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clinicaloptions.com/hep
Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Annual Report of HepatomaKeelung CGMH
Risk Factors, Surveillance Strategies, and Treatment Options for Hepatocellular Carcinoma
clinicaloptions.com/hep
Risk Factors, Surveillance Strategies, and Treatment Options for HCC
662,000 deaths from liver cancer yearly worldwide
Leading cause of death among male malignancies in
Taiwan (2007 )
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.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Sangiovanni A, et al. Gastroenterology. 2004;126:1005-1014.
Cause of Death, n (%) All Patients HCC-Free Patients
Patients Who Developed HCC
Tumor progression 54 (36) 0 (0) 54 (66)
Nonliver-related conditions 28 (19) 23 (34) 5 (6)
Liver failure 25 (17) 18 (27) 7 (9)
Gastrointestinal hemorrhage 21 (14) 13 (19) 8 (10)
OLT-related complications 2 (1) 0 (0) 2 (2)
Unknown 19 (13) 13 (19) 6 (7)
Total 149 (100) 67 (100) 82 (100)
1987-2001: Causes of Death in Patients With Compensated Cirrhosis HCC-free outpatients with compensated cirrhosis followed
for 148 months with periodic ultrasound in Italy (N = 417)
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Treatment for HCC Often Suboptimal Proportion of patients receiving potentially curative therapy
N = 2963 from 1992-1999 in USA
– 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
El-Serag HB, et al. J Hepatol. 2006;44:158-166.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
HCC Surveillance
clinicaloptions.com/hep
Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Is Surveillance “Worthwhile”?
How do we define “worthwhile”?
– Improvement in survival of 3 months[1]
Surveillance considered cost-effective if it achieves this 3-month improvement in survival at a cost of < $50,000 per life-year saved[2]
1. Naimark D, et al. J Gen Intern Med. 1994;9:702-707. 2. Laupacis A, et al. CMAJ. 1992;146:473-481.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Surveillance for HCC
Objective
– To reduce mortality from HCC
A single randomized controlled trial of 18,816 people with HBV infection or history of chronic hepatitis in urban Shanghai, China enrolled
– Surveillance group offered US and AFP every 6 months (n = 9373)
– Control group received no surveillance (n = 9443)
– surveillance hepatitis B carriers with semiannual AFP and US reduces HCC-related mortality by 37%
Zhang BH, et al. J Cancer Res Clin Oncol. 2004;130:417-422.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Identification of At-Risk Population for HCC Surveillance What level of risk makes surveillance worthwhile?
– Incidence
According to randomized controlled trials
– Hepatitis B: 0.28% per year[1]
According to cost-efficacy analyses
– Hepatitis B: 0.2% per year[3]
– Non-hepatitis B cirrhosis: > 1.4% per year[4]
1. Zhang BH, et al. J Cancer Res Clin Oncol. 2004;130:417-422. 2. Sarasin FP, et al. Am J Med. 1996;101:422-434. 3. Morris Sherman, MB BCh, PhD, FRCP(C). Data on file. 4. Arguedas MR, et al. Am J Gastroenterol. 2003;98:679-690.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
The Benefit of Surveillance
For HCC incidence of 1.5%/ year, → survival increases for 3 months after surveillance
For HCC incidence of 6%/year → increase of 9 months.
Cost-effective -when the incidence of HCC > 1.4%. .
Recommendation :Surveillance for risk of HCC >=1.5%/year
Sarasin, FP, Am J Med 1996;101:422-434. Arguedas Am J Gastroenterol 2003;98679-690.
