1. The role of adjuvant TACE after curative liver resection for HCC
Anthony Fong
Prince of Wales Hospital

2. Hepatocellular Carcinoma
5th most common cancer in the world
> 500,000 new cases per year
600,000 people die globally due to HCC each year
1. Surgeon Jun;3(3):210-5.
The continuing challenge of hepatic cancer in Asia.
Lai EC, Lau WY. J Am Coll Surg Jul;205(1):27-36.
2. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics,
2002. CA Cancer J Clin 2005; 55: 74–108

3. Curative treatment for HCC
Surgical resection / transplantation
Loco-regional ablation
Radiofrequency ablation
Microwave ablation

4. Surgical resection Poor survival rate despite curative resection
5-year survivals of 39% - 50%
High recurrence rate
1,3,5 years recurrence rate : 30.1%, 62.3%, 79% respectively
1. Lang H, Sotiropoulos GC, Brokalaki EI, Schmitz KJ, Bertona C, Meyer G, Frilling A, Paul A, Malagó M, Broelsch CE.
Survival and recurrence rates after resection for hepatocellular carcinoma in noncirrhotic livers.
J Am Coll Surg Jul;205(1):27-36.
2. Dupont-Bierre E, Compagnon P, Raoul JL, Fayet G, de Lajarte-Thirouard AS, Boudjema K.
Resection of hepatocellular carcinoma in noncirrhotic liver: analysis of risk factors for survival.
J Am Coll Surg 2005; 201: 663–70
3. mamura H, Matsuyama Y, Tanaka E et al.
Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy.
J Hepatol 2003; 38: 200–7.

5. Adjuvant Therapy

6. Adjuvant Therapy Adjuvant therapy: TACE Systemic chemotherapy
Immunotherapy
Interferon
Acyclic retinoid acid

7. TransArterial ChemoEmbolization
TACE
TransArterial ChemoEmbolization

8. TACE Survival benefit in un-resectable HCC
? TACE as an adjuvant treatment
Llovet JM, Bruix J
Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival
Hepatology 37:429, 2003

9. TACE as adjuvant therapy after curative liver resection

10. TACE as adjuvant therapy
Izumi R, Shimizu K, Iyobe T et al. Postoperative adjuvant hepatic arterial infusion of Lipiodol containing anticancer drugs in patients with hepatocellular carcinoma. Hepatology 1994; 20: 295–301.
Lai EC, Lo CM, Fan ST, Liu CL, Wong J. Postoperative adjuvant chemotherapy after curative resection of hepatocellular carcinoma: a randomized controlled trial. Arch Surg 1998; 133: 183–8.
Li Q, Wang J, Sun Y, Cui YL, Juzi JT, Qian BY, Hao XS. Postoperative transhepatic arterial chemoembolization and portal vein chemotherapy for patients with hepatocellular carcinoma: a randomized study with 131 cases. Dig Surg. 2006;23(4):
Zhong C, Guo RP, Li JQ et al. A randomized controlled trial of hepatectomy with adjuvant transcatheter arterial chemoembolization versus hepatectomy alone for Stage IIIA hepatocellular carcinoma. J Cancer Res Clin Oncol 2009; 135: 1437–45.
Peng BG, He Q, Li JP, Zhou F. Adjuvant transcatheter arterial chemoembolization improves efficacy of hepatectomy for patients with hepatocellular carcinoma and portal vein tumor thrombus. Am J Surg 2009; 198: 313–8.

11. TACE as adjuvant therapy
Patient selection – tumor extent
Timing for TACE
Chemotherapy agent
Side effects

12. Patient selection for adjuvant TACE

13. TMN Staging for HCC T-staging N-staging M-staging
T1 - Solitary tumor without vascular invasion
T2 - Solitary tumor with vascular invasion or multiple tumors none more than 5 cm
T3 - Multiple tumors more than 5 cm or tumor involving a major branch of the portal or hepatic vein(s)
T4 - Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum
N-staging
N0 - Indicates no nodal involvement
N1 - Indicates regional nodal involvement
M-staging
M0 - Indicates no distant metastasis
M1 - Indicates metastasis presence beyond the liver
Overall Staging
Stage I T1 N0 M0
Stage II T2
Stage IIIA Stage IIIB Stage IIIC T3 T4 Tx N1
Stage IV Nx M1

