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Hepatocellular Carcinoma

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Thomas Hargrave M.D. January 16, 2009 HCC: Summary HCC is one the most rapidly increasing cancers in the US The 5-year survival is 8-12% Less than 20% are candidates ... – PowerPoint PPT presentation

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Title: Hepatocellular Carcinoma


1
Hepatocellular Carcinoma
  • Thomas Hargrave M.D.
  • January 16, 2009

2
HCC 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

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.
3
HCC Epidemiology
Worldwide Incidence of Hepatocellular Carcinoma
High (gt 30100,000)
El-Serag HB, Gastroenterology 2004
Intermediate (3-30100,000)
Low or data unavailable (lt 3100,000)
4
Recent Changes in the Incidence of HCC
HCC Epidemiology
Changes in the Incidence of HCC 1978-1992
-30
Singapore, Chinese
-24
Spain, Zaragoza
-20
India, Bombay
-18
China, Shanghai
10
Switzerland, Geneva
12
Hong Kong
14
NewZealand, Maori
21
NewZealand, Non-Maori
46
Japan, Osaka
50
UK, So. Thames
71
Canada, Alberta
83
Italy, Varese
90
France, Bas-Rhin
108
Australia, NSW
-40
-20
0
20
40
60
80
100
120
McGlynn K, et al, Int J Cancer 2001
5
Age-Adjusted Incidence Rates For HCC (1976-2002)
HCC Epidemiology
3.5
3.3
3.1
3
2.7
2.5
2.3
Rate per 100,000
2.0
2
1.8
1.6
1.4
1.4
1.5
1
0.5
0
76-78
79-81
82-84
85-87
88-90
91-93
94-96
97-99
2000-02
Year
El-Serag HB, Mason A, N Engl J Med 1999 El-Serag
HB et al, Ann Intern Med 2003
6
Racial Distribution of HCC in the United States
HCC Epidemiology
3000
Asian
2500
Black
2000
White
Number of Cases
1500
1000
500
0
75-77
81-83
84-86
87-89
90-92
93-95
96-98
78-80
Year
El-Serag HB, Mason A, N Engl J Med 1999
7
Racial Incidence Rates For HCCIn The United
States
HCC Epidemiology
8.4
White
Black
Other (Asian)
8
7.9
7.2
7.2
6.6
6.3
6
5.2
5
Age-Adjusted Incidence Rate per 100,000
4.6
3.9
3.7
3.4
2.9
2.6
2.5
2.5
2.5
2.3
1.9
1.7
1.4
1.3
1.1
1.1
1
76-78
82-84
85-87
88-90
91-93
94-96
97-99
2000-02
79-81
Year
El-Serag HB et al, Ann Intern Med 2003
8
Temporal Trends in The Age Distribution of
Hepatocellular Carcinoma
HCC Epidemiology
1982 84 1991 93 2000 02
Incidence Rate per 100,000 PY
20-24
30-34
40-44
50-54
60-64
70-74
80-84
35-39
45-49
55-59
25-29
65-69
75-79
85
Age (years)
El-Serag HB, Mason A, N Engl J Med 1999
9
Risk Factors for HCC in US Patients
  • Worldwide, 75 to 80 of HCC attributable to
    chronic HBV (50 to 55) or HCV (25 to 30)

Known Risk Factor in the US Viral Hepatitis (N
691)
100
80
60
47
Presence of Risk Factor Among HCC Patients ()
33
40
15
20
5
0
HBV
HBV HCV
HCV
Neither
Di Bisceglie AM, et al. Am J Gastroenterol.
2003982060-2063. El-Serag HB. Gastroenterology.
2004127S27-S34. Bosch FX, et al.
Gastroenterology. 2004127S5-S16.
10
Risk Factors for HCC
HCC Epidemiology
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

11
HCV Cirrhosis and HCC
HCC Epidemiology
HCV Cirrhosis and HCC
Multiple smallfoci of HCC
12
Why HCC is Rising?
HCC Epidemiology
Why is HCC Incidence Rising?
Increasing prevalence of patients with cirrhosis
  • Rising incidence of cirrhosis
  • HCV (main reason)
  • HBV
  • Other (?NAFLD/insulin resistance)
  • Improved survival of patients with cirrhosis

