Updates in Hepatocellular Carcinoma
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The Global Impact of Liver Cancer
Akinyemiju T, et al. JAMA Oncol 2017.EASL CPG; J Hepatol 2018.
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Incidence in the U.S.
White DL, et al. Gastro 2017.
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Malignant Transformation
Normal liver
Liver cirrhosis
Hepatitis CHepatitis B
EthanolNASH
Epigenetic alterationsGenetic alterations
HCC[2]
Dysplastic nodules[1]
1. Tornillo L, et al. Lab Invest. 2002;82:547-553. 2. Verslype C, et al. AASLD 2007.
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Incidence of HCC is rising
www.seer.cancer.gov
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HCC Mortality from 1990-2015…
Fitzmaurice, et al. JAMA Oncol 2017.
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High Mortality Rates in HCC
Khalaf N, et al. CGH 2016.
518 untreated patients: survival stratified by stage
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HCC Risk Factors
El Serag HB. Gastro 2007, Bruix J. Hepatology 2010. Collier J. Hepatology 1998. Marrero JA. J Hepatol 2005.
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Alcohol and HCC risk
Donato F, et al. Am J Epid 2002.
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NAFLD and HCC risk
Kanwal F, et al. Gastro 2018.
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HCC preventive interventions
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Modifying HCC risk
Singal AG. Clin Gastro Hep 2010. Nishiguchi S. Lancet 1995. Valla DC. Hepatology 1999. Lok AS. Gastro 2011.
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Impact of Universal Vaccination in Taiwan
Chang MH. NEJM 1997
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Hep B viral load and HCC incidence
Chen CJ. JAMA 2006.
REVEAL Study (n=3,653)
10
6
4
2
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Cu
mu
lati
ve
inci
den
ce o
f H
CC
(% s
ub
ject
s)
12
8
Baseline HBV DNA level, copies/mL
≥106 (n=627)
105–<106 (n=349)
104–<105 (n=643)
300–<104 (n=1,161)
<300 (n=873)
Log rank test of trend
p<0.001
14.9%
12.2%
3.6%
1.4%1.3%
Year of follow-up
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Antiviral Therapy in Hepatitis BP
ati
en
ts w
ith
dis
ease
pro
gre
ss
ion
(%
)
Time to disease progression (months)
“Proof of Principle”
LiawY-F et al. N Engl J Med. 2004;351:1521-1531.
Lamivudine (n=436)
Placebo (n=215)
P=0.001
21%
9%
25
20
15
10
5
0
30181260 36
n=198
n=173
n=417
n=385
n=43
n=122
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HCV treatment reduces HCC risk
Kanwal, et al. Gastro 2017.
• SVR vs no SVR (0.90 vs 3.45 HCC/100 person-years; HR 0.28)• Cirrhosis + SVR vs. no Cirrhosis + SVR (1.82 vs 0.34/100 person-years; HR 4.73)
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Surveillance for HCC
El-Serag HB. Gut 2011. Trevisani F. Am J Gastro 2002.
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Surveillance improves early stage diagnosis
Singal, et al. PLoS Med 2014.
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Surveillance for HCC Reduces MortalityA Randomized Controlled Trial
Zhang BH. J Cancer Res Clin Oncol 2004.
Time (Years)
Su
rviv
al P
rob
abili
ty (%
)
0 1 2 3 4 50
.8
.6
.2
.4
Screening
Control
HCC-related mortality reduced by 37%
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Surveillance improves survival in cirrhosis
Singal, et al. PLoS Med 2014.
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Surveillance for HCC
• Ultrasound every 6 months
• AFP with US increases sensitivity to 63.4% (clinical practice)
Bruix J, Sherman M. Hepatology 2010.Singal AG. AP&T 2009. Singal AG. Canc Epid Bio Prev 2012. Marrero JA. Gastro 2009.
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Surveillance for HCC
Hepatology, 68(2), 2018
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Surveillance rates for HCC
Singal AG. J Gen Int Med 2012.
Pooled meta-analysis: <20% surveillance rates for cirrhotic patients
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PCP reported barriers to surveillance
Provider-reported Barriers Percent
Lack of knowledge about guidelines 68.2%
Competing interests in clinic 51.6%
Lack of time in clinic 41.5%
Difficulty recognizing at-risk patients 35.4%
Ultrasound capacity 23.0%
Doubt patients will complete 9.3%
Dalton-Fitzgerald, et al. CGH 2015.
