Hepatocellular Carcinoma: The growing disease burden
Paul Y Kwo, MDProfessor of Medicine
Medical Director, Liver TransplantationGastroenterology/Hepatology DivisionIndiana University School of Medicine
975 W. Walnut, IB 327Indianapolis, IN 46202-5121
phone 317-274-3090fax 317-274-3106
Hepatocellular Carcinoma (HCC)
• Hepatocellular carcinoma (HCC) is the 6th most common cancer in the world
•Third leading cause of cancer related death
•Age-adjusted US incidence has increased 2-fold: 1985-1998
•American Cancer Society statistics for liver cancer in 2008•Most patients with HCC in US have liver cirrhosis mainly by hepatitis B and C viruses•Estimation of new cases: 21,370•Estimation of deaths: 17,000
• Hepatitis B virus is the most frequent underlying cause world wide• 85% of HCC cases occur in Eastern and Southeastern Asian and Sub Saharan Africa (endemic HBV infection)• In the US, HCV-related HCC is a rapidly rising cancer (50-70% of cases)• Other risk factors in the United States include alcohol use, nonalcoholic fatty liver disease , inherited liver disease, smoking*
• Hemochromatosis (highest risk, though low disease penetrance)•Cirrhosis is a pre-malignant condition
HCC: Epidemiology
Rising Mortality Rate from HCC in US (Age Adjusted)
Age-Specific Incidence of HCC among White Men in SEER Database
Origin of HCC• Cirrhotic liver
– All causes• Noncirrhotic liver
– Hepatitis B– Fibrolamellar variant– Rare metabolic diseases
(eg, glycogenosis, porphyria)– Hepatitis C (rare)– Other
Incidence of HCC as it relates to etiology of cirrhosis
Non-alcoholic fatty liver disease
1991-1992: 7 Taiwanese townships 1991-1992: 7 Taiwanese townships Individuals aged 30-65 years eligibleIndividuals aged 30-65 years eligible
(N = 89,293)(N = 89,293)
REVEAL: Baseline HBV DNA and Liver Disease Progression
Prospective, multicenter, observational cohort study
Chen CJ, et al. JAMA 2006;295:65-73.Iloeje UH, et al. Gastroenterology 2006;130:678-686.
HCC AnalysisHCC Analysis(n = 3653)(n = 3653)
2004: 41,779 PYs follow-up2004: 41,779 PYs follow-up164 HCC patients (4.5%)164 HCC patients (4.5%)
HCC-free individuals enrolledHCC-free individuals enrolled(n = 23,820)(n = 23,820)
Cirrhosis AnalysisCirrhosis Analysis (n = 3774)(n = 3774)
2004: 42,115 PYs follow-up2004: 42,115 PYs follow-up395 cirrhotic patients (10.5%)395 cirrhotic patients (10.5%)
Excluded if cirrhotic within 6 months
Cumulative incidence of HCC (%) (n = 3653)
Chen CJ, et al. JAMA. 2006;295:65-73.Iloeje UH, et al. Gastroenterology. 2006;130:678-686.
< 300 (Undetectable)
300-9,999
10,000-99,999
100,000-999,999
≥ 1 Million
REVEAL Study: HBV DNA Levels and Long-Term Outcomes
1.37%
3.57%
14.89%
1.30%
12.17%
0
5
10
15
20
3.6
9.7
2.0
1.0
10.6
0
2
4
6
8
10
12
Multivariate-adjustedrelative risk of cirrhosis (n = 3482)
Viral Load at Baseline
HCC: Pathogenesis• Carcinogenesis is typically a stepwise
process– Sequential genetic mutations– Oncogene activation– Tumor suppressor gene inactivation
• No dominant pathways of hepatocellular carcinogenesis have been identified
Molecular Pathogenesis of HCC
• 2 key mechanisms implicated in development of HCC– Liver cirrhosis following tissue damage (infectious or toxic
damage)– Mutations occurring in 1 or more oncogenic or tumor
suppressor genes• Abnormalities in cellular signaling pathways
– Raf/MEK/ERK – PI3K/AKT/mTOR– Wnt/β-catenin – Angiogenic signaling
Chronic liver damage
Cirrhosis
Hepatocyte regeneration
HCC
Genetic alterations
Marotta F et al. Clin Ter. 2004;155:187-199. Thorgeirsson SS, et al. Nat Genet. 2002;31:339-346. Wiesenauer CA, et al. J Am Coll Surg. 2004;198:410-421. Wang XW, et al. Toxicology. 2002;181-182:43-47. Feitelson MA, et al. Surg Clin North Am. 2004;84:339-354. Avila MA, et al. Oncogene. 2006;25:3866-3884. Adapted from CCO
0
24
6
8
1012
14
<30 30-90 90-150 150-210 >210
Doubling Time (Days)Doubling Time (Days)
Num
ber o
f Cas
es
Num
ber o
f Cas
es
Growth Rates of HCC
Sheu J-C, et al. Gastroenterology. 1985;89:259.