Lin OS, Aliment Pharmacol Ther 2004;19:1159-1172
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Hepatitis B Carriers Suitable for HCC Surveillance Hepatitis B carriers[1-4]
– 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: mainly Asian and African
Beasley RP, et al. Lancet. 1981;2:1129-1133. Koike K, et al. Oncology. 2002;62(suppl 1):29-37. Beasley RP. Hepatology. 1982;2(suppl):21S-26S. Fattovich G, et al. Gut. 1991;32:294-298. Manno M, et al. Gastroenterology. 2004;127:756-763. Hsu YS, et al. Hepatology. 2002;35:1522-1527. Fattovich G. J Hepatol. 2003;39(suppl 1):S50-S58.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Factors Affecting HCC Risk
Active disease
– Elevated ALT
Persistently elevated AFP
Low platelet count
HBV DNA level
Histologic changes
– Dysplasia
– Geographic morphologic changes
– PCNA (Proliferating cell nuclear antigen) positive
Use of TIPS (?)
Beasley RP, et al. Lancet. 1981;2:1129-1133. Degos F, et al. Gut. 2000;47:131-136. Oka H, et al. Hepatology. 1994;19:61-66. Zhang JY, et al. Am J Trop Med Hyg. 1998;59:947-951. Colombo M, et al. N Engl J Med. 1991; 325:675-680.Ganne-Carrie N, et al. Hepatology. 1996;23:1112-1118. Lee RG, et al. Hepatology. 1997;26:1415-1422. Chen CJ, et al. JAMA. 2006;295:65-73.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Screening and Surveillance Methodology:
Serologic Tests and Radiology
Current Serologic Screening Tests Are Insufficiently Sensitive
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Sensitivity of AFP Surveillance for HCC
Study Sensitivity, %
Case-control studies
Trevisani 2001 60
Surveillance studies
Tanaka 1990 64
Pateron 1994 50
Borzio 1995 47
Sherman 1995 64
Solmi 1996 54
Zoli 1996 62
McMahon 2000 97
Bolondi 2001 41
Tong 2001 59Trevisani F, et al. J Hepatol. 2001;34:570-575. Tanaka S, et al. Cancer. 199015;66:2210-2214. Pateron D, et al. J Hepatol. 1994;20:65-71. Borzio M, et al. Gastroenterology. 1995;108:812-817. Sherman M, et al. Hepatology. 1995;22:432-438. Solmi L, et al. Am J Gastroenterol. 1996;91:1189-1194. Zoli M, et al. Cancer. 1996;78:977-985. 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.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Specificity of AFP Surveillance for HCC
*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.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Other Tumor Markers Des-gamma-carboxy prothrombin (DGCP), also known
as Prothrombin Induced by Vitamin K Absence II (PIVKA) 40 mAU/ml≧
The ratio of glycosylated AFP L3 (Lectin fraction)
to total AFP>15%, alpha fucosidase and glypican
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
HCC Surveillance by Ultrasound
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.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
HCC Surveillance by CT Scan
No evidence to support the use of CT scanning for routine HCC surveillance
– PPV and NPV unknown
– Accurate use of CT requires 4-phase contrast CT
– Radiation exposure is significant
– In the absence of contrast CT, false-positive rate very high
– Cannot distinguish small HCC from dysplastic nodules or arterialized cirrhotic nodules
– Flow abnormalities create diagnostic difficulty
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Standard angiography and CTAP angiography
Contrast enhanced ultrasound (CEUS) could also be used for this non-invasive diagnosis.
Other radiological tests. In particular lipiodol angiography is not sensitive for small HCC.
Standard angiography and CTAP( arterioportal angiography) should not be routinely performed.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Surveillance 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
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.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
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 National Comprehensive Cancer Network
(21家世界頂級癌症中心組成的非營利性學術聯盟 )
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
Bruix J, et al. Hepatology. 2005;42:1208-1236. National Comprehensive Cancer Network.Available at: http://www.nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf. Accessed October 14, 2008.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Japan Society of Hepatology (JSH) - 2007Consensus-Based Clinical Practice Manual
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Population at Risk for HCC
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Summary
At-risk patients should be screened for HCC
Ultrasound surveillance is preferable
– AFP increased the detection rate
Surveillance should take place at 3-6-month intervals for high risk patients
– Evidence for better survival than 12-month intervals
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Diagnosis of Hepatoma
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
EASL conference on HCC diagnosisTumors>2 cm
The diagnosis of HCC can be made without biopsy :
In Cirrhotic patients who have a mass> 2 cm that shows characteristic arterial vascularization on two imaging modalities,
- Triphasic CT scan and MRI.