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Diagnosing HCC
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• Vascular supply of HCC arises from the hepatic artery through neovascularization.
• Multi-phase imaging is key
• Radiological hallmark: arterial hypervascularity with washout in the venous/delayed phase
Yu JS. Am J Roentgenol 1999
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Pre-contrast Arterial Phase Portal Venous/ Delayed
HCC Diagnosis
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Arterial phase 2-min delayed
5-min delayedArterial phase
Washout in HCCWashout in HCC
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Marrero, et al. Hepatology 2018.
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30
HCC StagingPatient
TumorLiver
ECOG
PS
Child-
PughTNM
BCLC
• Staging is used for prognosis and to guide treatment
• Factors affecting staging systems
– Tumor stage
– Liver function
– Functional status
• Links stage with treatment options and prognosis
1. Llovet JM. Gastroenterol. 2005;40:225-235; 2. Marrero JA, et al. Clin Liver Dis. 2006;10:339-351; 3. Bruix J, et al. J Hepatol. 2001;35:421-430;
4. Llovet JM, et al. Semin Liver Dis. 1999;19:329-338; 5. Chevret S, et al. J Hepatol. 1999;31:133-141; 6. Schafer DF, et al. Lancet. 1999;353:1253-1257;
7. Leung T, et al. Cancer. 2002;94:1760-1769; 8. CLIP. Hepatology. 1998;28:751-755; 9. Makuuchi M, et al. World J Gastroenterol. 2006;12:828-829.
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BCLC Staging System
Marrero JA. Hepatology 2005
100
Su
rviv
al P
rob
abili
ty 80
60
40
20
0
0 10 20 30 40 50 60 70
Log Rank PA vs. B P < .0001B vs. C P = .04C vs. D P = .01
A
B
CD
Time (Months)
BCLC Staging System
HCC Staging
• BCLC was best predictor of survival
• Homogeneity in survival across each stage
• Validated BCLC compared to other staging systems
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Barcelona Staging
Marrero, et al. Hepatology 2018.
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Bruix J, Sherman M. J Hepatol 2011.
HCC Staging & Prognosis
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Treatment of Early Stage HCC
EASL CPG. J Hep 2018.
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Outcome of Surgical Resection for HCC in Cirrhosis
Llovet JM. Hepatology 1999.
Patients with a single tumor <= 5 cm and Child A cirrhosis
Months
00
Pro
bab
ility
(%)
12 24 36 48
20
100
40
60
80
Log Rank 0.00001
60 72 84 96
Nl portal pressure, Bili <1
Portal pressure, Bili <1
Portal pressure, Bili 1
*Other surrogates for portal htn =
HVPG ≥ 10mmHg ; plt <100
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Four -Year Survival
0
10
20
30
40
50
60
70
80
Unselected 1991 Milan Criteria Other Dx
40%
75% 76%
%
Surviving
Mazzafero V. NEJM 1996.
Liver Transplant for HCC
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Intermediate HCC (Stage B)
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Chemoembolization
Prolongs 2-yr survival: 63% vs. 27% for best supportive care (p<0.001)
Llovet JM. Lancet 2002.
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Radioembolization with Yttrium (Y90) microspheres in HCC (TARE)
Kulik LM. Hepatology. 2008. Salem R. Gastro 2010. Hilgard P. Hepatology 2010. Sangro B. Dig Dis 2009.
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TARE likely has a role for Intermediate Stage HCC
Salem et al. Gastro 2016.
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Advanced HCC (Stage C)
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SHARP: Overall Survival Sorafenib
Sorafenib median:46.3 weeks (10.7 months)(95% CI, 40.9-57.9)
Placebo median: 34.4 weeks (7.9 months) (95% CI, 29.4-39.4)
Llovet JM et al. NEJM 2008.
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SHARP results
Llovet JM et al. NEJM 2008.
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Subsequent negative HCC trials…
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Lenvatinib is non-inferior to Sorafenib
Kudo et al. Lancet 2018.
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Current treatment landscape…
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Henry Ford HCC: Multidisciplinary Approach
Radiation
Oncology
Pathology
Oncology
Radiology
Hepatobiliary
Surgery
Hepatology
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Conclusion – Key Learnings
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