hepatocellular carcinoma thomas hargrave m.d. january 16, 2009

Hepatocellular Carcinoma


Thomas Hargrave M.D.

January 16, 2009

Thomas Hargrave M.D.

January 16, 2009

HCC Is Common and IncreasingHCC Is Common and Increasing

662,000 deaths from liver cancer yearly worldwide

Age-adjusted US incidence has increased 2-fold: 1985-1998

American Cancer Society statistics for liver cancer in 2008 Estimation of new cases: 21,370 Estimation of deaths: 18,410 5th leading cause of cancer deaths in males

662,000 deaths from liver cancer yearly worldwide

Age-adjusted US incidence has increased 2-fold: 1985-1998

American Cancer Society statistics for liver cancer in 2008 Estimation of new cases: 21,370 Estimation of deaths: 18,410 5th leading cause of cancer deaths in males

World Health Organization. Available at: http://www.who.int/whosis/en/. Accessed October 6, 2008. American Cancer Society. Cancer facts & figures 2008. Atlanta: American Cancer Society; 2008.

Worldwide Incidence of Hepatocellular Carcinoma

High (> 30:100,000)High (> 30:100,000)

Low or data unavailable (< 3:100,000)Low or data unavailable (< 3:100,000)Intermediate (3-30:100,000)Intermediate (3-30:100,000)

HCC EpidemiologyHCC Epidemiology

El-Serag HB, Gastroenterology 2004

El-Serag HB, Gastroenterology 2004

Changes in the Incidence of HCC 1978-1992 Changes in the Incidence of HCC 1978-1992

McGlynn K, et al, Int J Cancer 2001McGlynn K, et al, Int J Cancer 2001

-40-40 -20-20 00 2020 4040 6060 8080 100100 120120

-30-30-24-24-20-20

-18-18101012121414

21214646

50507171

83839090

108108

Singapore, ChineseSingapore, Chinese

Spain, ZaragozaSpain, Zaragoza

India, BombayIndia, Bombay

China, ShanghaiChina, Shanghai

Switzerland, GenevaSwitzerland, Geneva

Hong KongHong Kong

NewZealand, MaoriNewZealand, Maori

NewZealand, Non-MaoriNewZealand, Non-Maori

Japan, OsakaJapan, Osaka

UK, So. ThamesUK, So. Thames

Canada, AlbertaCanada, Alberta

Italy, VareseItaly, Varese

France, Bas-RhinFrance, Bas-Rhin

Australia, NSWAustralia, NSW

Recent Changes in the Incidence of HCCRecent Changes in the Incidence of HCC


Age-Adjusted Incidence Rates For HCC (1976-2002)

Age-Adjusted Incidence Rates For HCC (1976-2002)

El-Serag HB, Mason A, N Engl J Med 1999El-Serag HB et al, Ann Intern Med 2003El-Serag HB, Mason A, N Engl J Med 1999El-Serag HB et al, Ann Intern Med 2003

YearYear

76-7876-78 79-8179-81 82-8482-84 85-8785-87 88-9088-90 91-9391-93 94-9694-96 97-9997-99 2000-022000-02

1.41.4 1.41.41.61.6

1.81.8 2.02.02.32.3

2.72.7

3.13.13.53.5

3 3

2.52.5

22

1.51.5

11

0.50.5

00

Ra

tep

er

10

0,0

00

Ra

tep

er

10

0,0

00

3.33.3


Racial Distribution of HCC in the United States

Racial Distribution of HCC in the United States

YearYear75-7775-77 81-8381-83 84-8684-86 87-8987-89 90-9290-92 93-9593-95 96-9896-98

WhiteWhiteBlackBlackAsianAsian

78-8078-80

Nu

mb

er o

f C

ases

Nu

mb

er o

f C

ases

30003000

25002500

20002000

15001500

10001000

500500

00


El-Serag HB, Mason A, N Engl J Med 1999El-Serag HB, Mason A, N Engl J Med 1999

Racial Incidence Rates For HCCIn The United States

Racial Incidence Rates For HCCIn The United States

YearYear

76-7876-78 82-8482-84 85-8785-87 88-9088-90 91-9391-93 94-9694-96 97-9997-99 2000-022000-02Ag

e-A

dju

ste

d In

cid

en

ce R

ate

pe

r 1

00

,00

0A

ge

-Ad

jus

ted

Inc

ide

nce

Ra

tep

er

10

0,0

00

99887766554433221100

11

2.52.5

66

1.11.1

WhiteWhite BlackBlack Other (Asian)Other (Asian)

79-8179-81

2.52.5

55

88

2.52.5

5.25.2

1.11.1

2.62.6

6.36.3

1.31.3

2.92.9

6.66.6

1.41.4

3.43.4

7.27.2

1.71.7

3.73.7

7.27.2

1.91.9

3.93.9

8.48.4

2.32.3

4.64.6

7.97.9


El-Serag HB et al, Ann Intern Med 2003El-Serag HB et al, Ann Intern Med 2003

Temporal Trends in The Age Distribution of Hepatocellular Carcinoma

Temporal Trends in The Age Distribution of Hepatocellular Carcinoma

Inci

den

ce

Rat

ep

er

10

0,0

00

PY

Inci

den

ce

Rat

ep

er

10

0,0

00

PY

Age (years)Age (years)

20-2420-24 30-3430-3435-3935-39

40-4440-4445-4945-49

50-5450-5455-5955-5925-2925-29

0022446688

101012121414161618182020

1982 – 841991 – 932000 – 02

1982 – 841991 – 932000 – 02

60-6460-6465-6965-69

70-7470-7475-7975-79

80-8480-8485+85+



Risk Factors for HCC in US PatientsRisk Factors for HCC in US Patients

Worldwide, 75% to 80% of HCC attributable to chronic HBV (50% to 55%) or HCV (25% to 30%)


Di Bisceglie AM, et al. Am J Gastroenterol. 2003;98:2060-2063. El-Serag HB. Gastroenterology. 2004;127:S27-S34. Bosch FX, et al. Gastroenterology. 2004;127:S5-S16.Di Bisceglie AM, et al. Am J Gastroenterol. 2003;98:2060-2063. El-Serag HB. Gastroenterology. 2004;127:S27-S34. Bosch FX, et al. Gastroenterology. 2004;127:S5-S16.

