Adjuvant antiviral therapy in prevention of hcc recurrence post curative therapy su 20130522 v4

Role of antiviral therapy for hepatocellularcarcinoma patients after curative treatment

Chien-Wei Su

Division of Gastroenterology, Department of Medicine,

Taipei Veterans General Hospital

Taipei

Overview

• Natural history of HBV-related HCC

• Rationale for the application of antiviral therapy for HCC after curative therapy

• Efficacy and prognosis of antiviral therapy as tertiary prevention for HBV-related HCC

– Interferon therapy

– Nucleos(t)ide analogue (NUC) therapy

Schematic representation of factors that influence the progression of HBV-related liver disease

Liaw YF. Liver Int 2006; 26: 23-29

REVEAL: Relationship Between Baseline HBV DNA Levels

and HCC Incidence Entire Cohort, N = 3653

14

12

10

8

6

4

2

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Year of Follow-up

Cumulative Incidence of HCC (%)

Baseline HBV DNA Level (copies/mL)

1 Million100,000-999,99910,000-99,999300-9,999<300

No. at RiskBaseline HBV DNA Level (copies/mL)

1 Million

100,000-999,999

10,000-99,999

300-9,999

<300

627 621 611 604 593 582 571 561 550 541 528 513 499 414

349 346 342 338 333 327 321 317 310 304 302 294 288 228

643 637 633 633 627 625 622 615 609 606 597 588 586 490

1161 1155 1146 1139 1137 1131 1129 1123 1119 1113 1102 1091 1082 879

873 865 862 854 850 845 836 826 823 819 814 807 802 720

Chen CJ, et al. JAMA. 2006;295:65-73.

Nomogram for risk of HCC

Yang HI, et al. J Clin Oncol 2010;28:2437-44

1957Interferon discovered

1991Interferon alfa-2b approved for HBV

1998Lamivudine (3TC) approved as first

nucleoside analogue for HBV

1991 3TC anti-HBV and

anti-HIV activity discovered

1990 PMEA anti-HBV

activity discovered

2002-9Adefovir dipivoxil (PMEA prodrug)

approved for HBV

1998 Entecavir anti-HBV activity discovered

2005-4 Entecavir / 2005-5

peginterferon alfa-2a approved for HBV

2006-10Telbivudine

approved for HBV

2001 Telbivudine anti-HBV activity discovered

HBV Treatment: 2013

2008-8Tenofovir

approved for HBV

Antiviral therapy could reduce the incidence of HCC for CHB patients

Sung JJY, et al. Aliment Pharmacol Ther 2008;28:1067-77

IFN

RR: 0.66

NUC

RR: 0.22

Short Summary

• Active viral replication and ongoing hepatic necro-inflammation are crucial for the development of HCC for patients with chronic HBV infection.

• Adequate anti-viral therapy could reduce the risk of HCC in such patients.

Strategy for Preventing HBV-HCC

Primary prevention

• HBV vaccination

Secondary prevention

• Adequate antiviral therapy

• Close surveillance (sonography and AFP)

Overview

• Natural history of HBV-related HCC

• Rationale for the application of antiviral therapy for HCC after curative therapy

• Efficacy and prognosis of antiviral therapy as tertiary prevention for HBV-related HCC

– Interferon therapy

– Nucleos(t)ide analogue (NUC) therapy

Curative therapy for HCC

After propensity score matching, RFA was not inferior to SR in overall survival; but SR had lower incidence of developing

recurrence than RFA

Overall Survival RecurrenceHung HH, Chiou YY, Hsia CY, et al. Clin Gastroenterol Hepatol 2011;9:79-86

After propensity score matching, patients in the RFA group and SR group still had similar prognosis both in

overall survival and recurrence in BCLC stage 0 HCC

Overall survival Recurrence

Hung HH, Chiou YY, Hsia CY, et al. Clin Gastroenterol Hepatol 2011;9:79-86

De Lope Rodriguez C. J Hepatol 2012:S75-87

Rationale for the application of antiviral therapy for HBV-related

HCC after curative therapy

Predictors of HCC prognosis

Tumor factor

Liver functional

reserve

Hepatic fibrosis

Viral factors

Multivariate analysis of factors independently associated with tumor recurrence after resection

Variable Relative cumulative risk (95% CI) of tumor recurrence

P

Age >60 yr 4 (1.4-11.1) 0.01

AFP >1000ng/mL 7.4 (2.0-26.9) 0.02

Tumor size >5cm 5.1 (1.3-19.8) 0.02

HBV DNA > 2000 IU/mL at the time of resection

22.3 (3.3-150.5) 0.001

Hung IFN, et al. Am J Gastroenterol 2008;103:1663-73

Multivariate analysis of factors associated with early recurrence (< 2 year after resection)

