HCC20121001

Hepatocellular Carcinoma

台北榮民總醫院內科部胃腸科蘇建維醫師

Outline

• Epidemiology• Diagnosis• Staging• Management

Improving prognosis of patients with HCC in Japan

Ikai I, et al. Hepatol Res 2010:40:1043-59

39.3%

26.8%

9.5%

5 year survival rate

Santi V, et al. J Hepatol 2012;56:397-403

Surveillance improves HCC prognosis

Kuo YH, Lu SN, Chen CL, et al. Eur J Cancer 2010:46:744-51

Epidemiology

• The major risk factor for HCC : – HBV chronic infection (52% of all HCC) – Followed by chronic HCV infection and alcohol intake

• Other HCC risk factors : male, aflatoxin, obesity, type II DM, hereditary hemochromatosis, primary biliary cirrhosis, several hereditary metabolic conditions

Risk factors of HCC

de Lope CR, Tremosini S, Forner A, et al. J Hepatol 2012;56 Suppl:S75-87.

Surveillance for HCCBarcelona-2000 EASL conference

Bruix J, et al. J Hepatol 2001;35:421-30

Gender, age, viral status and HCC prognosis

Chen CH, et al. Liver Int 2006;26:766-73

2008 Korea

台灣 B 型肝炎與肝癌相關之危險性

Yang HI, et al NEJM, 2002; 347:168-74. This article has been cited for 805 times till Sep. 2012

HBsAg HBeAg ALT Risk

- - Normal 1 (23/71,105 person/yr)

- - Elevated 5.4

+ - Normal 10.3

+ - Elevated 29.3

+ + Normal 61.3

+ + Elevated 109

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 13Year of Follow-up

Cumulative Incidence of HCC (%)

Baseline HBV DNA Level (copies/mL)³1 Million100,000-999,99910,000-99,999300-9,999<300

No. at Risk Baseline HBV DNA Level (copies/mL)

³1 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. This article has been cited for 1362 times till Sep. 2012

Nomogram for risk of HCC

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

Serum HCV RNA and ALT levels predict HCV outcomes

High HCV RNA levels: > 3.5 x 105 U/ML

Lee MH, et al. J Clin Oncol 2010;28:4587-93

Diagnostic accuracies of four thresholds of ULN of ALT for predicting unhealthy status in male

Sensitivity (%)

(95% CI)

Specificity (%)

(95% CI)

Youden’s index AUROC

(95% CI)Training setCurrent 20.3(19.5-21.0) 96.4(95.3-97.4) 0.167 0.583(0.575-0.592)

Kang 34.8(33.9-35.7) 91.0(89.3-92.6) 0.258 0.629(0.620-0.638)

Prati 36.9(36.0-37.8) 89.4(87.6-91.1) 0.263 0.632(0.623-0.640)

Wu (this study) 65.1(64.2-66.0) 67.7(65.1-70.3) 0.328 0.664(0.656-0.673)

Validation setCurrent 25.1(24.0-26.2) 96.9(95.2-98.0) 0.220 0.610(0.598-0.621)

Kang 41.7(40.4-42.9) 90.3(87.7-92.4) 0.320 0.660(0.648-0.671)

Prati 44.2(43.0-45.5) 89.2(86.6-91.5) 0.334 0.667(0.656-0.678)

Wu (this study) 74.5(73.4-75.6) 63.6(59.8-67.2) 0.381 0.690(0.679-0.701)

ULN threshold of ALT: current 40 IU/L; Kang: 31 IU/L for male and 23 IU/L for female; Prati: 30 IU/L for male and 19 IU/L for female; Wu: 21 IU/L for male and 17 IU/L for female