Known Risk Factor in the US: Viral Hepatitis (N = 691)Known Risk Factor in the US: Viral Hepatitis (N = 691)

515

33

47

0

20

40

60

80

100

HBV + HCV HBV HCV Neither

Pre

sen

ce o

f R

isk

Fac

tor

Am

on

g H

CC

Pat

ien

ts (

%)

Risk Factors for HCC Risk Factors for HCC • Cirrhosis from any cause (3-8%/yr)

• HCV • HBV• Heavy alcohol consumption• Non-alcoholic fatty liver disease

• HBV without cirrhosis (0.02-0.06%/yr)• Inherited metabolic diseases

• Hemochromatosis • Alpha-1 antitrypsin deficiency • Glycogen storage disease• Porphyria cutanea tarda• Tyrosinemia • Autoimmune hepatitis

• Cirrhosis from any cause (3-8%/yr)• HCV • HBV• Heavy alcohol consumption• Non-alcoholic fatty liver disease

• HBV without cirrhosis (0.02-0.06%/yr)• Inherited metabolic diseases

• Hemochromatosis • Alpha-1 antitrypsin deficiency • Glycogen storage disease• Porphyria cutanea tarda• Tyrosinemia • Autoimmune hepatitis

Risk Factors for HCC Risk Factors for HCC


HCV Cirrhosis and HCCHCV Cirrhosis and HCC

Multiple smallfoci of HCCMultiple smallfoci of HCC

HCV Cirrhosis and HCCHCV Cirrhosis and HCC


Why is HCC Incidence Rising?Why is HCC Incidence Rising?

• Rising incidence of cirrhosis• HCV (main reason)

• HBV

• Other (?NAFLD/insulin resistance)

• Improved survival of patients with cirrhosis

• Rising incidence of cirrhosis• HCV (main reason)

• HBV

• Other (?NAFLD/insulin resistance)

• Improved survival of patients with cirrhosis

Increasing prevalence of patients with cirrhosisIncreasing prevalence of patients with cirrhosis

Why HCC is Rising?Why HCC is Rising?


El-Serag HB, Gastroenterology 2004El-Serag HB, Gastroenterology 2004

Prevalence of HCV in United States Males:1999-2002

Prevalence of HCV in United States Males:1999-2002

0%

2%

4%

6%

8%

10%

12%

14%

16%

16-19 20-29 30-39 40-49 50-59 60-69

blackwhitehispanic

0%

2%

4%

6%

8%

10%

12%

14%

16%

16-19 20-29 30-39 40-49 50-59 60-69

blackwhitehispanic

Annals Internal Medicine 2006; 144:705

Projected Rates of HCV-Related Cirrhosis and HCC

Projected Rates of HCV-Related Cirrhosis and HCC

Cirrhosis

0

250000

500000

750000

1000000

2000 2010 2020 2030 2040

Calendar Year

Pre

vale

nce

(No)

Cirrhosis

0

250000

500000

750000

1000000

2000 2010 2020 2030 2040

Calendar Year

Pre

vale

nce

(No)

Davis GL, et al. Liver Transpl. 2003;9:331.


0

5000

10000

15000

2000 2010 2020 2030 2040

Calendar YearPr

eval

ence

(No)

Alcohol Intake and the Risk of HCCAlcohol Intake and the Risk of HCC

Donato F, et al, Am J Epidemiol 2002Donato F, et al, Am J Epidemiol 2002

00

55

1010

1515

2020

2020 4040 6060 8080 100100 120120 140140

Grams of Alcohol / DayGrams of Alcohol / Day

Od

ds

Rat

ios

Od

ds

Rat

ios No HCVNo HCV with HCVwith HCV

Alcohol Intake and the Risk of HCCAlcohol Intake and the Risk of HCC


HBV DNA Associated with Increased Risk of HCC in Non-Cirrhotics

HBV DNA Associated with Increased Risk of HCC in Non-Cirrhotics

•Likelihood of HCC in individuals with detectable HBV DNA is 3.9 times more than those with undetectable HBV DNA

•Risk associated with increasing HBV DNA levels

•These data support possibility of preventing long-term risk of HCC by inducing sustained suppression of HBV replication

•Likelihood of HCC in individuals with detectable HBV DNA is 3.9 times more than those with undetectable HBV DNA

•Risk associated with increasing HBV DNA levels

•These data support possibility of preventing long-term risk of HCC by inducing sustained suppression of HBV replication

Yang HI, et al, N Engl J Med 2002Yang HI, et al, N Engl J Med 2002

HBV DNA Associated with Increased Risk of HCC

HBV DNA Associated with Increased Risk of HCC

HBe Antigen and Risk of HCC HBe Antigen and Risk of HCC

Yang HI, et al, N Engl J Med 2002Yang HI, et al, N Engl J Med 2002

Per

cen

t cu

mu

lati

ve

inci

den

ceP

erce

nt

cum

ula

tive

in

cid

ence

00

YearYear

HBsAg+, HBeAg+(RR = 60.2)HBsAg+, HBeAg+(RR = 60.2)

