Joint Hospital Surgical Grand Round16th Jan 2010

Dr James FungDepartment of SurgeryUnited Christian Hospital

Surgery Liver resection Liver transplantation

Local ablation Physical (RFA, microwave, cryothreapy) Chemical (ethanol, acetic acid)

Regional therapy TACE (Transarterial chemoembolization) IAI (Intraarterial radiotherapy)

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%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

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

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.

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.

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

Can it improve survival?Who can benefit?

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

Author Journal Year

Design Result

Takenaka K et al

Am J Surg 1995

Case series Improved DFS (from historical record)

Kohno H et al Arch Surg 1996

Retrospective case-control

No benefit

Shimoda M et al

Hepatogastroenterology

2001

Retrospective case-control

Borderline survival benefit

Cheng et al World J Gastroenterology

2005

Retrospective case-control

Borderline survival benefit

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)

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

Overall recurrence: No significant

difference Solitary recurrence:

Borderline difference favouring HT

Potentially treatable recurrence: Favouring HT

Survival

Hepatectomy + TACE

Hepatectomy alone

p-value

3YDFS 9.3% 3.5% 0.004

3YOS 33.3% 19.4% 0.048

Borderline survival benefit after resection

Adjuvant TAC(E) may be beneficial to patient with high risk of disease recurrence after surgery

Can it improve survival?Can it improve resectability?

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

Author Journal Year Design Result

Majno et al Ann Surg 1997 Retrospective case-control

Improved DFS

Zhang et al Cancer 2000 Retrospective case-control

Improved DFS

Choi et al World J Surg 2007 Retrospective case-control

No benefit

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)

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

No significant difference in terms of recurrence pattern

Survival

TACE + Hepatectomy

Hepatectomy alone

p-value

3YDFS 25.5% 21.4% 0.372

3YOS 40.4% 32.1% 0.679

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

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