The positive predictive value of the clinical and radiological findings exceeds 95%
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Tumors 1-2 cm in diameter
Lesions between 1-2 cm in a cirrhotic liver have a high likelihood of being HCC.
These lesions should be biopsied irrespective of their vascular profile
Biopsy of small lesions (2 cm) may not be reliable
Needle placement may be difficult
D.D. Dysplasia and well-differentiated HCC
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Lesions Less Than 1 cm in Diameter
Low likelihood of being HCC
Malignancy is even less likely if they do not show contrast uptake on dynamic imaging
Even if CT or MRI show tiny nodules with arterial vascularization. They may not correspond to HCC foci.
Need to be followed-up every 3-6 months. (level III).
Lack of growth over a period of more than 2 years suggests that the lesion is not HCC
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Recommendations
if the vascular profile on imaging is not characteristic or if the nodule is detected in a non-cirrhotic liver,
-- Biopsy should be performed (level II).
Biopsies of small lesions should be evaluated by expert pathologists. If the biopsy is negative for HCC patients should be followed by ultrasound or CT scanning at 3-6 monthly intervals
If the lesion enlarges but remains atypical for HCC a repeat biopsy is recommended (level III).
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Diagnosis in High Risk Patients
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Atypical Image on Dynamic CT/MRI(JSH)
When a lesion is intensely enhanced in the early arterial phase and becomes low-attenuation in the equilibrium phase,,
R/O FNH and A-P shunt,
Uptake by Kupffer cells is investigated by
1.SPIO (superparamagnetic iron oxide -enhanced MRI )
2.Sonazoid-enhanced ultrasonography.
When high SPIO-enhanced MRI signals or a defect in the
Kupffer phase of Sonazoid-enhanced ultrasonography
are confirmed, the lesion is diagnosed as HCC
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Tumor Staging
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Currently there are 3 staging systems for HCC:
(1) TNM staging as tumor spreading staging,
(2) liver function staging
(3) systems integrating (1) and (2). For TNM staging,
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Staging System
UICC( international union against cancer) or AJCC (American joint
committee on cancer) classification is used internationally (2005)
These are thought inappropriate because the cut-off tumor size is set to 5 cm (JSH)
Portal microinvasion and intrahepatic metastasis occurs in 27% and 10% of tumors with a tumor size of 2 cm or more
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
TNM Stage by LCSG
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Functional staging & TNM
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Barcelona-Clinic- Liver-Cancer (BCLC) staging system
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Barcelona-Clinic- Liver-Cancer (BCLC) staging system
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Cancer of the Liver Italian Program (CLIP)
The CLIP score retrospective evaluation of 435 Italian patients with HCC diagnosed from 1990 to 1992.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Japan Integrated Staging Score
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
The Treatment of HCC
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
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.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Treatment: Chemoembolization
Normal liver gets 75% of blood supply from portal vein and 25% of blood supply from hepatic artery
