Hepatocellular Carcinoma

Ahmed Zeeneldin
Associate Professor of Medical Oncology/Hematology
NCI, Egypt
 Risk factors
— Hepatitis B and/or C ,
— External sources:
— alcohol , aflatoxin,
— Particular comorbidities or conditions:
— inherited errors of metabolism: hereditary hemochromatosis,
porphyria cutanea tarda, α1-antitrypsin deficiency, and Wilson’s
disease,
— autoimmune hepatitis and primary biliary cirrhosis.
— non-alcoholic fatty liver disease and steatohepatitis [NASH]

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 HCC and Cirrhosis
— Risk factors for HCC are also risk factors for liver cirrhosis.
— 60%-80% of HCC have cirrhosis
— Cirrhosis is a prerequisite for HCC in inherited metabolic
diseases and autoimmune D.
— annual incidence rate of HCC in hepatitis C-related cirrhosis:
2-8%.

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 Screening for HCC
— Aim: Early asymptomatic curable
— China:
— Hepatitis B or history of chronic hepatitis
— Screening: AFP and US q 6m
— <60% completed the screening program (5-10 times).
— biannual screening reduced HCC mortality by 37%
— Zhang et al, J Cancer Res Clin Oncol. 2004;130:417-422.

Screening Control
N 9,373 9,443
Total HCC n 86 67
Subclinical HCC n 52 (60%) 0
Small HCC 39 (45%) 0
Resection 40 (47%) 5
OS at 1,3,5y 66, 53, 46% 31,7,0% (S)
Death 32 54 (S)
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 Screening methods
— AFP and US
— US > AFP but operator dependednt
— Both are better

HCC No-HCC
test + True + False + PPV=TP/TP+FP
AFP: 5% AFP: 3%
US : 3% US : 7%
Both: 7% Both: 3%
- False – True – NPP= TN/TN+FN

Sensitivity: TP/TP+FN Specificity: TN/TN+FP

AFP: 70%
US : 85%
Both: 92%
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 Indications for screening
— Patients at risk for HCC:
— Cirrhosis
— Hepatitis B, C
— Alcohol
— Genetic hemochromatosis
— Auto immune hepatitis
— Non-alcoholic steatohepatitis
— Primary biliary cirrhosis
— Alpha1-antitrypsin deficiency
— Without cirrhosis
— Hepatitis B carriers
— Non-alcoholic steatohepatitis

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 Screening

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 Clinical picture
— Symptoms
— Signs
— Paraneoplastic syndromes
— hypercholesterolemia,
— erythrocytosis,
— hypercalcemia, and
— hypoglycemia.

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 Blood supply of the liver
— Normal:
— 1-portal vein
— 2 Hepatic artery
— 3 hepatic vein
— Malignant:
— 1-Hepatic artery
— 2-portal vein
— 3- hepatic vein

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 Imaging of hepatic tumors
— Triphasic CT, MRI, US*
— 1-arterial phase (malignancy)
— 2-portal venous phase (normal)
— 3-venous phase after a delay

— How classic HCC look in triphasic imaging

— Arterial phase: intense arterial uptake or enhancement (White)
— Delayed veous phase: washout or hypointensity (Grey)

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 CT normal liver

A eraly arterial, Hepatic artery opacified

B late arterial, portal vein opacified
C potal venous phase: middle hepatic vein opacified

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 HCC CT

CT evaluation of the liver during the early arterial (2a), late arterial (2b), and portal
venous (2c) phases of enhancement.
The mass in segment III (white arrow) demonstrates the classic pattern of enhancement for
HCC.

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 HCC US
(a) RT hepatic lobe hypoechoic FL
(b) Dynamic contrast enhanced US
with SonoVue. The early arterial phase
: peripheral tumoural vessels (arrows)
with enhancement filling from the
periphery.
(c) The arterial phase
: homogeneous tumoural
enhancement with a small hypoechoic
area (arrow).
(d) In the portal phase, the HCC
(arrows) became relatively hypoechoic
to the surrounding enhanced liver
parenchyma.

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 HCC MRI

(A) shows the arterial phase of the MRI, indicating an arterially

enhancing mass in the right lobe of the liver near the dome (arrow), with an
enhancing rim around the mass.

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 HCC MRI

(B) shows the 3-minute delayed image of the hepatic mass. The mass
appears hypointense compared with the rest of the liver (arrow), consistent
with a marked decrease in arterial blood supply to the mass. This process is
called “washout of contrast.”
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 HFL in US
— Size >2cm
— One imaging modality (triphasic CT, MRI, US)
— Classic = HCC
— None classic: Bx
— Size 1-2 cm
— 2 imaging modalities:
— Both classic = HCC
— One classic: biopsy
— None classic: Bx
— Size <1cm
— One imaging modality q3-4 m
— Stable for 18 m: imaging q 6-12
— Enlarging as before

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 Needle biopsy
— Sampling error, particularly 1-2 cm.
— Negative biopsy : follow up closely