Median Doubling Time =117 Days (Range: 29-398)
1
9
13
2
5
Actuarial Survival of Patients With Untreated HCC
Llovet JM, et al. Hepatology. 1999;29:62.
0 12 24 36 48 60
102102 5757 4040 2121 8 8 1 1Patients at RiskPatients at RiskMonthsMonths
Prob
abili
ty (%
)Pr
obab
ility
(%)
20
40
60
80
100
1
Spread of HCC
2
34
ExtrahepaticSpread to:
LungsBoneAdrenals
ExtrahepaticSpread to:
LungsBoneAdrenals
55
How do we screen for HCC• No studies define unequivocally the best modality for diagnosing HCC
• Ultrasonography (US)every 6-12 months with alpha-fetoprotein (AFP) every six months is current standard of care for screening high risk patients
•US has technical limitations (operator dependence, reduced efficacy in those with elevated BMI)•US if subject has normal BMI
•AFP alone is not sufficient unless imaging modalities are not available
•Our practice at IU: MRI every 9 months or Dual Phase Spiral CT , or US every 6-12 months if normal BMI
•MRI or US preferred due to radiation risk with CT scan
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
HCC Screening: Caveats with Ultrasound
• Detection of hypo- or hyperechoic nodule should raise suspicion of HCC in a cirrhotic patient– Less than half of nodules less than 1 cm size
correspond to hepatocellular carcinoma– Nodules less than 1 cm are followed with repeat
ultrasound every three months until lesion greater than 1 cm
– Absence of growth does not rule out HCC
How is HCC Diagnosed: Dynamic Imaging (CT scan or MRI)
• HCCs have blood supply from hepatic artery• Dual Phase Spiral CT scan or MRI with
intravenous contrast allows rapid acquisition of images during hepatic arterial phase and portal venous phases
• Lesions seen during the arterial phase and which are less well seen during portal venous phase are suspicious for HCC– Requires relatively preserved renal function for both
Triple Phase CT Scan of HCC at 0 and 6 Months
6 months later: Arterial Phase Portovenous Phase
Time 0: No Contrast Arterial Phase Portovenous Phase
How is HCC Diagnosed: MRI• MRI provides another way of distinguishing
hepatocellular carcinoma from normal liver tissue
• Most tumors have a low signal intensity on T 1
-weighted images and a high signal intensity on T 2 -weighted images
• Gradient-echo sequences and turbo spin-echo sequences have greatly reduced the time needed for MRI. – (breath holding for 40 seconds for optimal images)
• Less dependent on normal renal function
MRI demonstrating HCC/Tumor Thrombosis
How is HCC Diagnosed?
•Nodules >1 cm can be confidently diagnosed with CT or MRI without needing a biopsy positive for HCC•If lesion has atypical enhancement, need 2 dynamic imaging studies with typical washout, otherwise, biopsy•A biopsy of a nodule negative for HCC should never be accepted as having excluded malignancy
Mass found with surveillance
Effect of Surveillance on Outcomes• Retrospective analysis of patients with cirrhosis and HCC (N = 269)
– Standard-of-care surveillance (n = 172)• Ultrasound or other abdominal imaging ≥ 1 time/year
– Substandard surveillance (n = 48)• Lack of abdominal imaging within 1 year of cancer diagnosis
– Absence of surveillance (n = 59)
Outcomes, % Standard-of-Care Surveillance
(n = 172)
SubstandardSurveillance
(n = 48)
Absence ofSurveillance
(n = 59)
P Value
HCC diagnosis atstages 1/2 69 35 18 < .001
Liver transplantation 32 13 7 < .05Mean 3-year survival from cancer diagnosis 40 27 13 < .005
Stravitz RT, et al. Am J Med. 2008;121:119-126.
Alpha-fetoprotein Levels•Values greater than 400 ng/ml have been validated as confirming hepatocellular carcinoma
•Viral liver disease often associated with transient increases of AFP coinciding with inflammatory flares of disease
•Values > 200 ng/ml with mass associated with high likelihood of HCC
Staging of HCC• Staging systems
– TNM nomenclature– Okuda system– BCLC (Barcelona Clinic Liver Cancer) – CLIP (Cancer of the Liver Italian Program)
• Key features– Tumor size – Liver function– Performance status of the patient
HCCFactors Affecting Survival
• Constitutional syndrome• Performance status• Vascular invasion• Extrahepatic spread
Llovet JM, et al. Hepatology. 1999;29:62.
