Current role of adjuvant treatment after curative treatment of HCC

Joint Hospital Surgical Grand RoundDr Arthur M. Y. Fung

Caritas Medical Centre19th October, 2013

Overview

• Only 10-30% of HCC are amenable to surgical resection1

• 50-90% of post-op death is due to recurrent disease2

• Sources of recurrence– Early recurrence (<2yr): intrahepatic metastasis of primary

tumour– Late recurrence (>2yr): multicentric de-novo

carcinogenesis• Objective of adjuvant treatment– Eradicate residual microscopic HCC foci– Prevent de-novo carcinogenesis

1. Zhong JH, Li H, Li LQ, You XM, Zhang Y, Zhao YN, et al. Adjuvant therapy options following curative treatment of hepatocellular carcinoma: a systematic review of randomized trials. Eur J Surg Oncol. 2012 Apr;38(4):286-95. doi: 10.1016/j.ejso.2012.01.006. Epub Jan 24.2. Lau WY, Lai EC, Lau SH. The current role of neoadjuvant/adjuvant/chemoprevention therapy in partial hepatectomy for hepatocellular carcinoma: a systematic review. Hepatobiliary Pancreat Dis Int. 2009 Apr;8(2):124-33.

Treatment modalities covered

• Transcatheter arterial chemoembolization• Intra-arterial lipiodol-Iodine-131• Interferon• Nucleoside analogue

Type Study Sample (T/C)

Follow-up

Child-Pugh (A/B)

Subgp Intervention Yr DFS (%) OS (%)

Tx gp Cx gp Tx gp Cx gp

RCT Peng et al. 2009

63 /63

9 yr 90 / 14

HCC w/ PVTT

Lip + 5-FU + Adriamycin + Gelfoam

1 No significant difference

50.9 33.3

3 33.8 17.0

5 21.5 8.5

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 Sep;198(3):313-8. doi: 10.1016/j.amjsurg.2008.09.026. Epub 9 Mar 12.

Transcatheter arterial chemoembolization in HCC with portal vein tumour thrombus

Type Study Sample (T/C)

Follow-up

Child-Pugh (A/B)

Subgp Intervention Yr DFS (%) OS (%)

Tx gp Cx gp Tx gp Cx gp

RCT Zhong et al. 2009

59 /59

4 yr NR Stage III A HCC. Multiple tumours 74.8%, two tumours in 50.4%, Invasion to main portal / hepatc vein 41.7%

Carboplatin + mitromicin + Epirubicin + Lip at 4-6wks

1 29.7 14 68.6 56.6

3 9.3 3.5 26.4 19.4

5 9.3 1.7 20.2 17.5

Median survival (Months)

6 4 20 14

Transcatheter arterial chemoembolization

Zhong C, Guo RP, Li JQ, Shi M, Wei W, Chen MS, et al. A randomized controlled trial of hepatectomy with adjuvant transcatheter arterial chemoembolization versus hepatectomy alone for Stage III A hepatocellular carcinoma. J Cancer Res Clin Oncol. 2009 Oct;135(10):1437-45. doi: 10.007/s00432-009-0588-2. Epub 2009 May 1.

Type Study Sample

(T/C)Follow-up

Child-Pugh (A/B)

Subgp Intervention Yr DFS (%) OS (%)

Tx gp Cx gp Tx gp Cx gp

RETRO.

COHORT

Chen et al. 2013

766/1158

Mean: 29m

> 90% Child’s A

5-FU + Mit C + Cisplatin + Lip. A repeat TACE at 2-4 months.

1No significant difference in recurrence.

Only tumours >5cm, high risk

benefit in survival

77.1 60

4 groups (post resection) 2 60.7 45.5

Tumour ≤5cm, low risk

Tumour ≤5cm, high risk

3 49.0 39.8

Tumour >5cm, low risk

4 41.1 34.4

Tumour >5cm, high risk

5 35.2 28.6

Transarterial chemo-embolization

Chen X, Zhang B, Yin X, Ren Z, Qiu S, Zhou J. Lipiodolized transarterial chemoembolization in hepatocellular carcinoma patients after curative resection. J Cancer Res Clin Oncol. 2013 May;139(5):773-81. doi: 10.1007/s00432-012-1343-7. Epub 2013 Feb 3.

TACE

• Subgroup benefits– Portal vein tumour thrombus (Peng et al.)– Stage IIIA HCC (Zhong et al.)– >5cm tumour with high risk features, recurrence

within 2 years (Chen et al.)• Role– Early detection and treatment of residual tumour – ↓early recurrence – Overall survival benefit?