El-Serag HB, Gastroenterology 2004
13
Prevalence of HCV in United States Males1999-2002
Annals Internal Medicine 2006 144705
14
Projected Rates of HCV-Related Cirrhosis and HCC
Davis GL, et al. Liver Transpl. 20039331.
15
Alcohol Intake and the Risk of HCC
HCC Epidemiology
Alcohol Intake and the Risk of HCC
20
No HCV
with HCV
15
10
Odds Ratios
5
0
20
40
60
80
100
120
140
Grams of Alcohol / Day
Donato F, et al, Am J Epidemiol 2002
16
HBV DNA Associated with Increased Risk of HCC
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

Yang HI, et al, N Engl J Med 2002
17
HBe Antigen and Risk of HCC
11,893 Noncirrhotic Taiwanese Males Followed 8
Yrs
12
HBsAg, HBeAg (RR 60.2)
10
8
Percent cumulative incidence
6
4
HBsAg, HBeAg- (RR 9.6)
2
HBsAg-, HBeAg-
0
0
1
2
3
4
5
6
7
8
9
10
Year
Yang HI, et al, N Engl J Med 2002
18
HBV DNA and Risk of HCC Untreated Non-Cirrhotic
HBeAg
HBV DNA (copies/mL)
  • 3465 HBeAg () Non-cirrhotic Taiwanese Patients
    followed for a mean of 11.5years
  • 65 had HBV DNA gt 100,000,000

Incidence of HCC
Per Year ()
Chen et al. JAMA. 200629565-73 (B).
19
Risk Factors for HCC in US Patients
  • Worldwide, 75 to 80 of HCC attributable to
    chronic HBV (50 to 55) or HCV (25 to 30)

Known Risk Factor in the US Viral Hepatitis (N
691)
100
80
(?NAFLD/insulin resistance?)
60
47
Presence of Risk Factor Among HCC Patients ()
33
40
15
20
5
0
HBV
HBV HCV
HCV
Neither
Di Bisceglie AM, et al. Am J Gastroenterol.
2003982060-2063. El-Serag HB. Gastroenterology.
2004127S27-S34. Bosch FX, et al.
Gastroenterology. 2004127S5-S16.
20
Non-alcoholic Fatty Liver Disease (NAFLD) and HCC
HCC Epidemiology
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

Marrero J, et al, Hepatology 2002
21
Prospective Study Cancer Mortality in Obese US
Adults (n900,053)1982-1998
Men
Prostate (gt35)
1.34
Non-Hodgkins Lymphoma(gt35)
1.49
1.52
All Cancers (gt40)
All Other Cancers (gt30)
1.68
1.70
Kidney (gt35)
Type of Cancer (Highest BMI Category)
Multiple Myeloma (gt35)
1.71
Gall Bladder (gt30)
1.76
Colon and Rectum (gt35)
1.84
1.91
Esophagus (gt30)
1.94
Stomach (gt35)
Pancreas (gt35)
2.61
4.52
Liver (gt35)
0
1
2
3
4
5
6
7
Relative Risk of Death (95 Confidence Interval)
Calle EE, et al, N Engl J Med 2003
22
Obesity and Liver Cancer
HCC Epidemiology
8
35 to 39.9
48
6
30 to 34.5
19
BMI
5
20 to 29.9
10
5
18.5 to 25
9
Death Rate per 100,000
Calle, et al, NEJM 2003
23
Impact of Diabetes and Overweighton Liver Cancer
Occurrence in Cirrhosis
771 Compensated ETOH or HCV Cirrhotics
Prospectively Screened for HCC
1.0
.8
BMI lt23.9, diabetes - BMI lt23.9, diabetes BMI
23.9-27.3 diabetes - BMI 23.9-27.3 diabetes BMI
gt27.3, diabetes - BMI gt27.3, diabetes
.6
Probability of HCC Free Survival
Plt0.0001
.4
.2
N 771
0
0
2
4
6
8
10
Time (Years)
NKontchou G, Clin Gastro Hepatol 2005
24
Cancer and Insulin Resistance
Excess weight / adiposity
FFA , TNFa Resistin ,
Adiponectin
Tumor development
Insulin resistance
Insulin
IR
Target cells Apoptosis
Cell proliferation
Blood and tissue IGFBP 1
IGFBP2
IGF1R
IGF1 bioavailability
25
Screening / Surveillance for Hepatocellular
Carcinoma
26
Cost-Effectiveness of HCC Surveillance
HCC Screening
Cost-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