HBsAg+, HBeAg-(RR = 9.6)HBsAg+, HBeAg-(RR = 9.6)

HBsAg-, HBeAg-HBsAg-, HBeAg-

22

44

66

88

1010

1212

0011 22 33 44 55 66 77 88 99 1010

11,893 Noncirrhotic Taiwanese Males Followed 8 Yrs

HBV DNA and Risk of HCC: Untreated Non-Cirrhotic HBeAg+

HBV DNA and Risk of HCC: Untreated Non-Cirrhotic HBeAg+

3465 HBeAg (+) Non-cirrhotic Taiwanese Patients followed for a mean of 11.5years

65% had HBV DNA > 100,000,000

3465 HBeAg (+) Non-cirrhotic Taiwanese Patients followed for a mean of 11.5years

65% had HBV DNA > 100,000,000

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4 <300

~ 1000

~ 10,000

~ 100,000

~ 1,000,000

HBV DNA (copies/mL)

Inci

den

ce o

f H

CC

Per

Yea

r (%

)

Chen et al. JAMA. 2006;295:65-73 (B).

Risk Factors for HCC in US PatientsRisk Factors for HCC in US Patients



Di Bisceglie AM, et al. Am J Gastroenterol. 2003;98:2060-2063. El-Serag HB. Gastroenterology. 2004;127:S27-S34. Bosch FX, et al. Gastroenterology. 2004;127:S5-S16.Di Bisceglie AM, et al. Am J Gastroenterol. 2003;98:2060-2063. El-Serag HB. Gastroenterology. 2004;127:S27-S34. Bosch FX, et al. Gastroenterology. 2004;127:S5-S16.

Known Risk Factor in the US: Viral Hepatitis (N = 691)Known Risk Factor in the US: Viral Hepatitis (N = 691)

515

33

47

0

20

40

60

80

100

HBV + HCV HBV HCV Neither

Pre

sen

ce o

f R

isk

Fac

tor

Am

on

g H

CC

Pat

ien

ts (

%)

(?NAFLD/insulin resistance?)(?NAFLD/insulin resistance?)

Non-alcoholic Fatty Liver Disease (NAFLD) and HCC

Non-alcoholic Fatty Liver Disease (NAFLD) and HCC

Single center study, Univ. Michigan

•105 consecutive patients with HCC• 51% due to HCV-associated cirrhosis• Cryptogenic cirrhosis in 29%

• Half had histologic features consistent with NASH

• Estimated that 13% of HCC and cryptogenic cirrhosis may have NAFLD/NASH

Single center study, Univ. Michigan

•105 consecutive patients with HCC• 51% due to HCV-associated cirrhosis• Cryptogenic cirrhosis in 29%

• Half had histologic features consistent with NASH

• Estimated that 13% of HCC and cryptogenic cirrhosis may have NAFLD/NASH

Marrero J, et al, Hepatology 2002Marrero J, et al, Hepatology 2002

Non-alcoholic Fatty Liver Disease (NAFLD) and HCCNon-alcoholic Fatty Liver Disease (NAFLD) and HCC


Prospective Study Cancer Mortality in Obese

US Adults (n=900,053):1982-1998

Prospective Study Cancer Mortality in Obese

US Adults (n=900,053):1982-1998

Calle EE, & et al, N Engl J Med 2003Calle EE, & et al, N Engl J Med 2003

00 11

Prostate (>35)Prostate (>35)

Relative Risk of Death (95% Confidence Interval)Relative Risk of Death (95% Confidence Interval)Relative Risk of Death (95% Confidence Interval)Relative Risk of Death (95% Confidence Interval)

1.341.341.491.49

1.521.52

1.68*1.68*1.701.70

1.711.711.761.76

1.841.841.91*1.91*

1.941.94

2.61*2.61*4.524.52

MenMenMenMen

Ty

pe

of

Can

cer

Ty

pe

of

Can

cer

(Hig

hes

t B

MI C

ate

go

ry)

(Hig

hes

t B

MI C

ate

go

ry)

Ty

pe

of

Can

cer

Ty

pe

of

Can

cer

(Hig

hes

t B

MI C

ate

go

ry)

(Hig

hes

t B

MI C

ate

go

ry)

22 33 44 55 66 77

Non-Hodgkin’s Lymphoma(>35)Non-Hodgkin’s Lymphoma(>35)All Cancers (>40)All Cancers (>40)

All Other Cancers (>30)All Other Cancers (>30)Kidney (>35)Kidney (>35)

Multiple Myeloma (>35)Multiple Myeloma (>35)Gall Bladder (>30)Gall Bladder (>30)

Colon and Rectum (>35)Colon and Rectum (>35)Esophagus (>30)Esophagus (>30)

Stomach (>35)Stomach (>35)Pancreas (>35)Pancreas (>35)

Liver (>35)Liver (>35)

Obesity and Liver CancerObesity and Liver Cancer

Calle, et al, NEJM 2003Calle, et al, NEJM 2003

WomenMenWomenMen

55

88

Death Rate per 100,000Death Rate per 100,000

5050404030302020101000 6060

35 to 39.935 to 39.9

30 to 34.530 to 34.5

20 to 29.920 to 29.9

18.5 to 2518.5 to 25

4848

66

1919

1010

55

99

BMIBMI


Impact of Diabetes and Overweighton Liver Cancer Occurrence in Cirrhosis

Impact of Diabetes and Overweighton Liver Cancer Occurrence in Cirrhosis

N’Kontchou G, Clin Gastro Hepatol 2005N’Kontchou G, Clin Gastro Hepatol 2005

BMI <23.9, diabetes -BMI <23.9, diabetes -BMI <23.9, diabetes +BMI <23.9, diabetes +BMI 23.9-27.3 diabetes -BMI 23.9-27.3 diabetes -BMI 23.9-27.3 diabetes +BMI 23.9-27.3 diabetes +BMI >27.3, diabetes -BMI >27.3, diabetes -BMI >27.3, diabetes +BMI >27.3, diabetes +