Prognosis of Patients With HCCPatient Survival
Therapy 1 Year 3 Years
No “radical” therapy 54% 28%Surgical resection 81% 44%Ethanol injection 82% 38%Transplantation 84% 74%
Castells A, et al. Hepatology. 1993;18:11211. Llovet JM, et al. Hepatology. 1998;27:1572. Llovet JM, et al. Hepatology. 1999;29:62.
HCC Treatment Options: 2012
• Surgical resection
• Liver transplantation
• Transarterial Chemo-embolization or Radioembolization (Yttrium-90 microspheres)
• Stereotactic Radiation
• Radiofrequency ablation
• Sorafenib
Surgical Resection
• Small group of cirrhotics with HCC (<5% of HCC patients) are candidates
• HCC without cirrhosis are also candidates• Criteria
– Child-Pugh class A– Normal bilirubin– Absence of portal hypertension– <5 cm in diameter
• 5-year survival rate: 60%-70%• Tumor recurrence: 50% in 3 years
Llovet JM, et al. Hepatology. 1999;30:1434.
Survival Following Surgical Resection for HCC
N = 77N = 77100
80
60
40
20
00 12 24 36 48 60 72 84 96
Postoperative MonthPostoperative Month
Prob
abili
ty o
f Sur
viva
l (%
)Pr
obab
ility
of S
urvi
val (
%)
Log Rank 0.00001Log Rank 0.00001
No portal No portal hypertension hypertension (<10 mm Hg)(<10 mm Hg)
Portal hypertension Portal hypertension + bilirubin <1 mg/dL+ bilirubin <1 mg/dL
Portal hypertension Portal hypertension + bilirubin >1 mg/dL+ bilirubin >1 mg/dL
Transplantation for HCC:Milan Criteria
• 1 lesion ≤ 5 cm• 3 lesions ≤ 3 cm• No vascular invasion• No extrahepatic metastases
Mazzaferro V, et al. N Engl J Med. 1996;334:693.
Survival and Recurrence-Free Survival Following Liver Transplantation for HCC
Months After TransplantationMonths After Transplantation0 6 12 18 24 30 36 42 48
48 45 40 32 27 21 17 9 5
0
20
40
60
80
100
Ove
rall
Surv
ival
(%)
Ove
rall
Surv
ival
(%)
Patients at RiskPatients at RiskMonths After TransplantationMonths After Transplantation0 6 12 18 24 30 36 42 48
48 43 38 29 25 19 15 9 5
0
20
40
60
80
100
Rec
urre
nce-
Free
R
ecur
renc
e-Fr
ee
Surv
ival
(%)
Surv
ival
(%)
Patients at RiskPatients at Risk
Transplantation for HCC:UCSF Criteria
• Lesion ≤ 6.5 cm• 2-3 lesions
• - largest ≤ 4.5 cm• - total < 8 cm diameter
• No vascular invasion• No extrahepatic metastases
Survival Following OLT for HCCMilan and UCSF Criteria
CP1078048-2
Survival distribution
function
Years after liver transplantation
UCSF
Milan
Liver Transplantation 8:769, 2002
0.0
0.2
0.4
0.6
0.8
1.0
0 1 2 3 4 5
Survival Following LT for HCC
CP1238402-7
0.0
0.2
0.4
0.6
0.8
1.0
0 1 2 3 4 5
Surv
ival
dis
tribu
tion
func
tion
Years after liver transplantation
> UCSF (n=8)
UCSF (n=37)
Yao et al: Liver Transp 8:765, 2002
– Glass microspheresGlass microspheres20-30 20-30 μμ in diameter in diameterYttriumYttrium9090 is an integral component of the glass is an integral component of the glass
– Each 0.3 ml vial contains 1.2 - 8 million Each 0.3 ml vial contains 1.2 - 8 million microspheres (3-20 GBq Ymicrospheres (3-20 GBq Y9090))
– Activity/sphere = 2500 Becquerel (2400 Activity/sphere = 2500 Becquerel (2400 disintegrations per second)disintegrations per second)
YttriumYttrium9090-laden microspheres:-laden microspheres:Therasphere® Therasphere®
25 microns
Trans-arterial hepatic radioembolisation of yttrium-90
microspheres
Chemoembolization
Hepatocellularcarcinoma
Hepaticartery
CatheterIvalon plusCDDPAdriamycinMitomycin C
HCC: Transarterial Chemoembolization (TACE)
Pre-treatment Post-treatment
ASTRO - ACR PRACTICE GUIDELINES FOR SBRTInt. J. Rad. Oncol. Biol. Phys., 60: 1026–1032, 2004
• ASTRO definition: Stereotactic body radiation therapy (SBRT) is a method to very precisely deliver a high dose of radiation to an extracranial target within the body, using a single dose or a small number of fractions.– Specialized treatment planning results in high target dose
and steep dose gradients beyond the target. – Highly precise, accurate & reproducible target
localization, using a 3D coordinate system: IGRT
Treatment Logistics: Sterotactic Body radiation to the liver
• Patient positioning and immobilization in the SBF in a Vac-Lok, with diaphragmatic control device– Fluoroscopic evaluation of diaphragmatic excursion (≤ 0.5 cm)– CT scan with IV contrast (2.5 mm slice interval, 2mm
thickness)– GI contrast patients with medial liver lesions or in the caudate
lobe– TPCT, MRI scan or PET-CT fusion
Typical Response to SBRT
47 year old male with hepatitis C induced Child’s B-liver cirrhosis with a 2 cm hypervascular mass in segments 5 and 6. Arterial and venous phase post-gadolinium MR images 1 month after treatment show reduced enhancement of the mass (black arrows) but no significant change in size. Note peritumoral hyper enhancement in both phases (white arrows). Arterial phase image at 3 months showed the mass is almost completely necrotic, smaller, with thin enhancing rim (arrow).