Sarasin FP, et al, Am J Med 1996 Arguedas MR, et
al, Am J Gastroenterol 2003 Lin OS, et al,
Aliment Pharmacol Ther 2004
27
Alpha-fetoprotein Cross-Sectional Studies
HCC Screening
Sensitivity
No. of HCC
Cutoff
Author
Specificity
65
205
20
Peng
88
60
170
16
Trevisani
90
25
74
100
Cedrone
95
65
197
30
Soresi
89
53
54
200
Lee
79
79
63
163
20
Nguyen
Marrero JA, Clin Liver Dis 2005
28
Specificity of AFP Surveillance for HCC PPV 9-
46
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
5 prevalence of HCC.
Trevisani F, et al. J Hepatol. 200134570-575.
Pateron D, et al. J Hepatol. 19942065-71.
Sherman M, et al. Hepatology. 199522432-438.
McMahon BJ, et al. Hepatology. 200032842-846.
Bolondi L, et al. Gut. 200148251-259. Tong MJ,
et al. J Gastroenterol Hepatol. 200116553-559.
29
Current Serologic Surveillance Tests Not
Sufficiently Sensitive/Specific
  • Prospective analysis of 99 patients with
    histologically proven, unresectable HCC

100
85.9
84.8
84.8
80
73.7
72.7
67.7
61.6
60
Sensitivity ()
40
20
0
AFP-L3
DCP
AFP
AFP-L3 DCP
AFP-L3 AFP
DCP AFP
AFP-L3 DCP AFP
Tumor Marker
Carr BI, et al. Dig Dis Sci. 200752776-782.
30
Ultrasound in HCC in Cohort Studies
HCC Screening
Colli A, et al, Am J Gastro 2006
31
HCC Surveillance by Ultrasound NPV 98-100
  • Performance characteristics of ultrasound as a
    screening test

Performance Characteristic, Cohort 1 Years 1-5 Cohort 1 Years 6-8 Cohort 2 Years 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.
32
HCC Doubling TimeRationale for Surveillance
Every 6 Months
HCC Screening
Taouli B, et al, J Comput Assist Tomogr 2005
33
Surveillance Interval 6 vs 12 Months
  • Trevisani et al1
  • Survival similar with 6-month vs 12-month
    surveillance
  • Santagostino et al2
  • Rate of detection of single nodules (vs
    multinodular HCC) similar with 6-month vs
    12-month surveillance
  • Kim et al3
  • Survival improved with 6-month vs 12-month
    surveillance

1. Trevisani F, et al. Am J Gastroenterol.
200297734-744. 2. Santagostino E, et al. Blood.
200310278-82. 3. Kim DY, et al. AASLD 2007.
Abstract 368.
34
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
  • 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

NCCN, National Comprehensive Cancer
35
Surveillance for HCC Improves MortalityA
Randomized Controlled Trial
HCC Screening

Screened group
Control group Person-years in study 38,444 41,07
7 HCC occurrence Cases 86 67 Total incidence
(per 100,000) 223.7 163.1 Rate ratio (95
CI) 1.37 (0.99, 1.89) Deaths from
HCC Deaths 32 54 Total mortality (per
100,000) 83.2 131.5 Rate ratio (95 CI) 0.63
(0.41, 0.98)
36
Diagnosis of Hepatocellular Carcinoma
37
Clinical Features at Presentation
HCC Diagnosis
Symptoms Percent of Patients None 23 Abdomina
l Pain 32 Ascites 8 Jaundice
8 Anorexia/weight loss 10 Malaise
6 Bleeding 4 Encephalopathy 2
Gastroenterology 2002
38
Guidelines for Diagnosis of HCC
HCC Diagnosis
Ultrasound findings
lt 1 cm 1-2 cm gt 2 cm
Repeat US every 3-6 mo Dynamic CT, contrast US or MRI 2 tests Typical HCC Atypical biopsy Dynamic CT, contrast US or MRI 1 test Typical HCC Atypical biopsy
Typical features of HCC vascular nodule on
arterial phase with washout in delayed
phases
Bruix J, et al, Hepatology 2005
39
Dual Blood Supply of Liver
HCC Diagnosis
  • 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 1999
40
Triple Phase Imaging of Hepatocellular Carcinoma
HCC Diagnosis MRI
Arterial Phase
Pre-contrast
Portal Venous Phase
5-min Delayed
41
Dynamic MRI Spiral CT for Diagnosis of HCC
HCC Diagnosis
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
n 55 cirrhotics (29 with HCC)
Burrel M, et al, Hepatology 2003
42
Treatment of Hepatocellular Carcinoma
43
Population-based Survival Estimates in the United
States
HCC Treatment
HCC Survival Estimates in the United States
100
Median Survival 6-8 months
80
White
Hispanic
60
Black
Survival ()
Asian
40
20
0
Years Following Diagnosis
Davila J, El-Serag HB, Clin Gastroenterol
Hepatol. 2006
44
Key Concepts in the Management of Hepatocellular
Cancer
HCC Treatment
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