Tumor receives most of its blood supply from the hepatic artery
Injection into the hepatic artery spares most of the normal liver
Embolization of the hepatic artery prevents systemic absorption of chemotherapy agents and induces ischemic necrosis of tumor
Tumor
Liver
Portal vein
Hepaticartery
Catheter placement forchemoembolization
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Chemoembolization: Randomized Trials (Nearly Identical Techniques)
TechniqueSurvival, %
Year 1 Year 2 Year 3
TACE 57 31 26
Supportive care 32 11 3
TechniqueSurvival, %
Year 1 Year 2
TACE 82 63
Supportive care 63 27
Llovet et al[2]: N = 112 with unresectable HCC, 80% to 90% HCV positive, 5-cm tumors (~ 70% multifocal)
Lo et al[1]: N = 80 with newly diagnosed unresectable HCC, 80% HBV positive, 7-cm tumors (60% multifocal)
1. Lo CM, et al. Hepatology. 2002;35:1164-1171.2. Llovet JM, et al. Lancet. 2002;359:1734-1739.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Intra-arterial Locoregional Therapy
Established
– TACE
– Radioembolization: yttrium-90 radioactive microspheres
Undergoing clinical trials
– Drug-eluting beads
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Radioembolization: Use of intra-arterially delivered yttrium-90 microspheres emitting high-dose radiation for the treatment of liver tumors
Yttrium-90 microspheres
– Average diameter: 20-30 µm
– 100% pure beta emitter (0.9367 MeV)
– Physical half-life: 64.2 hours
– Irradiates tissue with average path length of 2.5 mm (maximum: 11 mm)
Intra-arterial Radioembolization With Yttrium-90: Rationale and History
Murthy R, et al. Biomed Imaging Interv J. 2006;3:e43.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Clinical Response to Yttrium-90 MicrospheresOutcome Dancey
et al[1]
(N = 20)
Carr et al[2]
(N = 65)Geschwind
et al[3]
(N = 80)
Salem et al[4]
(N = 43)
Response rate, % 39 47
Median survival 378 days(> 104 Gy)
Okuda stage I 649 days 628 days 24.4 mos
Okuda stage II 302 days 384 days 12.5 mos
1. Dancey JE, et al. J Nucl Med. 2000;41:1673-1681.2. Carr BI. Liver Transpl. 2004;10(2 suppl 1):S107-S110.3. Geschwind JF, et al. Gastroenterology. 2004;127(5 suppl 1):S194-S205.4. Salem R, et al. J Vasc Interv Radiol. 2005;16:1627-1639.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
27 patients with Child-Pugh A stage disease
Response rate (assessed by CT) at 6 months: 75%
1- and 2-year survival rates: 92% and 89%
– Median follow-up: 28 months
Varela M, et al. J Hepatol. 2007;46:474-481.
Do
xoru
bic
in a
t S
eru
m (
ng
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)D
oxo
rub
icin
at
Ser
um
(n
g/m
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DEB-TACE
Conventional TACE
Time Postprocedure
Time Postprocedure
0200400600800
1000
0200400600800
1000
BL 5 mins
20 mins
40 mins
60 mins
2 hrs6 hrs
24 hrs
48 hrs
7 days
BL 5 mins
20 mins
40 mins
60 mins
2 hrs6 hrs
24 hrs
48 hrs
7 days
TACE With Doxorubicin-Eluting Beads: Efficacy and Pharmacokinetics
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Targeted Molecular TherapiesMechanisms of Action (cont’d) Multiple pathways
– Sorafenib
– RAF/MEK/ERK signaling
– VEGFR-2
– PDGF-β
– Brivanib
– VEGFR-2
– FGFR-1 kinase
– Pazopanib
– VEGFR-1, -2, -3
– PDGF-α, -β
– c-KIT
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Sorafenib in Advanced HCC: The SHARP Trial Entry criteria
– Advanced HCC
– Not eligible for or failed surgical or locoregional therapies
– Child-Pugh class A disease
– At least 1 untreated target lesion
– Exclusions
– Previous chemotherapy
– Previous molecularly targeted therapy
Llovet JM, et al. N Engl J Med. 2008;359:378-390.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. © 2008, Massachusetts Medical Society. All rights reserved.