Pre Treatment1 month arterial1 month venous 3 months arterial
Radiofrequency Ablation
A 14 gauge needle is directed into the tumor by ultrasound or CT guidance and an alternating current is applied, similar to microwave, Best in tumors less than 5 cm.
HCC: Post RFA Treatment
Josep M Llovet, Sergio Ricci, Vincenzo Mazzaferro, Philip Hilgard, Jean-Luc Raoul, Stefan Zeuzem, Armando Santoro, MinghuaShan, Marius
Moscovici, Dimitris Voliotis, and Jordi Bruix, for the SHARP Investigators Study Group
Sorafenib Improves Survival in Hepatocellular Carcinoma: Results of a Phase III Randomized,
Placebo-Controlled Trial
Supported by Bayer HealthCare and Onyx Pharmaceuticals
Cellular targets of sorafenib
Wilhelm S, et al. Nat Rev Drug Discov 2006;5:835–44
Receptor autophosphorylation
Activation of RafSorafenib Cell survival (anti-apoptotic effects)
Neovascularisation Invasion andmetastasis
Tumour cell proliferation
MEK/ERK
VEGF
VEGFR
PDGFβ
PDGFR
SCF
c-Kit
GDNF
RET
SorafenibMedian: 46.3 weeks (10.7 mo)(95% CI: 40.9, 57.9)
Surv
ival
Pro
babi
lity
Weeks
Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.88). P=0.00058*
PlaceboMedian: 34.4 weeks (7.9 mo)(95% CI: 29.4, 39.4)
1.00
0
0.75
0.50
0.25
0 808 16 24 32 40 48 56 64 72
*O’Brien-Fleming threshold for statistical significance was P=0.0077.
0274 241 205 161 108 67 38 12 0Patients at risk
Sorafenib:0276 224 179 126 78 47 25 7 2Placebo:
299303
Phase III SHARP TrialOverall survival (Intention-to-treat)
0196 126 80 50 28 14 8 20192 101 57 31 12 8 2 1
Pro
babi
lity
of p
rogr
essi
on
Hazard ratio (S/P): 0.58 (95% CI: 0.44, 0.74) P=0.000007
546 12 18 24 30 36 42 480 Weeks
SorafenibMedian: 24.0 weeks (5.5 mo)(95% CI: 18.0, 30.0)
PlaceboMedian: 12.3 weeks (2.8 mo)(95% CI: 11.7, 17.1)
1.00
0
0.75
0.50
0.25
Patients at risk Sorafenib:
Placebo:299303
Phase III SHARP TrialTime to Progression (Independent central review)
Summary• HCC usually arises in cirrhotic liver
• Growth rate varies
• Long asymptomatic phase
• Child-Pugh stage and performance status are important determinants of survival
Conclusions• Liver transplantation offers best chance
for cure in selected cases (preoperative locoregional therapy may provide additional benefit)
• Living donor liver transplantation may provide timely transplantation
• Radical (Stereotactic radiation and RFA) therapies are effective for small tumors before OLT
Conclusions
• Radioembolization (Y90) in non-transplant patients appears to improve survival
• Sorafenib conferred a survival benefit in unresectable HCC is being studied in multiple patient populations with HCC
• Important to identify patients with end stage liver disease and other high risk groups, particularly Hepatitis B and C carriers as well as NAFL-D in the US