BMI <23.9, diabetes -BMI <23.9, diabetes -BMI <23.9, diabetes +BMI <23.9, diabetes +BMI 23.9-27.3 diabetes -BMI 23.9-27.3 diabetes -BMI 23.9-27.3 diabetes +BMI 23.9-27.3 diabetes +BMI >27.3, diabetes -BMI >27.3, diabetes -BMI >27.3, diabetes +BMI >27.3, diabetes +

P<0.0001P<0.0001

00

.2.2

.4.4

.6.6

.8.8

1.01.0

N = 771N = 771

Time (Years)Time (Years)00 22 44 66 88 1010P

rob

abil

ity

of

HC

C F

ree

Su

rviv

alP

rob

abil

ity

of

HC

C F

ree

Su

rviv

al

771 Compensated ETOH or HCV Cirrhotics Prospectively Screened for HCC

Cancer and Insulin ResistanceCancer and Insulin Resistance

Excess weight / adiposityExcess weight / adiposity

FFA , TNF Resistin , Adiponectin

FFA , TNF Resistin , Adiponectin

Insulin resistanceInsulin resistance

Blood and tissue: IGFBP 1

IGFBP2

Blood and tissue: IGFBP 1

IGFBP2

IGF1 bioavailabilityIGF1 bioavailability

InsulinInsulin

IRIR

IGF1RIGF1R

Tumor development

Tumor development

Target cells Apoptosis

Cell proliferation

Target cells Apoptosis

Cell proliferation

Screening / Surveillance for Hepatocellular Carcinoma

Screening / Surveillance for Hepatocellular Carcinoma

Cost-Effectiveness of HCC SurveillanceCost-Effectiveness of HCC Surveillance

• Surveillance with bi-annual alpha-fetoprotein (AFP) and ultrasonography in Child class A cirrhotics had cost-effectiveness ratios between $26,000 and $55,000 per QALY

• 2 other studies show cost-benefits of HCC surveillance

• Surveillance with bi-annual alpha-fetoprotein (AFP) and ultrasonography in Child class A cirrhotics had cost-effectiveness ratios between $26,000 and $55,000 per QALY

• 2 other studies show cost-benefits of HCC surveillance

Sarasin FP, et al, Am J Med 1996 Arguedas MR, et al, Am J Gastroenterol 2003 Lin OS, et al, Aliment Pharmacol Ther 2004

Sarasin FP, et al, Am J Med 1996 Arguedas MR, et al, Am J Gastroenterol 2003 Lin OS, et al, Aliment Pharmacol Ther 2004

Cost-Effectiveness of HCC SurveillanceCost-Effectiveness of HCC Surveillance

HCC ScreeningHCC Screening

Alpha-fetoprotein Cross-Sectional Studies

Alpha-fetoprotein Cross-Sectional Studies

Marrero JA, Clin Liver Dis 2005Marrero JA, Clin Liver Dis 2005

63631631632020NguyenNguyen

53535454200200LeeLee

65651971973030SoresiSoresi

25257474100100CedroneCedrone

60601701701616TrevisaniTrevisani

65652052052020PengPeng

Sensitivity%

Sensitivity%

No. of HCCNo. of HCCCutoffCutoffAuthorAuthor

79797979

8989

9595

9090

8888

Specificity%

Specificity%


Specificity of AFP Surveillance for HCC: PPV 9- 46%

Specificity of AFP Surveillance for HCC: PPV 9- 46%

*5% prevalence of HCC.

Study Specificity, % PPV, %

Case-control studies Trevisani 2001 91 25*

Surveillance studies Pateron 1994 86 33 Sherman 1995 91 9 McMahon 2000 95 31 Bolondi 2001 82 46 Tong 2001 91 11

Trevisani F, et al. J Hepatol. 2001;34:570-575. Pateron D, et al. J Hepatol. 1994;20:65-71. Sherman M, et al. Hepatology. 1995;22:432-438. McMahon BJ, et al. Hepatology. 2000;32:842-846. Bolondi L, et al. Gut. 2001;48:251-259. Tong MJ, et al. J Gastroenterol Hepatol. 2001;16:553-559.

Current Serologic Surveillance Tests Not Sufficiently Sensitive/Specific

Current Serologic Surveillance Tests Not Sufficiently Sensitive/Specific

Prospective analysis of 99 patients with histologically proven, unresectable HCC Prospective analysis of 99 patients with histologically proven, unresectable HCC

Carr BI, et al. Dig Dis Sci. 2007;52:776-782.

