The role of adjuvant TACE after curative liver resection for HCC Anthony 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: 663–70 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.

Adjuvant Therapy

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

TransArterial ChemoEmbolization TACE TransArterial ChemoEmbolization

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

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 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

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 = 0.0237 p = 0.5327 p = 0.04 p = 0.10 p = 0.345 p = 0.004 p = 0.048 p = 0.0094

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

Timing for TACE

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

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 Cisplatin Doxorubicin Cisplatin Carboplatin Carboplatin Epirubicin Doxorubicin

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

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

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

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

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