• Conclusion: further trials needed

Type Study Sample

(T/C)Follow-up

Child-Pugh (A/B)

Subgp (HBV / HCV)

Intervention Yr DFS (%) OS (%)

Tx gp Cx gp Tx gp Cx gp

RCT Lau et al. 1999, 2008

21 /22

Median FU 66 months

NR Tx: HBV = 19Cx: HBV = 19

Single dose 1850 MBq given within 6 weeks post-resection

1 85.2 59.1 90.5 86.4

3 74.5 36 84.4 46.3

5 61.9 31.8 66.7 63.4

7 52.4 31.8 66.7 31.8

Note: p >0.05 at 10 yrs

10 47.6 27.3 52.4 27.3

Intra-arterial lipiodol – Iodine - 131

Lau WY, Leung TWT, Ho SKW, Chan M, Machin D, Lau J, et al. Adjuvant intra-arterial lipiodol-iodine-131 for resectable hepatocellular carcinoma: a prospective randomised trial. The Lancet. 1999;353(9155):797-801.Lau WY, Lai EC, Leung TW, Yu SC. Adjuvant intra-arterial iodine-131-labeled lipiodol for resectable hepatocellular carcinoma: a prospective randomized trial-update on 5-year and 10-year survival. Annals of surgery. 2008 Jan;247(1):43-8. PubMed PMID: 18156922.

DFSOS

Type Study Sample (T/C)

Follow-up

Child-Pugh (A/B)

Subgp (HBV / HCV)

Intervention Yr DFS (%) OS (%)

Tx gp Cx gp Tx gp Cx gp

PROS

COHORT

Chua et al. 2010

41 /41

Medi-an FU : 34 m

Tx: 36/4Child C = 1

Cx: 34/7

Tx: HBV 39%, HCV 7.3%

Cx: HBV 34%, HCV 22%;

Median dose: 2000MBq at median of 59 days post-resection

1 70 45

3 42 24 73 30

5 20 18 54 23

Median (months) 24 10 104 19

Chua TC, Saxena A, Chu F, Butler SP, Quinn RJ, Glenn D, et al. Hepatic resection with or without adjuvant iodine-131-lipiodol for hepatocellular carcinoma: a comparative analysis. Int J Clin Oncol. 2011 Apr;16(2):125-32. doi: 10.1007/s10147-010-0143-9.

Interferon

Prevents 2nd

tumour

Inhibits micrometastasis

Delays cirrhosis

Adverse effects:FeverChillsFatigueMyalgiaHeadacheLeukocytopeniaThrombocytopenia

Rare adverse effects:Elevated ALTAlopeciaDepressionHyperthyroidism

Antiviral therapy - Interferon

• Systematic review by Zhong et al. 2012• 8 RCTs• Post-curative treatment (resection or local

ablation)• Treatment group: 3-10 million units of IFN

(intramuscular)• 2-year tumour recurrence and overall survival

Zhong JH, Li H, Li LQ, You XM, Zhang Y, Zhao YN, et al. Adjuvant therapy options following curative treatment of hepatocellular carcinoma: a systematic review of randomized trials. Eur J Surg Oncol. 2012 Apr;38(4):286-95. doi: 10.1016/j.ejso.2012.01.006. Epub Jan 24.

Characteristics of included studies

• ≥50% with cirrhosis• Mixed HBV and HCV population

• 2-year recurrence RR = 0.84 (95% CI 0.73 – 0.97, P = 0.02)

• 2-year overall survival RR = 1.15 (95% CI 1.07 – 1.22, P< 0.001)

Type Study Sample (T/C)

Follow-up

Child-Pugh (A/B)

Subgp (HBV / HCV)

Intervention Yr DFS (%) OS (%)

Tx gp Cx gp Tx gp Cx gp

RCT Lo et al. 2007

40 /40

5 yr NR 90 % HBV, 4 % HCV

interferon α -2b 10MIU/m2 x 3 / week for 16 weeks

1 No significant difference

97 85

(Post resection) 5 79 61

Interferon – individual studies

• Relative risk of death for interferon treatment = 0.42 (95% CI, 0.17–1.05; P0.063)

• DFS– Fewer recurrence at 6 months in stage III/IVa– Non-significant overall

Lo CM, Liu CL, Chan SC, Lam CM, Poon RT, Ng IO, et al. A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma. Ann Surg. 2007 Jun;245(6):831-42.