Median OSSorafenib: 10.7 mos
Placebo: 7.9 mosMedian TTSP
Sorafenib: 4.1 mosPlacebo: 4.9 mos
Median TTRPSorafenib: 5.5 mosPlacebo: 2.8 mos
The SHARP Trial: OS and Time to Progression
Months Since Randomization
Pro
ba
bil
ity
of
Su
rviv
al
0.00
0.25
0.50
0.75
1.00
0 1 2 3 4 5 6 7 8 9 10 1112 13 1415 16 17
P < .001
A OS
Months Since Randomization
Pro
ba
bil
ity
of
No
S
ym
pto
ma
tic
P
rog
res
sio
n
0 1 2 3 4 5 6 7 8 9 10 111213 1415 16 17
P - 0.77
B Time to Symptomatic Progression
180.00
0.25
0.50
0.75
1.00
Months Since Randomization
Pro
ba
bil
ity
of
Ra
dio
log
ic
Pro
gre
ss
ion
0 1 2 3 4 5 6 7 8 9 10 11
PlaceboSorafenibP < 0.001
C Time to Radiologic Progression
0.00
0.25
0.50
0.75
1.00
12
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Staging Strategy and Treatment for Patients With HCC
Liver transplant PEI/RF
Curative treatments
TACE
HCC
Single
Increased Associateddiseases
Normal No Yes No Yes
Terminalstage
PST 0-2, Child-Pugh A-B
Multinodular, PST 0
Portal invasion, N1, M1
Sorafenib
Portal pressure/bilirubin
3 nodules ≤ 3 cm
Intermediate stage
PST > 2, Child-Pugh C
Very early stageSingle < 2 cm
Early stageSingle or 3 nodules
≤ 3 cm, PST 0
Advanced stagePortal invasion,
N1, M1, PST 1-2
PST 0, Child-Pugh A
Resection
Symptomatic (unless LT)
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.Bruix J, et al. Hepatology. 2005;42:1208-1236.
RCTs (50%) Median survival: 11-20 mos
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Treatment Algorithm for Hepatoma
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Annual Report of Hepatoma 2008
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Annual Report of Hepatoma Patients 2008
A total of 126 patients were recruited from cancer registration, pathology report
Female : Male = 38:88
The age aged from 23 to 91 years old
Mean ± SD = 65.46 ± 13.28
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child
84 66.7 66.7 66.727 21.4 21.4 88.115 11.9 11.9 100.0
126 100.0 100.0
ABCTotal
ValidFrequency Percent Valid Percent
CumulativePercent
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
•HACE 33.3%•HACE 33.3%
•OP13.5%•OP13.5%
•Conservative13.5%•Conservative13.5%
•Transfer 5.6%•Transfer 5.6%
•RFA 24.6%•RFA 24.6%
•C/T 7.9%•C/T 7.9%
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Pathology
Pathology was obtained in 91 among 126 patients
9 were not diagnostic : Negative 1, Fatty liver 1 , cirrhosis 6, chronic active hepatitis 1
Grade I 2
Grade II 31
Grade III 30
Grade IV 2
HCC without grading 13
Carcinoma 4
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Diagnosis of Hepatoma The most sensitive modality capable of objectively
depicting the early carcinogenesis process among currently available imaging systems is
(1) CTAP
(2) CTHA (hepatic arteriography)
(3) contrast-enhanced ultrasonography(US)
(4) SPIO-MRI [24, 25]
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
The Risk of HCC in Patients with Chronic Hepatitis C
In cirrhotic patients, the incidence 2%-8% / year.
Anti-HCV-positive conferred a 20-fold increased risk of HCC (12,008 men)
Surveillance for cirrhosis or bridging fibrosis or transition to cirrhosis.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Staging system CLIP scores or BCLC stages are used in Europe and North America as
staging systems.
the BCLC stage is basically a treatment selection system for deciding on a therapeutic strategy,
CLIP and JIS scores are prognostic prediction stagings.
The CLIP score and BCLC stage tend to detect relatively large HCCs,
JIS score is most useful for countries where many
small liver cancers are detected.
28 Bruix J, Sherman M, Llovet JM, et al: Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL Conference. J Hepatol 2001; 35: 421–430.
29 Llovet JM, Bru C, Bruix J: Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19: 329–338
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Interferon & Lamivudine
No convincing evidence that interferon treatment of chronic hepatitis B reduces the incidence of HCC.