61.6

72.767.7

84.8

73.7

84.8 85.9

0

20

40

60

80

100

AFP-L3% DCP AFP AFP-L3%+ DCP

AFP-L3%+ AFP

DCP + AFP

AFP-L3%+ DCP+ AFP

Sen

siti

vity

(%

)

Tumor Marker

Ultrasound in HCC in Cohort Studies

Ultrasound in HCC in Cohort Studies


Author Year Sensitivity (%) Specificity (%) Pos Neg

Okazaki 84 86 99 66.0 0.14Maringhni 84 92 86 6.5 0.09Kobayashi 85 75 98 32.6 0.26Tanaka 86 47 100 589.0 0.41Dodd 92 43 98 21.5 0.58Saada 97 33 100 333.0 0.67Chalasani 99 59 92 8.4 0.45Rode 01 46 95 9.2 0.57Bennett 01 30 97 7.4 0.72Teefey 03 89 73 3.3 0.15Libbrecht 03 40 100 400.0 0.60

Author Year Sensitivity (%) Specificity (%) Pos Neg

Okazaki 84 86 99 66.0 0.14Maringhni 84 92 86 6.5 0.09Kobayashi 85 75 98 32.6 0.26Tanaka 86 47 100 589.0 0.41Dodd 92 43 98 21.5 0.58Saada 97 33 100 333.0 0.67Chalasani 99 59 92 8.4 0.45Rode 01 46 95 9.2 0.57Bennett 01 30 97 7.4 0.72Teefey 03 89 73 3.3 0.15Libbrecht 03 40 100 400.0 0.60

Likelihood RatioLikelihood Ratio

Pooled Estimates 60.5 96.9 17.7 0.5Pooled Estimates 60.5 96.9 17.7 0.5Colli A, et al, Am J Gastro 2006Colli A, et al, Am J Gastro 2006

HCC Surveillance by Ultrasound: NPV 98-100%

HCC Surveillance by Ultrasound: NPV 98-100%

Performance characteristics of ultrasound as a screening test

Performance characteristics of ultrasound as a screening test

Performance Characteristic, %

Cohort 1Years 1-5

Cohort 1Years 6-8

Cohort 2Years 1-3

Sensitivity 79 87 80

Specificity 94 87 91

PPV 15 13 14

NPV 98 100 100

Collier J and Sherman M. AASLD 1995. Morris Sherman, MB BCh, PhD, FRCP(C). Data on file.

HCC Doubling TimeRationale for Surveillance Every 6 Months

HCC Doubling TimeRationale for Surveillance Every 6 Months

Taouli B, et al, J Comput Assist Tomogr 2005Taouli B, et al, J Comput Assist Tomogr 2005


150150100100 200200 25025000

200200

300300

400400

100100

505000

500500

HC

C D

ou

blin

g T

ime

(da

ys)

HC

C D

ou

blin

g T

ime

(da

ys)

Baseline Tumor Volume (cc3)Baseline Tumor Volume (cc3)

XX XX

++

++

XX

Expected Doubling Time: Doubling time = 114 x (Baseline Volume)0.14 (P<0.002)Expected Doubling Time: Doubling time = 114 x (Baseline Volume)0.14 (P<0.002)95% Confidence band95% Confidence bandObserved Doubling time for Patients 1, 2, 4, 7, 8, 10, and 11Observed Doubling time for Patients 1, 2, 4, 7, 8, 10, and 11Observed Doubling time for Patient 3Observed Doubling time for Patient 3 ++ Observed Doubling time for Patient 5Observed Doubling time for Patient 5

XX Observed Doubling time for Patient 6Observed Doubling time for Patient 6XX Observed Doubling time for Patient 6Observed Doubling time for Patient 6 Observed Doubling time for Patient 9Observed Doubling time for Patient 9

Tumor Volume N=9Tumor Volume N=9

Surveillance Interval: 6 vs 12 MonthsSurveillance Interval: 6 vs 12 Months Trevisani et al[1]

Survival similar with 6-month vs 12-month surveillance

Santagostino et al[2]

Rate of detection of single nodules (vs multinodular HCC) similar with 6-month vs 12-month surveillance

Kim et al[3]

Survival improved with 6-month vs 12-month surveillance

Trevisani et al[1]

Survival similar with 6-month vs 12-month surveillance

Santagostino et al[2]

Rate of detection of single nodules (vs multinodular HCC) similar with 6-month vs 12-month surveillance

Kim et al[3]

Survival improved with 6-month vs 12-month surveillance

1. Trevisani F, et al. Am J Gastroenterol. 2002;97:734-744. 2. Santagostino E, et al. Blood. 2003;102:78-82. 3. Kim DY, et al. AASLD 2007. Abstract 368.

AASLD and NCCN Surveillance Guidelines


AASLD Guidelines Surveillance recommended in

at-risk groups

Specific hepatitis B carriers

Nonhepatitis B cirrhosis

US preferred surveillance tool

AFP alone should not be used unless US unavailable

Patients should be screened at - 6 to 12-month intervals


at-risk groups






NCCN Guidelines US and AFP, AP, and albumin

for surveillance in high-risk patients

Every 3-6 months

Continue screening every 3 months in those with high AFP but no evidence on imaging



Every 3-6 months


NCCN, National Comprehensive Cancer

Surveillance for HCC Improves MortalityA Randomized Controlled Trial

Surveillance for HCC Improves MortalityA Randomized Controlled Trial

Screened group Control group

Person-years in study 38,444 41,077HCC occurrence

Cases 86 67Total incidence (per 100,000) 223.7 163.1Rate ratio (95% CI) 1.37 (0.99, 1.89)

Deaths from HCCDeaths 32 54Total mortality (per 100,000) 83.2 131.5Rate ratio (95% CI) 0.63 (0.41, 0.98)

Screened group Control group

Person-years in study 38,444 41,077HCC occurrence

Cases 86 67Total incidence (per 100,000) 223.7 163.1Rate ratio (95% CI) 1.37 (0.99, 1.89)

Deaths from HCCDeaths 32 54Total mortality (per 100,000) 83.2 131.5Rate ratio (95% CI) 0.63 (0.41, 0.98)


Diagnosis of Hepatocellular Carcinoma

Diagnosis of Hepatocellular Carcinoma

Clinical Features at PresentationClinical Features at Presentation

Symptoms Percent of Patients

None 23%Abdominal Pain 32%Ascites 8%Jaundice 8%Anorexia/weight loss 10%Malaise 6%Bleeding 4%Encephalopathy 2%

