(Neo-)adjuvant TACE for resectable hepatocellular carcinoma

1. (Neo-)adjuvant TACE for resectablehepatocellular carcinoma Joint Hospital Surgical Grand Round16th Jan 2010 Dr James Fung Department of Surgery United Christian Hospital

2. Management options for HCC • Surgery • Liver resection • Liver transplantation • Local ablation • Physical (RFA, microwave, cryothreapy) • Chemical (ethanol, acetic acid) • Regional therapy • TACE (Transarterial chemoembolization) • IAI (Intraarterial radiotherapy)

3. Problems with liver resection • Limited by liver reserve • Disease recurrence1,2 • Intrahepatic recurrences (IHR) • Intrahepatic metastasis • De novo hepatoma • Extrahepatic recurrences (HER) • 1-yr, 3-yr and 5yr recurrence ~ 20%, 50% and 60% • 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. • Yamamoto J et al. Recurrence of hepatocellular carcinoma after surgery. BJS 83(9): 1219-22

4. Intrahepatic recurrence • Aggressive treatment of IHR improves survival1 • Treatment strategy2: • Surgical re-resection • Feasible in 10% of recurrent disease • Locoregional treatment (TACE, RFA, IAI) • As primary treatment in ~70% of recurrent disease • Systemic chemotherapy / Conservative • Lai ECS et al. Hepatic resection for hepatocellular carcinoma: an audit of 343 patients. Ann Surg 1995; 221:291-298. • 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. TACE – beyond palliation? • Efficacy: • For palliation of primarily unresectable HCC: 3YOS 26%1 • For palliation of unresectable IHR: 3YOS 38.2%2 • Lo CM et al. Randomized Controlled Trial of Transarterial Lipiodol Chemoembolization for Unresectable Hepatocellular Carcinoma. Hepatology 2002; 35:1164-71 • 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. (Neo-)adjuvant TACE • Potential benefits: • Treats microscopic tumours foci inside liver  decrease post-op recurrence • ?Increase resectability • ?Prevent tumour dissemination during surgery • Concerns: • Liver failure • Renal failure • Liver abscess • Delay surgical resection

7. Can it improve survival? Who can benefit? Adjuvant TAC(E) for resectable HCC

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. Adjuvant TAC(E) – previous studies

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. Treatment • 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 < 34, Cr 135, PT <3s prolong, Plt >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. Results (1) • Overall recurrence: • No significant difference • Solitary recurrence: • Borderline difference favouring HT • Potentially treatable recurrence: • Favouring HT

14. Result (2)

15. Conclusion - adjuvant TAC(E) • 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? Neoadjuvant TACE for resectable HCC

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. Neoadjuvant TACE –case-control studies

20. Treatment • 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. Results (1) • 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 = 276cm3 vs 299cm3 (p = 0.832) • Cirrhosis (by pathology) • Significantly worse in pre-op TACE group

22. Results (2) • No significant difference in terms of recurrence pattern

23. Results (3)

24. Conclusion - neoadjuvant TACE • No added value to hepatectomy alone • Does not decrease disease recurrence • Cannot improve survival • Cannot guarantee tumour shrinkage

25. Summary • 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

26. Thank you