Wu WC, Wu CY, Wang YJ, Su CW, et al. Aliment Pharmacol Ther 2012;36:560-568

2012 EASL recommendation for HCC surveillance

Cirrhotic patients, Child-Pugh stage A and B

Cirrhotic patients, Child-Pugh stage C awaiting liver transplantation

Non-cirrhotic HBV carriers with active hepatitis or family history of HCC

Non-cirrhotic patients with chronic hepatitis C and advanced liver fibrosis F3

2012 J Hepatol 2012:56:908-43

Diagnosis

Diagnostic criteria for HCC in Barcelona-2000 EASL conference

• Cyto-histological criteria• Non-invasive criteria (restricted to cirrhotic patients)

– Radiological criteria: two coincident imaging techniques• Focal lesion > 2cm with arterial hypervascularization

– Combined criteria: one imaging technique associated with AFP

• Focal lesion > 2cm with arterial hypervascularization• AFP levels > 400 ng/mL

• Four techniques considered: US, spiral CT, MRI and angiography

Bruix J, et al. J hepatol 2001;35:421-30

Diagnosis accuracy of CEUS and MRI

Diagnosis accuracy of combined CEUS and MRI

Forner A, Bruix J, et al. Hepatology 2008:47:97-104

Algorithm for investigation of a nodule found on ultrasound

Bruix J, Sherman M. Management of hepatocellular carcinoma. AASLD practice guideline. Hepatology 2005;42:1208-1236

Image:CEUS

CTMRI

Diagnosis accuracy of single imaging

Scan Sensitivity Specificity Positive predictive value

Negative predictive value

Accuracy

CEUS 53% 91% 75% 79% 78%

CT 53% 99% 95% 80% 83%

MRI 62% 100% 100% 84% 87%

Khalili K, Sherman M, et al. J Hepatol 2011;54:723-8

The sensitivity of HCC diagnosis by imaging is not influenced by the cirrhotic background

Imaging Liver cirrhosis Non-cirrhotic liver P

Liver CT (typical/atypical) (n=204) 81/14 (85.3%) 86/23(78.9%) 0.239

Tumor 1-2 cm (n=38) 15/6 (71.4%) 12/5 (70.6%) 1.000

Tumor > 2cm (n=166) 66/8 (89.2%) 74/18 (80.4%) 0.123

MRI (typical/atypical) (n=80) 48/12 (80%) 13/7 (65%) 0.226

Tumor 1-2cm (n=26) 19/5 (79.2%) 2/0 (100%) 1.000

Tumor >2cm (n=54) 29/7 (80.6%) 11/7 (61.1%) 0.188

Lin MT, Chen CL, Hu TH, et al. J Gastroenterol Hepatol 2011;26;745-50

Diagnostic criteria of HCC in 2012

De Lope CR, et al. J Hepatol 2012;56 Suppl 1:S75-87

Staging and Treatment

HCC staging• At least 10 systems have been raised

– Okuda (Japan)

– TNM/ AJCC (US)

– BCLC (Spain)

– CLIP (Italy)

– French

– CUPI (Hong Kong)

– JIS (Japan)

– NATURE scoring system (Taiwan)

– Taipei Integrated Scoring system (Taiwan)

• To best assess the prognosis of HCC patients it is recommended that the staging system take into account tumor stage, liver function and physical status. The impact of treatment should also be considered when estimating life expectancy.

• Currently, the BCLC system is the only staging system that accomplishes these aims (level II).

AASLD 2010

Staging system

Selecting an optimal staging system for HCC

Hsu CY, Huo TI, et al. Cancer 2010;116:3006-14

The Cancer of the Liver Italian Program (CLIP) scoring system

Variable Score Child-Pugh stage A B C

0 1 2

Tumor morphology Uninodular & extension 50% Multinodular & extension 50% Massive or extension > 50%

0 1 2

AFP < 400 400

0 1

Portal vein thrombosis No Yes

0 1

Hepatology 1998;28:751

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

BCLC staging system

Taipei Integrated Scoring (TIS) System

Parameter 0 1 2 3

TTV (cm3) <50 50-250 250-500 >500

CTP A B C

AFP (ng/mL) <400 >400

TTV: total tumor volumeCTP: Child-Turcotte-Pugh

Hsu CY, Huang YH, Huo TI, et al. J Hepatol 2010;53:108-117

Performance status in HCC patients

Hsu CY, Huo TI, et al. Hepatology (in press)