A single RCT suggests that lamivudine treatment reduce the incidence of HCC
in HBV-related cirrhosis ??
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Hepatitis C treated with interferon
A single RCT in Japan suggested that
the incidence of HCC was reduced in both responders and non-responders
In a meta-analysis, benefit is mainly seen in sustained virological responders, and
the effect was small.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Recommendations
17. Local ablation is safe and effective therapy for
patients who cannot undergo resection, or as a bridge to transplantation (level II).
18. Alcohol injection and radiofrequency are
equally effective for tumors <2 cm. However, the
necrotic effect of radiofrequency is more predictable in all tumor sizes and in addition, its efficacy is clearly superior to that of alcohol injection in larger tumors (level I).
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Surgical Recommendations
Recommendations
Patients who have a single lesion can be offered surgical resection if they are non-cirrhotic or have cirrhosis but still have well preserved liver function,
normal bilirubin and
hepatic vein pressure gradient <10 mmHg (level II).
Pre or post-resection adjuvant therapy is not
recommended (level II)
clinicaloptions.com/hep
Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Largest Prospective Study of TACE for Unresectable HCC to Date N = 8510 patients
Primary endpoint: OS
Multivariate analysis conducted of factors affecting survival
OS
– Year 1: 82%; Year 3: 47%; Year 5: 26%; Year 7: 16%
– OS better with lesser degree of liver damage
Factors affecting survival
– Child-Pugh stage
– TNM stage (OS better with stage I, increasingly worse progressing toward stage IV)
– Alpha-fetoprotein level
Takayasu K, et al. Gastroenterology. 2006;131:461-469.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Embolization: Summary
Well-performed comparative studies between chemoembolization, radioembolization, and bland embolization needed
Chemoembolization has longest “track record” and data suggest survival advantage
Radioembolization data rapidly accumulating
– Advantages include lack of induction of ischemia, outpatient procedure without postembolization syndrome
Bland embolization
– Response demonstrable but not clear if benefits in cost; questionable benefits in toxicity outweigh likely decreased response
– Potential role (especially niche role, such as in patients with poor hepatic function or in combination with ablative therapy) remains to be proven
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Transarterial Embolization and Chemoembolization Recommendations
19. TACE is recommended as first line non-curative
therapy for non-surgical patients with large/multifocal
HCC who do not have vascular invasion or extrahepatic
spread (level I).
20. Tamoxifen, antiandrogens, octreotide or hepatic
artery ligation/embolization are not recommended
(level I).
clinicaloptions.com/hep
Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Chemoembolization: Predictors of Survival Lo et al[1]
– Absence of presenting symptoms (ECOG PS < 2)
– Absence of portal vein obstruction
– Tumor size (≤ vs > 5 cm)
– Okuda stage (I vs II)
Llovet et al[2]
– Absence of constitutional syndrome (ECOG PS < 2)
– Low serum bilirubin
– Treatment response (modified WHO criteria, > 6 months)
1. Lo CM, et al. Hepatology. 2002;35:1164-1171.2. Llovet JM, et al. Lancet. 2002;359:1734-1739.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Targeted Molecular Therapies:Mechanisms of Action VEGF antagonists
– Cediranib
– ABT-869
NF-κB antagonists
– Perifosine
Proteasome inhibitors
– Bortezomib
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
32 patients with HCC and PVT
Median OS: 10 months
Child-Pugh score: best prognostic factor (ie, most strongly related to survival)
30-day mortality: 0%
No evidence of TACE-related hepatic infarction or acute liver failure
Safety & Efficacy of TACE in Patients With Unresectable HCC & PVT
Georgiades CS, et al. J Vasc Interv Radiol. 2005;16:1653-1659.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Diagnosis of HCC
AFP > 200 & radiological appearance suggestive of HCC (large and/or mutifocal disease with arterial hypervascularity), Biopsy is not essential.