45
Key Concepts in the Management of Hepatocellular
Cancer
HCC Treatment
Key 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

46
Management of Hepatocellular Carcinoma Requires a
Multidisciplinary Approach
HCC Treatment
Hepatobiliary Surgery
Oncology
Hepatology
Pathology
Radiology
Liver Transplant Program
47
Liver Transplantation for HCCMilan Criteria
(Stage 1 and 2)
Single tumor, not gt 5 cm
Up to 3 tumors, none gt 3 cm
Absence of macroscopic vascular
invasion, absence of extrahepatic spread
Mazzaferro V, et al. N Engl J Med.
1996334693-699.
48
Management of HCC in Patients with Cirrhosis
HCC Treatment
49
Surgical Resection of HCCOutcome in a US Cancer
Center
HCC Treatment
Ann Surg. 2003 238315-21.
50
Treatment of HCC in US atNon-Federal Hospitals
in 2000
  • 2 databases evaluated for trends in HCC
  • 48,349 HCC deaths 1980-1998

15
11.0
10
Treatment ()
5.5
4.9
5
3.5
1.8
0
Surgical Resection
Liver Transplant
Local Ablation
Embolization
Chemotherapy
Kim WR, et al. Gastroenterology. 2005129486-493.
51
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 lt 3 cm
  • 19.2 of patients with lesions gt 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

El-Serag HB, et al. J Hepatol. 200644158-166.
52
Outcomes of HCC Treatment Observational
Population-based study
2,963 patients with HCC diagnosed between 1992
and 1999 in SEER-Medicare datasets
1
Median Age74
0.8
0.6
Survival (Kaplan Meier Estimate)
Transplant
Resection
0.4
Ablation
TACE
0.2
0
Follow up Duration (Years)
El-Serag HB, et al, J Hepatology 2006 44158
53
Summary of NCCN Treatment Guidelines
Potentially resectable, inoperable mass
Unresectable/ Denies Surgery
Inoperable by PS, comorbidity (local disease)
Metastatic
Transplant if appropriate candidate
Not transplant candidate/has cancer-related
symptoms
Surgical eval/ biopsy
No cancer-related symptoms
Cancer-related symptoms
Extensive/ no cancer-related symptoms
  • Sorafenib
  • Chemo-embolization
  • Clinical trial
  • Ablation
  • Chemo RT
  • RT
  • Radio-embolization
  • Supportive care
  • Systemic/intra-arterial chemo

Resectable
  • Sorafenib
  • Ablation
  • Clinical trial
  • Chemo-embolization
  • RT
  • Radio-embolization
  • Supportive care
  • Sorafenib
  • Clinical trial
  • Sorafenib
  • Clinical trial
  • Supportive care
  • Sorafenib
  • Ablation
  • Clinical trial
  • Ablation
  • Transplant
  • Transplant

NCCN. Available at http//www.nccn.org/profession
als/physician_gls/PDF/hepatobiliary.pdf.
Accessed October 23, 2008.
54
HCC 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

55
Hepatitis B Carriers Suitable for HCC Surveillance
  • Hepatitis B carriers
  • Asian males gt 40 years (incidence 0.4 to
    0.6 per year)
  • Asian females gt 50 years (incidence 0.2 per
    year)
  • Africans older than 20 years of age (incidence
    unknown but likely gt 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)

56
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
  • 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

NCCN, National Comprehensive Cancer
57
Focus Screening Efforts on Patients Under Age 65
1982 84 1991 93 2000 02
Incidence Rate per 100,000 PY
20-24
30-34
40-44
50-54
60-64
70-74
80-84
35-39
45-49
55-59
25-29
65-69
75-79
85
Age (years)
El-Serag HB, Mason A, N Engl J Med 1999
58
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

59
HCC After IFN Therapy for HCV
HCC Epidemiology
30
25
20
No Response
Cumulative Incidence of HCC ()
15
10
Relapse
5
Sustained Response
0
0
1
2
3
4
5
6
7
Follow-up (yr)
Imai Y, et al, Ann Intern Med 1998
60
Statins vs HCC
  • Retrospective, case-controlled study
  • VA database gt1,400.000 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 InfectionDDW 2005. May 14-14
    Abstract S1535

61
Dont 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)

Hepatology 2007 Aug46(2)430-5
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