Treatment strategy stratified by BCLC stage

BCLC stage 0-A

AASLD 2010

Patients in the RFA group had lower overall survival rate and higher recurrence rate than those in the SR group

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

Comparison of demographic data between HCC patients underwent RFA or SRParameter RFA group (n=190) SR group (n=229) P

Patient demographicsAge (years) (mean±SD) 67.42±11.45 60.07±12.56 < 0.001

Sex (M: F) (%) 121/69 (63.7%/36.3%) 184/45 (80.3%/19.7%) < 0.001

Viral factorsHBsAg positive/negative 88/97(46.3%/51.1%) 137/81(59.8%/35.4%) 0.004

Anit-HCV positive/negative 85/101(44.7%/53.2%) 61/151(26.6%/65.9%) < 0.001

Serum biochemistry tests and liver function testsAlbumin (g/dL) (mean±SD) 3.85±0.55 4.09±0.40 < 0.001

Total bilirubin (mg/dL) (mean±SD) 0.99±0.60 0.81±0.48 0.001

ALT (U/L) (mean±SD) 71.84±56.08 59.83±49.75 0.022

AST (U/L) (mean±SD) 71.43±56.55 50.58±37.67 < 0.001

Alk-P(U/L) (mean±SD) 114.08±56.02 91.25±42.06 < 0.001

Creatinine (mg/dL) (mean±SD) 1.20±1.05 1.08±0.51 0.159

Glucose (mg/dL) (mean±SD) 117.40±57.83 105.91±40.47 0.026

ICG-15R (%) (median; 25 and 75 percentiles) 19.50;8.00-29.00 11.50;7.00-16.00 0.002

PT/ INR (mean±SD) 1.06±0.12 1.03±0.06 0.002

Platelet (/mm3) (mean±SD) 128889±62029 162078±61612 < 0.001

Tumor factorsTumor size (cm) (median; 25 and 75 percentiles) 2.20;1.70-2.90 2.70;2.00-3.70 < 0.001

Single tumor/multinodularity (%) 152/38 (80.0%/20.0%) 181/48 (79.0%/21.0%) 0.904

AFP (ng/ml) (median; 25 and 75 percentiles) 17.86;7.30-49.87 17.88;6.59-190.25 0.043

Multivariate analysis to determine factors associated with poor outcomes after curative therapy for HCC

Hazard ratio (95% confidence interval) P

Poor overall survivalAge > 65 years 1.988 (1.266-3.121) 0.003

Albumin ≦4 g/dL 1.751 (1.073-2.857) 0.025

Bilirubin > 1.6mg/dL 2.032 (1.033-3.998) 0.040

PT/INR > 1.1 2.114 (1.275-3.506) 0.004

AFP> 20 ng/mL 1.680 (1.079-2.617) 0.022

Multiple tumor 1.851 (1.139-3.007) 0.013

RecurrenceRFA/SR 1.949 (1.479-2.571) < 0.001

Platelet ≦105/mm3 1.420 (1.033-1.949) 0.031

Multiple tumor 1.798 (1.344-2.405) <0.001

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

A B

There was no statistical significance between RFA and SR in overall survival and recurrence for BCLC stage 0 HCC patients

A B

Survival of patients with HCC within Milan criteria

Lee YH, Hsu CY, Huo TI, et al. Aliment Pharmacol Ther 2012;36:551-59

Conclusions

• Patients with small HCCs (5 cm) have a higher rate of tumor recurrence following RFA than surgery, but overall survival rates are comparable between therapies.

• RFA is as effective as surgery in patients BCLC stage 0 HCC.


