The role of adjuvant TACE after curative

liver resection for HCCAnthony Fong

Prince of Wales Hospital

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. 2005 Jun;3(3):210-5.The continuing challenge of hepatic cancer in Asia.Lai EC, Lau WY. J Am Coll Surg. 2007 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

Curative treatment for HCC

Surgical resection / transplantation Loco-regional ablation

Radiofrequency ablation Microwave ablation

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. 2007 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: 663–703. 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.

Adjuvant Therapy

Adjuvant Therapy

Adjuvant therapy: TACE Systemic chemotherapy Immunotherapy Interferon Acyclic retinoid acid

TACETransArterial

ChemoEmbolization

TACE

Survival benefit in un-resectable HCC ? TACE as an adjuvant treatment

Llovet JM, Bruix JSystematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survivalHepatology 37:429, 2003

TACE as adjuvant therapy after curative liver

resection

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):235-40.

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.

TACE as adjuvant therapy

Patient selection – tumor extent Timing for TACE Chemotherapy agent Side effects

Patient selection for adjuvant TACE

TMN Staging for HCC T-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 N0 M0

Stage IIIA Stage IIIBStage IIIC

T3T4Tx

N0N0N1

M0M0M0

Stage IV Tx Nx M1

Author

Tumor extent

Sample size (Tx / Ctrl)

Median observation time (mths)

Disease free survival (Tx vs Ctrl)

Overall survival(Tx vs Ctrl)

Izumi(1994)

Vessel involvement / intrahepatic spreading

50 (23/27)

28.7 1 yr

64.5% vs 43%

1 yr

87% vs 81%

3 yr

32% vs 11.7%

3 yr

50.3% vs28.8%

Lai(1998)

Negative in Lipiodol CT, Angiography and USG 1 mth after OT

66 (30/36)

28.3 1 yr

50% vs 69% 3 yr

65% vs 67%

3 yr

18% vs 48%

Li(2006)

Solitary / Multiple tumor in one liver lobe

84 (39/45)

Not mentioned

1 yr

87.2% vs86.5%

Not stated

3 yr

60.7% vs47.8%

Zhong(2009)

Stage IIIa disease

118 (59/59)

20 1 yr

29.7% vs 14%

1 yr

80.7% vs56.5%

3 yr

9.3% vs 3.5%

3 yr

33.3% vs19.4%

Peng(2009)

HCC with PVTT (main or opposite branch <3 cm)

104 (51/53)

33.6 Not stated 1 yr

50.9% vs33.3%

3 yr

33.8% vs 17%

p = 0.0237 p = 0.5327

p = 0.04 p = 0.10

p = 0.004 p = 0.048

p = 0.0094

p = 0.345

Patient selection for adjuvant TACE

High risk tumor Tumor size (>5 cm) Vascular invasion Multiple tumor nodules

Timing for TACE

Timing for TACEAuthor Interval

between TACE and surgery

Number of courses

Outcome

Izumi (1994) 21-84 days 1 Improved DFS

Lai (1998) Both TACE and systemic chemoMean : 50 days

3 course of TACE 2 monthly8 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 1 Improve DFS and OS

Peng (2009) 3-4 weeks, repeated once every 1-2 month

2-5 Improved OS

Timing for TACE

4 weeks after hepatectomy Single course already showed

survival benefit

Chemotherapy agent

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

Doxorubicin

Doxorubicin

Cisplatin

Cisplatin Carboplatin

CarboplatinEpirubicin

Agent for TACE

Doxorubicin (Adriamycin) / Epirubicin Mitomycin 5-FU Cisplatin / Carboplatin

Agents for TACE

Cleared rapidly by the liver. Large difference in concentration between the liver and systemic circulation

Effective primarily at high doses

Side effects

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%)

NIL

Peng (2009) Fever (86%) , vomiting (66%), poor appetite (52%), Fatique (39%%)

NIL

Side effects

Fever Nausea / vomiting Impaired liver function Leukopenia Pain Local complications

Meta-analysis

Meta-analysis - Abstract

Our experience

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

Our experience

Follow up peroid

3-43 mths (median 15mths)

Tumor Size 1.5 – 14cm (Median 5.1cm)

Vascular invasion

61.5%

Surgical margin 0 - 5.8cm (Median 1cm)

Presence of multiple tumors

46%

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)

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

Thank you