Symptoms Percent of Patients

None 23%Abdominal Pain 32%Ascites 8%Jaundice 8%Anorexia/weight loss 10%Malaise 6%Bleeding 4%Encephalopathy 2%

Gastroenterology 2002Gastroenterology 2002

HCC Diagnosis

Guidelines for Diagnosis of HCCGuidelines for Diagnosis of HCC

< 1 cm< 1 cm 1-2 cm1-2 cm > 2 cm> 2 cm

Repeat US every Repeat US every 3-6 mo3-6 mo

Dynamic CT, Dynamic CT, contrast US or MRIcontrast US or MRI

2 tests2 tests

Typical = HCCTypical = HCC

Atypical = biopsyAtypical = biopsy

Dynamic CT, Dynamic CT, contrast US or MRIcontrast US or MRI

1 test1 test

Typical = HCCTypical = HCC

Atypical = biopsyAtypical = biopsy

Typical features of HCC = vascular nodule on arterial phase with washout in delayed phases

Typical features of HCC = vascular nodule on arterial phase with washout in delayed phases

Ultrasound findingsUltrasound findings

Bruix J, et al, Hepatology 2005Bruix J, et al, Hepatology 2005

HCC Diagnosis

Dual Blood Supply of LiverDual Blood Supply of Liver

• The vascular supply of HCC arises from the hepatic artery through neovascularization.

• Normal hepatocytes receive 80% of blood flow from portal vein

• Imaging of the liver has to be performed in a triple phase manner to account for the early arterial phase followed by the portal venous phase and the delayed phases

• The vascular supply of HCC arises from the hepatic artery through neovascularization.

• Normal hepatocytes receive 80% of blood flow from portal vein

• Imaging of the liver has to be performed in a triple phase manner to account for the early arterial phase followed by the portal venous phase and the delayed phases

Yu JS, et al, Am J Roentgenol 1999Yu JS, et al, Am J Roentgenol 1999

HCC Diagnosis

Triple Phase Imaging of Hepatocellular CarcinomaTriple Phase Imaging of Hepatocellular Carcinoma

Pre-contrastPre-contrast

Portal Venous PhasePortal Venous Phase

Arterial PhaseArterial Phase

5-min Delayed5-min Delayed

HCC Diagnosis: MRI

Dynamic MRI Spiral CT for Diagnosis of HCC

Dynamic MRI Spiral CT for Diagnosis of HCC

Variables Dynamic MRI Spiral CT

Sensitivity 76% (58/76) 61% (43/70)Specificity 75 % (18/24) 66% (12/18)PPV 90% (58/64) 87% (43/49)NPV 50% (18/36) 30% (12/39)LR positive test 3.04 1.79

Variables Dynamic MRI Spiral CT

Sensitivity 76% (58/76) 61% (43/70)Specificity 75 % (18/24) 66% (12/18)PPV 90% (58/64) 87% (43/49)NPV 50% (18/36) 30% (12/39)LR positive test 3.04 1.79

Burrel M, et al, Hepatology 2003Burrel M, et al, Hepatology 2003

n= 55 cirrhotics (29 with HCC)n= 55 cirrhotics (29 with HCC)

HCC Diagnosis

Treatment of Hepatocellular Carcinoma

Treatment of Hepatocellular Carcinoma

HCC Survival Estimates in the United States

HCC Survival Estimates in the United States

WhiteWhite

BlackBlackAsianAsian

HispanicHispanic

00

Years Following DiagnosisYears Following Diagnosis

Su

rviv

al (

%)

Su

rviv

al (

%)

2020

4040

6060

8080

100100

00 11 22 33

Davila J, & El-Serag HB, Clin Gastroenterol Hepatol. 2006 Davila J, & El-Serag HB, Clin Gastroenterol Hepatol. 2006

Population-based Survival Estimates in the United StatesPopulation-based Survival Estimates in the United States

HCC TreatmentHCC Treatment

Median Survival 6-8 months

Key Concepts in the Management of Hepatocellular Cancer


• Potentially Curative

• Liver transplantation (75% 5-year survival)

• Surgical resection

• Palliative

• Radiofrequency ablation (RFA)

• Transarterial chemoembolization (TACE)

• Percutaneous ethanol or acetic acid ablation

• Cryoablation

• Systemic Chemotherapy

• Potentially Curative

• Liver transplantation (75% 5-year survival)

• Surgical resection

• Palliative

• Radiofrequency ablation (RFA)

• Transarterial chemoembolization (TACE)

• Percutaneous ethanol or acetic acid ablation

• Cryoablation

• Systemic Chemotherapy

Key Concepts in the Management of Hepatocellular CancerKey Concepts in the Management of Hepatocellular Cancer




• Liver transplantation achieves the best outcome in HCC patients with decompensated cirrhosis who meet criteria

• Surgical resection is most effective for non-cirrhotic patients or those with cirrhosis and preserved liver function and can be followed by salvage OLT

• Patients with small tumors are best stratified for resection or OLT by the presence of clinically-significant portal hypertension and/or increased serum bilirubin

• Local ablative methods are an option for small solitary nodules and those who are not surgical candidates

• Transarterial chemoembolization improves survival in intermediate-advanced HCC

• Liver transplantation achieves the best outcome in HCC patients with decompensated cirrhosis who meet criteria

• Surgical resection is most effective for non-cirrhotic patients or those with cirrhosis and preserved liver function and can be followed by salvage OLT

