1. Joint Hospital Surgical Grand Round 16th Jan 2010 Dr James Fung Department of Surgery United Christian Hospital

2.  Surgery  Liver resection  Liver transplantation  Local ablation  Physical (RFA, microwave, cryothreapy)  Chemical (ethanol, acetic acid)  Regional therapy  TACE (Transarterial chemoembolization)  IAI (Intraarterial radiotherapy)

3.  Limited by liver reserve  Disease recurrence 1,2  Intrahepatic recurrences (IHR) ▪ Intrahepatic metastasis ▪ De novo hepatoma  Extrahepatic recurrences (HER)  1-yr, 3-yr and 5yr recurrence ~ 20%, 50% and 60% 1.Poon RT et al. Long-Term Survival and Pattern of Recurrence After Resection of Small Hepatocellular Carcinoma in Patients With preserved Liver Function: Implications for a Strategy of Salvage Transplantation. Ann Surg 2002(3): 373-82. 2.Yamamoto J et al. Recurrence of hepatocellular carcinoma after surgery. BJS 83(9): 1219-22

4. AAggressive treatment of IHR improves survival 1 TTreatment strategy 2 : SSurgical re-resection ▪F▪Feasible in 10% of recurrent disease LLocoregional treatment (TACE, RFA, IAI) ▪A▪As primary treatment in ~70% of recurrent disease SSystemic chemotherapy / Conservative 1.Lai ECS et al. Hepatic resection for hepatocellular carcinoma: an audit of 343 patients. Ann Surg 1995; 221:291-298. 2.Poon RT et al. Intrahepatic Recurrence After Curative Resection of Hepatocellular Carcinoma: Long-Term Results of Treatment and Prognostic Factors. Ann Surg 1999; 216-22.

5.  Efficacy: ▪ For palliation of primarily unresectable HCC: 3YOS 26% 1 ▪ For palliation of unresectable IHR: 3YOS 38.2% 2 1.Lo CM et al. Randomized Controlled Trial of Transarterial Lipiodol Chemoembolization for Unresectable Hepatocellular Carcinoma. Hepatology 2002; 35:1164-71 2.Poon RT et al. Intrahepatic Recurrence After Curative Resection of Hepatocellular Carcinoma: Long-Term Results of Treatment and Prognostic Factors. Ann Surg 1999; 216-22.

6.  Potential benefits:  Treats microscopic tumours foci inside liver  decrease post-op recurrence  ?Increase resectability  ?Prevent tumour dissemination during surgery CConcerns: LLiver failure RRenal failure LLiver abscess DDelay surgical resection

7. Can it improve survival? Who can benefit?

8.  Hepatology 1994; 20:295-301  The first clinical trial on adjuvant TAC(E)  Patients and treatment:  Hepatectomy + TAC(E) vs Hepatectomy = 23 : 27  All stage HCC  No detail on pre- / post-treatment liver function  Results:  No difference in overall survival  3YDFS: 32% vs 12% (p = 0.0237)  Complication:  Biloma, hepatic failure

9. AuthorJournalYearDesignResult Takenaka K et alAm J Surg1995Case seriesImproved DFS (from historical record) Kohno H et alArch Surg1996Retrospective case-control No benefit Shimoda M et alHepatogastroenterology2001Retrospective case-control Borderline survival benefit Cheng et alWorld J Gastroenterology2005Retrospective case-control Borderline survival benefit

10.  World J Gastroenterol 2004; 10(19): 2791-4  Retrospective case-control study  Patients and treatment:  Hepatectomy vs Hepatectomy + TAC(E) = 360: 185  Indication for adjuvant TAC(E) not clear  Stratification according to risk factor of recurrent tumour ▪ Tumour > 5cm, multiple tumours, vascular invasion  Results:  No survival benefit for pt without risk factor of recurrence  Small benefit for pt with risk factor of recurrence ▪ 3YOS: 70.4% vs 75.9% (p = 0.0216)

12.  Control arm: hepatectomy alone (HA) (estimated 5YOS 15%)  Treatment arm: hepatectomy + post-op TACE (HT) (estimated 5YOS 35%)  Post-op TACE performed 4-6 wks post-op if ▪ TBili 50, performance status 0/1  Sample size: 118 patient (56 in each arm)  One-sided, power 80%, alpha error 0.05  Attitude of anaylsis: intention-to-treat

13.  Overall recurrence:  No significant difference  Solitary recurrence:  Borderline difference favouring HT  Potentially treatable recurrence:  Favouring HT

14. SurvivalHepatectomy + TACEHepatectomy alonep-value 3YDFS9.3%3.5%0.004 3YOS33.3%19.4%0.048

15.  Borderline survival benefit after resection  Adjuvant TAC(E) may be beneficial to patient with high risk of disease recurrence after surgery

16. Can it improve survival? Can it improve resectability?

17.  Annals of Surgery 1996; 224(1): 4-9  Case-control study  Neoadjuvant TACE + hepatectomy vs hepatectomy = 105 : 35 (no limit on T stage)  Results:  3YOS 77.9% vs 67.8% (p = ns)  3YDFS 37.6% vs 33.7% (p = ns)  61% had tumour reduction after neoadjuvant TACE

18. AuthorJournalYearDesignResult Majno et alAnn Surg1997Retrospective case-control Improved DFS Zhang et alCancer2000Retrospective case-control Improved DFS Choi et alWorld J Surg2007Retrospective case-control No benefit

20.  Control arm: hepatectomy  Treatment arm: preoperative TACE +hepatectomy  Pre-op TACE  Stop TACE and proceed for hepatectomy if no evidence of tumour shrinkage  Hepatectomy  Performed within 2 weeks from randomization or within 8 weeks from last TACE  Sample size estimation: 100 (50 in each arm)

21.  5 patients in pre-op TACE group could not proceed to hepatectomy  Tumour progression = 4  Liver failure = 1  Tumour volume  Pre-op TACE vs control = 276cm 3 vs 299cm 3 (p = 0.832)  Cirrhosis (by pathology)  Significantly worse in pre-op TACE group

22.  No significant difference in terms of recurrence pattern

23. SurvivalTACE + HepatectomyHepatectomy alonep-value 3YDFS25.5%21.4%0.372 3YOS40.4%32.1%0.679

24.  No added value to hepatectomy alone  Does not decrease disease recurrence  Cannot improve survival  Cannot guarantee tumour shrinkage

25.  Current evidence is insufficient to conclude on the issue of (neo)adjuvant TACE  Adjuvant TACE may offer borderline survival benefit to suitable patient  Neoadjuvant TACE does not offer additional benefit for resectable HCC