If the imaging appearances are atypical. Tumor biospy should be considered.
clinicaloptions.com/hep
Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Selecting an HCC Surveillance Interval
Dependent on
– Tumor growth rate
– Prognosis of HCC at different sizes
– < 1-2 cm
– 2-3 cm
– > 3 cm
– Ideal surveillance interval unknown
– Tumor growth rates suggest every 4-12 months
Does not depend on degree of risk
clinicaloptions.com/hep
Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Targeted Molecular Therapies:Mechanisms of Action (cont’d) EGFR tyrosine kinase inhibitors
– Lapatinib
– Sunitinib
– Erlotinib
TRAIL receptor antibodies
– Mapatumumab
BCR-ABL inhibitors
– Dasatinib
clinicaloptions.com/hep
Risk Factors, Surveillance Strategies, and Treatment Options for HCC
CLIP score - prognostic system for patients with HCC
clinicaloptions.com/hep
Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Zhang BH, et al. J Cancer Res Clin Oncol. 2004;130:417-422.
Outcome of HCC Surveillance
18,816 people with HBV infection or history of chronic hepatitis in urban Shanghai, China enrolled
– Surveillance group offered US and AFP every 6 months (n = 9373)
– Control group received no surveillance (n = 9443)
223.7
163.1
0
50
100
150
200
250
300
Control
To
tal I
nci
den
ce
(per
100
,000
)
Screened
83.2
131.5
To
tal M
ort
alit
y (p
er 1
00,0
00)
0
50
100
150
200
250
300Rate ratio:
1.37 (95% CI; 0.99-1.89) Rate ratio:
0.63 (95% CI; 0.41-0.98)
ControlScreened
clinicaloptions.com/hep
Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Phase II study: N = 108 (37 with PVT, 71 without PVT)
Stratified by toxicity: Child-Pugh score (in cirrhotics), dose, location of PVT
Median dose: 134 Gy
Partial response rate: 42% (WHO), 70% (EASL)
Adverse event rate highest in patients with main PVT and cirrhosis
Median survival, main PVT: 260 days
– Branch PVT: 370 days
– No PVT: 460 days
Yttrium-90 Radiotherapy for HCC Patients With and Without PVT
Kulik LM, et al. Hepatology. 2008;47:5-7.
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Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Absolute contraindications
– Child-Pugh class C disease
– Poor performance status (ECOG PS > 2)
Relative contraindication
– Extrahepatic disease (benefit unclear)
Former contraindication
– PVT
– Minimize embolization and be more selective
Chemoembolization: Ineligibility Criteria
clinicaloptions.com/hep
Risk Factors, Surveillance Strategies, and Treatment Options for HCC
Incidence of HCC in Risk Groups
Subgroup Incidence per Year (%)
All hepatitis B carriers > 40 yrs of age 0.2
Cirrhotic hepatitis B carriers 3-8
Hepatitis C cirrhosis 3-5
Stage 4 primary biliary cirrhosis 3-5
Alcoholic cirrhosis ?
Genetic hemochromatosis ?
Nonalcoholic steatohepatitis ?
Beasley RP, et al. Lancet. 1981;2:1129-1133. Koike K, et al. Oncology. 2002;62(suppl 1):29-37. Beasley RP. Hepatology. 1982;2(suppl):21S-26S. Fattovich G, et al. Gut. 1991;32:294-298. Manno M, et al. Gastroenterology. 2004;127:756-763. Hsu YS, et al. Hepatology. 2002;35:1522-1527. Fattovich G. J Hepatol 2003;39(suppl 1):S50-S58. Fattovich G, et al. Gastroenterology. 1997;112:463-472. Niederau C, et al. Hepatology. 1998;28:1687-1695. Niederau C, et al. N Engl J Med. 1996;334:1422-1427. Degos F, et al. Gut. 2000;47:131-136. Caballeria L, et al. Am J Gastroenterol. 2001;96:1160-1163.