Variable Hazard ratio (95% confidence interval)

P

AFP > 20 ng/mL 3.891 (1.795-8.475) 0.001

Cut margin 1cm 3.333 (1.487-7.470) 0.003

Macroscopic venous invasion

4.693 (1.645-13.391) 0.004

Multinodularity 2.232 (1.021-4.878) 0.044

Wu JC, Huang YH, Chau GY et al. J Hepatol 2009;51:890-897

Tumor factors determine

early recurrence

Multivariate analysis of factors associated with late recurrence (> 2 year after resection)

Variable Hazard ratio (95% confidence interval)

P

Ishak activity > 6 4.658 (1.970~11.017) <0.001

Multinodularity 3.266 (1.417~7.526) 0.005

ICG- 15 > 10% 2.487 (1.095~5.650) 0.030

HBV DNA >106

copies/mL2.548 (1.040~6.240) 0.041

Wu JC, Huang YH, Chau GY, et al. J Hepatol 2009;51:890-897

Field factors determine

late recurrence

Cumulative early and late recurrences of HCC stratified by serum HBV DNA level

Early recurrence Late recurrence

Wu JC, Huang YH, Chau GY, et al. J Hepatol 2009;51:890-897

Minimal fibrosis

Advanced fibrosisP=0.018

P=0.018

Minimal fibrosis

Advanced fibrosis

Survival 1 yr 3yr 5yr 10yr

Mininal 100% 92.9% 92.9% 78.6%

Advanced 91.9% 71.0% 59.7% 29.2%

Recurrence 1 yr 3yr 5yr 10yr

Mininal 7.1% 21.4% 21.4% 28.6%

Advanced 24.4% 49.6% 60.3% 72.6%

Hung HH, Su CW, Chau GY, Huo TI, Wu JC, et al.

Hepatol Int 2010;4:691-699

The degree of liver fibrosis is critical in determining post-surgery

outcomes for patients with small HCC

Short Summary

• Tumor factors are associated with early HCC recurrence while high viral loads and hepatic inflammatory activity and fibrosis (field factors) are associated with late recurrence.

• As the impact of field factors may be overwhelmed by the tumor factors in advanced HCC, it plays a more important role in determining recurrence for small HCC.

Long-term ETV therapy results in the reversal of fibrosis/cirrhosis

Chang TT, Liaw YF, Wu SS, et al. Hepatology 2010;52:886-893

95%: ≧ 2-point decrease in the

Knodell necroinflammatory score

88%: ≧ 1-point decrease in the

Ishak fibrosis score

Long-term tenofovir therapy results in the reversal of fibrosis/cirrhosis

Marcellin P, et al. Lancet 2013; 381:468-75

Rationale for the application of antiviral therapy for HBV-related HCC

• Anti-viral therapy could suppress viral replication, ameliorate liver inflammation, reduce fibrosis, and improve liver functional reserve, which is crucial for determining outcomes in HCC patients.

• It is reasonable to expect antiviral therapy could improve prognosis for HBV-related HCC after curative therapies, especially in early tumor stage or in late recurrence.

Overview

• Natural history of HBV-related HCC

• Rationale for the application of antiviral therapy for HCC after curative therapy

• Efficacy and prognosis of antiviral therapy as tertiary prevention for HBV-related HCC

– Interferon therapy

– Nucleos(t)ide analogue (NUC) therapy

IFN therapy

IFN therapy for HCV-related HCC after curative therapies

Compare adjuvant interferon treatment vs. no treatment

in overall survival after curative treatment for HCC

OR: 0.40 (0.23-0.70)

Singal AK, et al. Aliment Pharmacol Ther 2010;32:851-8

Compare adjuvant interferon treatment vs. no treatment

in recurrence after curative treatment for HCC

RR: 0.86 (0.76-0.97)

Breitenstein S, et al. Brit J Surg 2009;96:975-981

IFN does not affect overall recurrence, but could

reduce late recurrence for HCV-related HCC

Mazzaferro V, et al. Hepatology 2006:44:1543-1554

IFN improves recurrence-free survival

1 year: 7.8%

(95% CI: 3.7-11.8%)

2 years: 35.4%

(95% CI: 30.7-40.0%)

