1. Current Evidence in Ablative Therapy for Hepatocellular Carcinoma Joint Hospital Surgical Grand Round Dr Chu Ka Wan Queen Mary Hospital

2. 70% presented as unresectable hepatocellular carcinoma (HCC) –Inadequate liver function –Multifocal HCC –Proximity to major vessels 5-year recurrence rate > 50% after “curative” hepatectomy Grazi GL et al. Aliment Pharmacol Ther 2003 Inoue K et al. Liver Transpl 2004 Llovet JM et al. Lancet 2003

3. HIFU

4. Local Ablative Therapy for Hepatocellular Carcinoma Percutaneous ethanol injection (PEI) Cryoablation Microwave coagulation therapy Radio-frequency ablation (RFA) High-intensity Focused Ultrasound Ablation (HIFU)

6. 1- year survival ReferenceRFAPEIWeight (%)Risk ratio Brunello et al. 200866 of 7059 of 6913.60.39 (0.13-1.20) Lencioni et al. 200352 of 5248 of 501.90.19 (0.01-3.91) Lin et al. 200441 of 5237 of 5236.70.73 (0.37-1.44) Lin et al. 200551 of 6246 of 6236.10.69 (0.35-1.36) Shiina et al. 2005114 of 118107 of 11411.70.55 (0.17-1.84) Total324 of 354 (92%) 297 of 347 (86%) 1000.62 (0.41-0.94) p=0.02 3- year survival ReferenceRFAPEIWeight (%)Risk ratio Brunello et al. 200818 of 7017 of 6931.20.99 (0.81-1.20) Lin et al. 200418 of 526 of 5228.50.74 (0.59-0.92) Lin et al. 200538 of 6226 of 6216.80.67 (0.46-0.97) Shiina et al. 200572 of 11851 of 11423.40.71 (0.53-0.93) Total146 of 302 (48%) 100 of 297 (34%) 1000.79 (0.65-0.96) p=0.02 Tiong L and Maddern GJ. Br J Surg 2011 RCTs comparing PEI with RFA

7. RCTs comparing PEI and RFA: –More local tumour recurrence –More treatment sessions required Allowing treatment of tumours near sensitive organs No “heat-sink” effect adjacent to vessels Applicability is limited Inferior compared with RFA

9. Cohorts comparing cryoablation with RFA Prosepctive cohort Study period 1992-1998 Mean follow-up 15 months HCC and metastatic tumours (41:105) Laparotomy with intra- operative ultrasound Tumour recurrence: –3 of 138 in RFA –12 of 88 in cryoablation CryoablationRFAP Number of patients (tumour nodules)54 (88)92 (138) Local recurrence13.6%2.2%0.01 Complications Haemorrhage Perihepatic abscess Intrahepatic abscess Renal insufficiency Symptomatic pleural effusion Pneumothorax / injured diaphragm 27 (40.7%) 2 (3.7%) 10 (18.5%) 2 (3.7%) 8 (14.8%) 2 (3.7%) 3 (3.3%) 1 (1.2%) 2 (2.4%) 0 <0.001 Death10 Pearson AS et al. Am J Surg. 1999

10. High complication rate reported by multiple studies –Higher haemorrhagic complication Ablation zone of probes is generally smaller than RFA The zone of complete lethality lies a variable distance inside the edge of the ice ball Being questioned for its use in HCC Pearson AS et al. Am J Surg. 1999 Xu KC et al. World J Gastroenterol 2009 Adam R et al. Arch Surg 2002

11. Antenna 60W, 915MHz generator Fiber optic temperature monitor

12. RCT compared RFA and microwave coagulation therapy Study period 1999-2000 No blinding <4cm, up to 3 nodules Percutaneous RFA group: n=36 (48 nodules Percutaneous microwave coagulation: n=36 (46 nodules) No survival data Shibata T et al. Radiology 2002 Local recurrence rate between RFA and microwave coagulation therapy

13. Higher temperature in shorter treatment time Less affected by heat-sink effect Ground pads are not required Unmatched series reported inferior survival compared with RFA Complication rate similar as RFA Ohmoto K et al. J Gastroenterol Hepatol 2009

15. Radiofrequency ablation Alternating electrical current Frequency 200k-20M Hz in the range of radio-waves Electric power 10 W to 200 W Circuit completed with grounding pads Agitation of ionic dipolar molecules producing frictional heating Coagulative necrosis and tissue desiccation Strasberg S et al. Curr Probl Surg 2003

16. RFA vs resection for small HCC

17. RCT compared RFA with hepatectomy (Guangzhou) RCT (blinding not possible) Study period 1999-2004 Solitary HCC < 5cm Percutaneous RFA n=71 (per-protocol) Hepatectomy n=88 Both intention-to-treat and per-protocol analysis Chen MS et al. Ann Surg 2006

18. Overall and disease-free survivals with percutaneous RFA and hepatectomy for HCC 0.05)

19. Overall and disease-free survivals with percutaneous RFA and hepatectomy for HCC 3.1 – 5 cm (p>0.05)

20. RCT compared RFA with hepatectomy (Chengdu) RCT Study period 2003-2005 Solitary HCC<5cm / up to 3 nodules, each <3cm Percutaneous RFA n=115 Hepatectomy n=115 Intention to treat analysis Huang J et al. Ann Surg 2010

21. Overall survivals with percutaneous RFA and hepatectomy for HCC conforming to Milan Criteria (p=0.001)

22. Overall survivals with percutaneous RFA and hepatectomy for HCC ≤ 3cm (p=0.03)

23. Recurrence rate according to treatment group. 5-year recurrence rate for hepatectomy group: 41.7% 5-year recurrence rate for RFA group: 63.5% (p=0.024)

24. RFA vs resection for recurrent HCC

25. RFA and hepatectomy for recurrent HCC Retrospective cohort Study period 1999- 2007 Hepatectomy group n=44 Percutaneous RFA group n=66 Initial treatment: hepatectomy Recurrence up to 3 HCC, largest <5cm Liang HH et al. Ann Surg Oncol. 2008. Survival for patients treated with repeat hepatectomy or percutaneous RFA (p=0.787) after treatment of recurrence

26. Retrospective cohort Study period 2001- 2008 Hepatectomy group n=29 RFA group n=45 (open n=23, percutaneous n=22) Size up to 6cm Chan AC et al. World J Surg. 2012. Survival for patients treated with repeat hepatectomy or percutaneous RFA (p non-significant) after treatment of recurrence RFA and hepatectomy for recurrent HCC

27. HIFU No heat sink effect

28. HIFU Unresectable HCC Primary or recurrent <10cm No extrahepatic metastasis Fit general anaesthesia

29. Prospective controlled trial Unresectable HCC Alternately enrolled into 2 treatment group Study period 1998-2000 Mean tumour size 4- 14cm, number 1-4 TACE group: n=26 TACE + HIFU: n=24 TACE + HIFU TACE Survival of patient treated with TACE alone and TACE + HIFU, p=0.007 Wu F et al. Radiology 2005

30. Summary A meta-analysis of 5 RCTs indicated RFA was better than PEI Cryoablation causes more complication than RFA Comparison between RFA and microwave coagulation therapy was inconclusive HIFU as a non-invasive tool with limited evidence

31. Summary (RFA) IndicationCurrent evidence Unresectable HCCRFA-TACE was found to be superior to TACE alone Resectable HCCStill considered inferior to hepatectomy Recurrence HCCComparable to hepatectomy (retrospective cohort) Ruptured HCC Cheng BQ et al. JAMA 2008 Manikam J et al. Hepatogastroenterology 2009