• Patients with small tumors are best stratified for resection or OLT by the presence of clinically-significant portal hypertension and/or increased serum bilirubin

• Local ablative methods are an option for small solitary nodules and those who are not surgical candidates

• Transarterial chemoembolization improves survival in intermediate-advanced HCC

Key Concepts in the Management of Hepatocellular CancerKey Concepts in the Management of Hepatocellular Cancer


Management of Hepatocellular Carcinoma Requires a Multidisciplinary Approach

Management of Hepatocellular Carcinoma Requires a Multidisciplinary Approach

Liver Transplant Program

Liver Transplant Program

PathologyPathology

OncologyOncology

RadiologyRadiology

Hepatobiliary Surgery

Hepatobiliary Surgery

HepatologyHepatology


Liver Transplantation for HCC:Milan Criteria (Stage 1 and 2)

Liver Transplantation for HCC:Milan Criteria (Stage 1 and 2)

+Absence of macroscopic vascular invasion,

absence of extrahepatic spread

Single tumor, not > 5 cm Up to 3 tumors, none > 3 cm

Mazzaferro V, et al. N Engl J Med. 1996;334:693-699.

Management of HCC in Patients with CirrhosisManagement of HCC in Patients with Cirrhosis

Child class ANo Portal HypertensionNormal Bilirubin

Child class ANo Portal HypertensionNormal Bilirubin

Surgical ResectionSurgical

ResectionOrthotopic Liver Transplantation

Orthotopic Liver Transplantation

Advanced Disease Massive tumor Multiple nodules Extrahepatic spread

Advanced Disease Massive tumor Multiple nodules Extrahepatic spread

Child class A with Portal HTN and/or Increased Bilirubin

Child class B or C

Child class A with Portal HTN and/or Increased Bilirubin

Child class B or C

Transplant Candidate?Transplant Candidate?

YesYes NoNo

SalvageSalvage

Management of HCC in Patients with CirrhosisManagement of HCC in Patients with Cirrhosis

Early Disease• One 5 cm tumor• 2 or 3 3 cm tumors• No extrahepatic spread

Early Disease• One 5 cm tumor• 2 or 3 3 cm tumors• No extrahepatic spread

Systemic Chemotherapy or Targeted Therapy

Systemic Chemotherapy or Targeted Therapy

Local Chemo- or Radio-therapy

(Chemoembolization, Radioembolization

“TheraSphere”)

Local Chemo- or Radio-therapy

(Chemoembolization, Radioembolization

“TheraSphere”)

Ablation(RF or EtOH)

• 3 tumors• 4 cm

Ablation(RF or EtOH)

• 3 tumors• 4 cm

Resectable?Resectable?

YesYes NoNo

Intermediate Disease Large tumor Multiple nodules No extrahepatic spread

Intermediate Disease Large tumor Multiple nodules No extrahepatic spread

No BiopsyNo Biopsy BiopsyBiopsy


Surgical Resection of HCC:Outcome in a US Cancer Center

Surgical Resection of HCC:Outcome in a US Cancer Center

78% with cirrhosis78% with cirrhosis

Transplant EligibleTransplant EligibleTransplant Ineligible74 pts (80%)

Transplant Ineligible74 pts (80%)

Unresectable385 pts (70%)Unresectable385 pts (70%)

Resected180 pts (30%)

Resected180 pts (30%)

HCC Pts Evaluated1989 – 2001

611 pts

HCC Pts Evaluated1989 – 2001

611 pts

36 pts (20%)


Ann Surg. 2003; 238:315-21.

Treatment of HCC in US atNon-Federal Hospitals in 2000

Treatment of HCC in US atNon-Federal Hospitals in 2000

2 databases evaluated for trends in HCC 48,349 HCC deaths 1980-1998

2 databases evaluated for trends in HCC 48,349 HCC deaths 1980-1998

Kim WR, et al. Gastroenterology. 2005;129:486-493.

0

5

10

15

4.9

1.83.5

5.5

11.0

SurgicalResection

LiverTransplant

LocalAblation

Embolization Chemotherapy

Tre

atm

ent

(%)

Treatment for HCC Often Suboptimal

Treatment for HCC Often Suboptimal

Proportion of patients receiving potentially curative therapy (N = 2963) 34.0% of patients with single lesions 34.0% of patients with lesions < 3 cm 19.2% of patients with lesions > 10 cm 4.9% of patients with metastatic disease

11.5% of patients ideal for transplantation received it 12.9% of patients ideal for surgical resection

received it

Proportion of patients receiving potentially curative therapy (N = 2963) 34.0% of patients with single lesions 34.0% of patients with lesions < 3 cm 19.2% of patients with lesions > 10 cm 4.9% of patients with metastatic disease

11.5% of patients ideal for transplantation received it 12.9% of patients ideal for surgical resection

received itEl-Serag HB, et al. J Hepatol. 2006;44:158-166.

Su

rviv

al(K

apla

n M

eier

Est

imat

e)S

urv

ival

(Kap

lan

Mei

er E

stim

ate)

00 0.50.5 11 1.51.5 22 2.52.5 33 3.53.5 44 4.54.5 55

Follow up Duration (Years) Follow up Duration (Years)

TransplantTransplant

ResectionResection

AblationAblationTACETACE

11

0.80.8

0.60.6

0.40.4

0.20.2

00

Outcomes of HCC Treatment: Observational Population-based study

El-Serag HB, et al, J Hepatology 2006 44:158El-Serag HB, et al, J Hepatology 2006 44:158

2,963 patients with HCC diagnosed between 1992 and 1999 in SEER-Medicare datasets

Median Age:74

Not transplant candidate/has cancer-related

symptoms

Summary of NCCN Treatment Guidelines

Summary of NCCN Treatment Guidelines

Surgical eval/ biopsy

Resectable

Ablation Transplant

Transplant

Sorafenib Chemo-embolization Clinical trial Ablation Chemo + RT RT Radio-embolization Supportive care Systemic/intra-

arterial chemo

Transplant if appropriate candidate

Sorafenib Clinical trial

No cancer-related

symptoms

Sorafenib Ablation Clinical trial

Sorafenib Ablation Clinical trial Chemo-

embolization RT Radio-

embolization Supportive care

Sorafenib Clinical trial Supportive

care

Cancer-related

symptoms

NCCN. Available at: http://www.nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf. Accessed October 23, 2008.