Shen YC, Hsu C, Cheng AL, et al. J Hepatol 2010;52:889-894

IFN reduces recurrence for small HCV-HCC following ablation or resection

Singal AK, et al. Aliment Pharmacol Ther 2010;32:851-8

OR: 0.26

IFN therapy for HBV-related HCC after curative therapies

Post-operative IFN postponed recurrence and improved overall survival for HBV-HCC

118 patients in each group

IFN 18 months

Control

IFN 18 months

Control

P= 0.1425

P= 0.0003

Sun HC, et al. J Cancer Res Clin Oncol 2006;132:458-465

Post-operative IFN postponed recurrence and improved overall survival for HBV-HCC

IFN 18 months

Control

IFN 18 months

ControlP= 0.009

P= 0.082

Qu LS, et al. J Surg Oncol 2010;102:796-801

Overall survival Recurrence

Adjuvant IFN ɑ-2b for 53 weeks did not reduce post-operative recurrence in HBV-related HCC

Chen LT, Chen MF, Li LA, et al. Ann Surg 2012;255:8-17

Overall survival

Disease-free survival

Summary for IFN therapy after curative therapy for HCC

• IFN therapy could preserve liver functional reserve and improve overall survival for HCC patients after curative therapies

• IFN may decrease the incidence of recurrence

– Late recurrence

– Early stage HCC

• However, as patients enrolled in the previous studies are mainly HCV-related HCC, the efficacy of PEG-IFN therapy for HBV-HCC patients after curative therapy needs more large scale, prospective studies to be validated.

NUC therapy for tertiary prevention of HBV-HCC

Antiviral therapy could decrease post-operative recurrence in HBV-related HCC with early tumor stage

Chan ACY, Poon RTP, Fan ST, et al. Arch Surg 2011; 146:675-81

Disease-free survival

AJCC stage I and II AJCC stage III

Antiviral therapy could decrease post-operative recurrence in HBV-related HCC with early tumor stage

Chan ACY, Poon RTP, Fan ST, et al. Arch Surg 2011; 146:675-81

Disease-free survival

AJCC stage I and II AJCC stage III

Antiviral therapy could decrease post-operative recurrence in HBV-related HCC

Su CW, Wu JC, et al. PLoS ONE (in press)

The impact of anti-viral therapy on recurrence stratified by BCLC stage

The effect of anti-viral therapy in decreasingrecurrence is more apparent in early stage HCC

Su CW, Wu JC, et al. PLoS ONE (in press)

The impact of anti-viral therapy on recurrence stratified by viral factors: HBV DNA levels

P< 0.001 P=0.038

Su CW, Wu JC, et al. PLoS ONE (in press)

The impact of anti-viral therapy on recurrence stratified by viral factors: serum HBsAg levels

P= 0.001 P=0.037

The effect of anti-viral therapy in decreasingrecurrence is irrespective of viral load

Su CW, Wu JC, et al. PLoS ONE (in press)

The effect of antiviral therapy on HCC patients after RFA therapy

Overall survival

Recurrence

Kao WY, Chiou YY, Hung HH, et al. J Clin Gastroenterol 2012; 46:62-70

The effect of NUC for HBV-related HCC after curative therapies

Overall survival

Recurrence

Wong JSW, Wong GLH, Chan HLY, et al. Aliment Pharmacol Ther 2011;33:104-12

Post-operative adjuvant antiviral therapy with LAM for HBV-related HCC: recurrence

1 year

OR: 0.59, P= 0.24

2 years

OR: 0.82, P= 0.60

3 years

OR: 0.43, P= 0.07

5 years

OR: 0.21, P= 0.03

Miao RY, et al. World J Gastroenterol 2010;16: 2931-42

NUC could reduce recurrence for HBV-related HCC after resection surgery

Wu CY, et al. JAMA 2012; 308:1906-1913.

Recurrence Mortality

Summary for NUC after curative therapy for HCC

• NUC could improve overall survival for HBV-HCC patients after curative therapies

• NUC may decrease the late recurrence for HBV-HCC patients after curative therapies

• NUC may decrease the incidence of recurrence for early stage HCC.

• However, large scale randomized controlled study is still lacking.

Strategy for Preventing HBV-HCC

Primary prevention

• HBV vaccination

Secondary prevention

• Adequate antiviral therapy

• Close surveillance (sonography and AFP)

Tertiary Prevention

• Adjuvant anti-tumor therapy (such as target therapy) for reducing early recurrence

• Antiviral therapy for improving liver functional reserve and reducing late recurrence

Thanks for

Attendance

台北市 大屯夕照