14. Median observation time (mths) Disease free survival (Tx vs Ctrl)
Author
Tumor extent
Sample size (Tx / Ctrl)
Median observation time (mths)
Disease free survival
(Tx vs Ctrl)
Overall survival
Izumi
(1994)
Vessel involvement / intrahepatic spreading
50 (23/27)
28.7
1 yr
64.5% vs 43%
87% vs 81%
3 yr
32% vs 11.7%
50.3% vs28.8%
Lai
(1998)
Negative in Lipiodol CT, Angiography and USG 1 mth after OT
66 (30/36)
28.3
50% vs 69%
65% vs 67%
18% vs 48% Li
(2006)
Solitary / Multiple tumor in one liver lobe
84 (39/45)
Not mentioned
87.2% vs86.5%
Not stated
60.7% vs47.8%
Zhong
(2009)
Stage IIIa disease
118 (59/59) 20
29.7% vs 14%
80.7% vs56.5%
9.3% vs 3.5%
33.3% vs19.4%
Peng
HCC with PVTT (main or opposite branch <3 cm)
104 (51/53)
33.6
50.9% vs33.3%
33.8% vs 17%
p =
p =
p = 0.04
p = 0.10
p = 0.345
p = 0.004
p = 0.048
p =

15. Patient selection for adjuvant TACE
High risk tumor
Tumor size (>5 cm)
Vascular invasion
Multiple tumor nodules

16. Timing for TACE

17. Timing for TACE Author Interval between TACE and surgery
Number of courses
Outcome
Izumi (1994)
21-84 days 1
Improved DFS
Lai (1998)
Both TACE and systemic chemo
Mean : 50 days
3 course of TACE 2 monthly
8 doses of systemic chemo 6-weekly
Decreased DFS
Li (2006)
4 weeks
3 Course , 2 weekly
No sig. difference in DFS
Zhong (2009)
4-6 weeks
Improve DFS and OS
Peng (2009)
3-4 weeks, repeated once every 1-2 month
2-5
Improved OS

18. Timing for TACE 4 weeks after hepatectomy
Single course already showed survival benefit

19. Chemotherapy agent

20. Agent for TACE Author TACE Agent Outcome Izumi (1994)
(20mg/m2) + Mitomycin C (10mg/m2), Lipiodol (3ml)
Improved DFS
Lai (1998)
Systemic chemo : Epirubicin hydrochloride (40mg/m2)
TACE : (10mg), Lipiodol (10ml)
Decreased DLS
Li (2006)
(30mg), Mitomycin (20mg), (80-100mg) / (400mg)
No sig. difference in DFS
Zhong (2009)
(200mg/m2), Mitomycin (6mg/m2), Lipiodol (4-5ml), hydrocholride (40mg/m2)
Improve DFS and OS
Peng (2009)
5-FU (500mg/m2), (30mg/m2), Lipiodol (10-20ml)
Improved OS
Doxorubicin
Cisplatin
Doxorubicin
Cisplatin
Carboplatin
Carboplatin
Epirubicin
Doxorubicin

21. Agent for TACE Doxorubicin (Adriamycin) / Epirubicin Mitomycin 5-FU
Cisplatin / Carboplatin

22. Agents for TACE
Cleared rapidly by the liver. Large difference in concentration between the liver and systemic circulation
Effective primarily at high doses

23. Side effects

24. Author
Side effects
Serious side effects
Izumi (1994)
Fever, nausea
Hepatic injury required ICU care, Biloma
Lai (1998)
Cellulitis
Necrosis of lesser curve of stomach
Li (2006)
Nausea and loss of appetite, impaired liver function, leukopenia and thrombocytopenia.
NIL
Zhong (2009)
Nausea / Vomiting (50.9%), Increase ALT (29.8%), Pain (19%), Increase in bilirubin (19%), Leukopenia (1.8%)
Peng (2009)
Fever (86%) , vomiting (66%), poor appetite (52%), Fatique (39%%)

25. Side effects Fever Nausea / vomiting Impaired liver function
Leukopenia
Pain
Local complications

26. Meta-analysis

28. Meta-analysis - Abstract

29. Our experience

30. Our experience
13 Patients underwent adjuvant TACE after liver resection of curative intent
Criteria of adjuvant TACE :
Large tumor (>5 cm)
Satellite nodules
Vascular invasion
Close surgical margin

31. Duration between OT and TACE
Operation
Tumor size (cm)
Margin (cm)
Vascular invasion
Multiple tumor
Duration between OT and TACE
Disease Free survival
Overall Survival
FU peroid (mth)
Seg6 /7 Wedge resection
5.1
1.5 Y N 4 3
Right hepatectomy
3.5
0.3 8 7
Lap Seg 5 wedge resection 6 9
4.3 10 14
Left Hepatectomy
0.5
3.2
5.8 15
0.2
7.5 5 17 1 20 28 30 38 43

32. Our experience Follow up peroid 3-43 mths (median 15mths) Tumor Size
1.5 – 14cm (Median 5.1cm)
Vascular invasion
61.5%
Surgical margin
cm (Median 1cm)
Presence of multiple tumors
46%

33. Our experience 2 Patients had recurrence (15%)
Both from lung metastasis
Disease free survival : 3 mths / 15 mths
1 mortality from recurrence (Overall survival 15mths)

34. Conclusion
Role of adjuvant TACE after curative liver resection is still controversial
Some trials showed promising results in patients with advanced disease
TACE is well tolerated in most studies
Need further large scale study for evaluation

35. Thank you