• OS– Stage I/II: no benefit– Stage III/IVA: improved 5-year survival from 24%

to 68% (p = 0.038)

• Multivariate analysis found pTNM stage was the only significant prognostic factor for survival

• Side effects– 3/31 stopped– 22/31 required dose reduction

Type Study Sample (T/C)

Follow-up

Child-Pugh (A/B)

Subgp (HBV / HCV)

Intervention Yr Recurrence (%) Mortality (%)

Tx gp Cx gp Tx gp Cx gp

RETRO

COHORT

Hsu et al. 2013

213 / 850

2.01 +/- 1.67 yrs

NR.Matched in terms of cirrhosis.

0/1065

Post resection. IFN α-2a 180ug/wk or IFN α-2b 1.5ug/kg/wk + 800-1200mg ribavirin x 16wks

1 16.2 24.5 2.8 6.9

3 41.8 54.3 10.8 24.8

5 52.1 63.9 15.4 47.0

Peg-interferon + Ribavirin on HCV related HCC

Recurrence

MortalityHsu YC, Ho HJ, Wu MS, Lin JT, Wu CY. Postoperative peg-interferon plus ribavirin is associated with reduced recurrence of hepatitis C virus-related hepatocellular carcinoma. Hepatology. 2013 Jul;58(1):150-7. doi: 10.1002/hep.26300. Epub 2013 May 15.

Interferon

• Generalizability is in doubt• Systematic review: mixed HBV & HCV

population• Lo et al. with HBV predominant population:

only stage III/IVa benefit?• HCV related HCC: favourable• Further RCTs should target HBV & HCV

population separately

Type Study Sample

(T/C)Follow-up

Child-Pugh (A/B)

Subgp (HBV / HCV)

Intervention Yr DFS (%) OS (%)

Tx gp Cx gp Tx gp Cx gp

R.

COHORT

Chan et al. 2011

42/ 94

51 m

Tx: 42/0Cx: 84/ 10

136/0 Post major hepatectomy.Lamivudine (38), Entecavir (4)

1 66.5 48.9 88.1 76.5

3 51.4 33.8 79.1 47.5

5 51.4 33.8 71.2 43.5

OS DFS

Nucleoside Analogue

OS DFS

Stage I, II tumours

Stage III tumours

Chan AC, Chok KS, Yuen WK, Chan SC, Poon RT, Lo CM, et al. Impact of antiviral therapy on the survival of patients after major hepatectomy for hepatitis B virus-related hepatocellular carcinoma. Arch Surg. 2011 Jun;146(6):675-81. doi: 10.1001/archsurg.2011.125.

OS DFS

Without major vascular invasion

With major vascular invasion

Type Study Sample

(T/C)Follow-up

Child-Pugh (A/B)

Subgp (HBV / HCV)

Intervention Yr Cumulative recurrence (%)

Cumulative mortality (%)

Tx gp Cx gp Tx gp Cx gp

R.COHORT

Wu et al. 2012

518 / 4051

Tx: 2.64 yr

Cx: 2.18 yr

NR All HBV Post resection.Lamivudine (159), Entecavir (292), Telbuvidine (36),>1 drug (31)

6 45.6 (95%

CI: 36.5 – 54.6)

54.6 (95%

CI: 52.5 – 56.6)

29.0 (95%

CI: 20.0 – 38.0)

42.4 (95%

CI: 40.0

– 44.7)

Wu C-Y. Association Between Nucleoside Analogues and Risk of Hepatitis B Virus–Related Hepatocellular Carcinoma Recurrence Following Liver Resection. Jama. 2012;308(18):1906.

TACE Systemic chemo

Intraportal chemo

I-131 IFN Nucleoside analogue

Sorafenib

Meta-analysis

2

Systematic review

1

RCT 5 2 1 2

1

2Cohort 1 1 1 1 2

Case-control 1 1 2 1

Case report 1

BeneficialControversial, benefit only in DFS / OS Harmful

Bring home message• TACE: areas of further RCTs– Portal vein tumour thrombus– Stage IIIA HCC– >5cm tumour with high risk features, recurrence within 2

years• I-131: beneficial, but need larger RCTs• Interferon– Beneficial for HCV– Separate HBV & HCV studies are needed

• Nucleoside analogue– Beneficial for HBV– Clarify its role in early vs. advanced stage HCC