Potentially resectable, inoperable mass

Unresectable/ Denies Surgery

Inoperable by PS, comorbidity (local disease) Metastatic

Extensive/ no cancer-

related symptoms

http://www.nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf

HCC: SummaryHCC: Summary HCC is one the most rapidly increasing

cancers in the US The 5-year survival is 8-12% Less than 20% are candidates for

surgery/transplant at diagnosis Treatment is mainly palliative Referral to a tertiary center indicated Screening to detect early HCC is the main

priority of primary care physicians

HCC is one the most rapidly increasing cancers in the US

The 5-year survival is 8-12% Less than 20% are candidates for

surgery/transplant at diagnosis Treatment is mainly palliative Referral to a tertiary center indicated Screening to detect early HCC is the main

priority of primary care physicians

Hepatitis B Carriers Suitable for HCC Surveillance

Hepatitis B Carriers Suitable for HCC Surveillance

Hepatitis B carriers Asian males > ~ 40 years (incidence ~ 0.4% to 0.6% per

year) Asian females > ~ 50 years (incidence ~ 0.2% per year) Africans older than 20 years of age (incidence unknown

but likely > 0.2% per year) Cirrhosis (HCC incidence: 3% to 5%/year) Family history of HCC: Screen from the time of

diagnosis (mainly Asian and African)

Hepatitis B carriers Asian males > ~ 40 years (incidence ~ 0.4% to 0.6% per

year) Asian females > ~ 50 years (incidence ~ 0.2% per year) Africans older than 20 years of age (incidence unknown

but likely > 0.2% per year) Cirrhosis (HCC incidence: 3% to 5%/year) Family history of HCC: Screen from the time of

diagnosis (mainly Asian and African)




at-risk groups







at-risk groups








Every 3-6 months




Every 3-6 months


NCCN, National Comprehensive Cancer

Focus Screening Efforts on Patients Under Age 65

Focus Screening Efforts on Patients Under Age 65

Inci

den

ce

Rat

ep

er

10

0,0

00

PY

Inci

den

ce

Rat

ep

er

10

0,0

00

PY

Age (years)Age (years)

20-2420-24 30-3430-3435-3935-39

40-4440-4445-4945-49

50-5450-5455-5955-5925-2925-29

0022446688

101012121414161618182020

1982 – 841991 – 932000 – 02

1982 – 841991 – 932000 – 02

60-6460-6465-6965-69

70-7470-7475-7975-79

80-8480-8485+85+


HCC: Preventative Measures?HCC: Preventative Measures?

Although unproven, data suggest that maximal suppression of HBV DNA may reduce the annual incidence of HCC Obscenely expensive

Eradication of HCV significantly reduces the risk of HCC

Minimize ETOH Minimize risk factors for hyperinsulinemia Statins? Coffee

Although unproven, data suggest that maximal suppression of HBV DNA may reduce the annual incidence of HCC Obscenely expensive

Eradication of HCV significantly reduces the risk of HCC

Minimize ETOH Minimize risk factors for hyperinsulinemia Statins? Coffee

HCC After IFN Therapy for HCVHCC After IFN Therapy for HCV

Follow-up (yr)Follow-up (yr)

Cu

mu

lati

ve I

nci

den

ceo

f H

CC

(%

)C

um

ula

tive

In

cid

ence

of

HC

C (

%)

Imai Y, et al, Ann Intern Med 1998Imai Y, et al, Ann Intern Med 1998

00 11 22 33 44 55 66 77

No ResponseNo Response

Relapse55

1010

1515

2020

2525

3030

00

SustainedResponse


Statins vs HCCStatins vs HCC

Retrospective, case-controlled study VA database >1,400.000 veterans 14,021 HVC positive

34% on statins HCC diagnosed in 409 After controlling for age, genotype,

statin use was associated with a significant reduction in risk for HCC

Retrospective, case-controlled study VA database >1,400.000 veterans 14,021 HVC positive

34% on statins HCC diagnosed in 409 After controlling for age, genotype,

statin use was associated with a significant reduction in risk for HCC

• V. Khurana et al. “Statins Are Protective Against HCC in HCV Infection”DDW 2005. May 14-14 Abstract S1535

Don’t Forget Your CoffeeDon’t Forget Your Coffee

Meta-analysis of published studies on HCC that included quantitative information on coffee consumption

Ten studies were retrieved: 2,260 HCC cases The overall summary RR for low or moderate

coffee drinkers was 0.70 (95% CI 0.57-0.85), and that for high drinkers was 0.45 (95% CI 0.38-0.53)

Meta-analysis of published studies on HCC that included quantitative information on coffee consumption

Ten studies were retrieved: 2,260 HCC cases The overall summary RR for low or moderate

coffee drinkers was 0.70 (95% CI 0.57-0.85), and that for high drinkers was 0.45 (95% CI 0.38-0.53)

Hepatology 2007 Aug;46(2):430-5

hepatocellular carcinoma thomas hargrave m.d. january 16, 2009

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