrence after hepatectomy

19. Intrahepatic recurrence after Hepatectomy with successful completed liver resection for colorectal liver metastases Topal B et al European Journal of Surgical Oncology 2003 RFA in intrahepatic recurrence intraheaptic recurrence43% extrahepatic recurrence60%

20. F/62 Carcinoma of sigmoid colon Laparoscopic sigmoid colectomy in August 2004 pathology - pT3N0 No postoperative chemotherapy Liver metastases detected in Jan 2005 with posterior sectionectomy + non-anatomical resection in Feb 2005 Chemotherapy after liver resection (5-FU + Irinotecan) new intrahepatic liver metastases after completion of chemotherapy 2 cm diameter in segment 8 RFA in intrahepatic recurrence

21. Choice of treatment Re-hepatectomy technically challenging related mortality 2% in specialized centre morbidity 25 – 30% advantage of finding of extrahepatic disease 10 – 20% Local ablative therapy Wanebo HJ et al Surgery 1996 Neeleman N et al British Journal of Surgery 1996 RFA in intrahepatic recurrence Intrahepatic recurrence after hepatectomy Our choice Percutaneous RFA target USG – difficult to demonstrated with trans-abdominal USG adjacency of large bowel

22. Final procedure Open radiofrequency ablation with large bowel displaced contrast CT follow-up 1 month after Open RFA RFA in intrahepatic recurrence 1 3 2 4

23. RFA as re-treatment option in intrahepatic recurrence Evidence in literature difficult to find Case series admix with other liver metastatic tumors Authorn% colorectal Previous hepatectomy % of sample Solbiati L Radiology 2001 1171002420.5 Poon R Ann Surg 2004 10015%41 Gillans AR Eur Radio 2004 1671002616 Berber E J Clin Oncol 2005 1351001914 assessment of survival difficult only implication  RFA being taken as re-treatment option for intrahepatic recurrence after hepatectomy RFA in intrahepatic recurrence

24. Dominique Elias et al British Journal of Surgery 2002 47 patients with liver-only recurrence after hepatectomy 27 colorectal liver metastases 5 HCC 15 neuroendocrine, cholangiocarcinoma, gastric carcinoma, sarcoma … etc mean age 59.4 yr (13 – 85 ) mean number of metastases 1.4 ( 1 – 3 ) per patient mean diameter 2.1 cm ( 9 – 35 ) mean follow-up 14.4 months ( 5.5 – 40 ) 1 operative mortality 3 postoperative complications ( abscess ; bleeding ) local recurrence 9% ablated lesion Retrospective comparison with case series from same centre Survival No of patients 1 year2 year Percutaneous RFA after hepatectomy 4788%55% Re-hepatectomy 4684%60% RFA in intrahepatic recurrence

25. Conclusion Radio frequency ablation of colorectal liver metastases as primary treatment of resectable liver metastases  data not enough to support routine usage  high local recurrence rate as treatment of unresectable liver metastases  published series supported  pending EORTC trial for better answer as primary treatment in intrahepatic recurrence after hepatectomy  preliminary data support  allow repeated treatments with acceptable mortality / morbidity

26. Thank You