Prognosis of RFA

HCC tumorigenesis

Tumor factor

Liver functional

reserve

Hepatic fibrosis

Viral factors

Viral factors

Viral etiology does not impact on the outcome of small HCC patients who undergo RFA

Overall Survival

Disease-free Survival

Propensity score matching analysis

Chen PH, Kao WY, Chiou YY, et al. Ann Hepatol (in press)

Hepatic Fibrosis

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

APRI could predict prognosis of HCC patients undergoing resection

APRI could serve as a feasible marker for predicting the prognosis of patients with small HCC undergoing resection surgery

Hung HH, Su CW, Chau GY, Huo TI, Wu JC, et al. Hepatol Int 2010;4:691-699

Aspartate Aminotransferase-Platelet Ratio Index (APRI) predicts RFA outcomes

Kao WY, Chiou YY, Hung HH, et al. Eur J Gastroenterol Hepatol 2011;23:528-536

Patients with splenomegaly had poorer overall survival rate than those with normal splenic volume

Wu WC, Chiou YY, Hung HH. J Clin Gastroenterol 2012; 46;789-95

AFP response

AFP Response Predicts Outcome of Patients with Initial serum AFP Levels ≥100ng/mL

Overall Survival Recurrence

100%

Optimal AFP responseOptimal AFP response

Non-optimal AFP response

Non-optimal AFP responseP<0.001

P=0.001

Optimal response: reduction 20% ≧baseline AFP one month after RFA

Kao WY, Chiou YY, Hung HH, et al. Clin Radiol 2012; 67:429-436

BCLC stage B


Resection is superior to TACE in patients with HCC beyond Milan criteria

Hsu CY, Huo TI, et al. Ann Surg Oncol 2012;19:842-9

Propensity score matching analysis

Resection is superior to TACE in patients with HCC beyond Milan criteria

Chang WC, Kao WY, Chau GY, et al. Surgery (in press)

Variable HR 95%CI p

Overall survival

Albumin 4 / > 4 g/dL 1.570 1.225-2.012 <0.001

ICGR-15 >10%/ 10% 1.290 1.009-1.650 0.042

Creatinine > 1.2 / 1.2 mg/dL 1.462 1.029-2.077 0.034

Multiple tumor (yes/no) 1.517 1.154-1.994 0.003

Edmondson stage III or IV / I or II 1.485 1.164-1.895 0.001

Macroscopic vascular invasion (yes) 1.585 1.217-2.064 0.001

The impact of poor respond to TACE on overall survival

Tsai YJ, Hsu CY, Huo TI, et al. Hepatol Int 2011;5:975-84

Liver failure after TACE

Hsin IF, Hsu CY, Huo TI, et al. J Clin Gastroenterol 2011;45:556-62

BCLC stage C


62

Sorafenib is the First Systemic Targeted Therapy to Show Significant Survival Benefits

1. Llovet JM, et al. N Engl J Med. 2008;359:378-90. 2. Cheng A, et al. Lancet Oncol. 2009;10:25-34.

Surv

ival

pro

babi

lity

1.00

0.75

0.50

0.25

Months0 4 6 8 10 12 14 162

0.00

Sorafenib (n = 299)Median OS: 10.7 months

Placebo (n = 303)Median OS: 7.9 months

18

HR = 0.69

Surv

ival

pro

babi

lity

1.00

0.75

0.50

0.25

Months0 4 8 12 22

0.00

Sorafenib (n = 150)Median OS: 6.5 months

Placebo (n = 76)Median OS: 4.2 months

2 6 10 14 16 18 20

HR = 0.68

SHARP1 Asia–Pacific2

Results from pivotal trials demonstrated that sorafenib consistently increased overall survival in different patient populations across geographic regions and etiologies1,2

TACE prolongs survival of patients with metastatic HCC

Lee IC, Huo TI, Huang YH, et al. Hepatol Int (in press)


BCLC staging system

Thanks for Your Attention

西班牙巴塞隆納

Health & Medicine

HCC20121001