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 HCC staging
— M1: Distant metastasis
— N1: Regional lymph node metastasis
— T1: Solitary tumor without vascular
invasion
— T2: Solitary tumor with vascular
invasion OR
multiple tumors none more than 5 cm
— T3: Multiple tumors more than 5 cm
OR tumor involving a major branch of
the portal or hepatic vein(s)
— T4: direct invasion of adjacent organs
other than the gallbladder or with
perforation of visceral peritoneum
— F0: Fibrosis score 0-4 (none to
moderate fibrosis)
— F1: Fibrosis score 5-6 (severe fibrosis or
cirrhosis)

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 Serum biomarkers
— AFP: not a sensitive or specific.
— Diagnosis of HCC should not be based solely on the AFP
level, regardless of how high it may be.
— AFP in conjunction with other tests.
— Additional imaging studies (ie, CT/MRI) with a rising serum
AFP level in the absence of a liver mass

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 Serum biomarkers
— AFP: not a sensitive or specific.
— Diagnosis of HCC should not be based solely on the AFP
level, regardless of how high it may be.
— AFP in conjunction with other tests.
— Rising serum AFP level in the absence of a liver mass suggests
additional imaging studies (ie, CT/MRI)
— If still no masses: more frequent AFP and Imaging q 3 m
— Mass > 2 cm with classic imaging , AFP > 200 ng/ml: is
diagnostic of HCC

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 workup
— HP
— Hepatic function?
— Portal ypertension?
— Is there hepatitis B/C?
— Comorbidities?
— Is there metastasis?
— lung, abdominal lymph nodes and the bone.

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 Assessments
— liver function tests:
— Bilirubin
— Aspartate transaminase (AST),
— alanine transaminase (ALT),
— Alkaline phosphatase, lactate dehydrogenase (LDH),
— albumin, and protein.
— kidney function tests: BUN and creatinine
— Others: PT/PC or INR and CBCD

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 Child-Pugh classification
Measure 1 point 2 points 3 points units
Bilirubin (total) <34 (<2) 34-50 (2-3) >50 (>3) μmol/l (mg/dl)
Serum albumin >35 28-35 <28 g/l
INR <1.7 1.71-2.20 > 2.20 no unit
Ascites None Mild Severe no unit
Grade I-II (or
Hepatic Grade III-IV (or
None suppressed with no unit
encephalopathy refractory)
medication)

One year Two year

Points Class
survival survival
5-6 A 100% 85%
7-9 B 81% 57%
10-15 C 45% 35%
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 Child-Pugh classification
— Advantages
— Simple
— Includes clinical parameters (ascites, encephalopathy)
— Disadvatages
— Lacks data on portal hypertension (esophagogastric varices,
splenomegaly, abdominal collaterals)
— Clinical data are subjective
— Interpretation
— Class A: compensated cirrhosis
— Class B and C: decompensated cirrhosis

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 Model for End-Stage Liver Disease (MELD)
— MELD = 3.78[Ln serum bilirubin (mg/dL)] + 11.2[Ln INR] +
9.57[Ln serum creatinine (mg/dL)] + 6.43
— Predict death within 3 months after (TIPS) surgery transjugular
intrahepatic portosystemic shunt
— 40 or more — 100% mortality
— 30–39 — 83% mortality
— 20–29 — 76% mortality
— 10–19 — 27% mortality
— <10 — 4% mortality
— Advantage:
— Includes renal function
— No subjectivity
— Prioritize liver transplant

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 Pathology of HCC
— Gross
— Nodular (Cirrohsis): well
circumscribed nodules.
— Massive (noncirrhotic):
large area with or without
satellite nodules
— Diffuse: small indistinct
tumor nodules throughout
the liver.

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 Histology
Cirrhotic nodules in upper left and Hepatocellular carcinoma
lower right areas, separated by a
fibrous band,

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 Prognostic Factors in HCC:
— Tumor: stage, aggressiveness and growth rate:
— AJCC TNM staging
— Patient: general health
— ECOG PS
— Karnofsky PS
— Liver: functions
— Child-Pugh, MELD
— Treatments

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 Other systems
— Okuda system:
— based on tumor size, ascites, jaundice and serum albumin
— The French classification (GRETCH) system
— Karnofsky performance , measurements of liver function and
serum AFP
— Cancer of the Liver Italian Program (CLIP)
— Child-Pugh stage, tumor morphology, alpha-fetoprotein (AFP),
and portal vein thrombosis.
— Barcelona Clinic Liver Cancer (BCLC),

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 Management of HCC

=MULTIDICIPLINARY

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 HCC management
— Patient, liver, tumor
— Multidiscplinary
— hepatologists,
— pathologists
— cross-sectional radiologists,
— Interventional radiologists,
— transplant surgeons,
— surgical oncologists,
— medical oncologists,

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 Modalities
— Surgery
— Local Regional Therapy
— Bland embolization and chemoembolization
— Conformal or stereotactic radiation therapy
— Systemic therapy
— Best supportive care

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 Surgery
— Partial Hepatectomy
— Early-stage HCC who are eligible to undergo the procedure.
— solitary tumors without major vascular invasion.
— 3 or fewer tumors of 3 cm or less (debateable)
— Child-Pugh A, No portal HT, adequate reserve
— Low operative morbidity and mortality (5% or less).
— 5 year OS: ~ 50%
— 5 year recurrences: ~70%
— Hepatic reserve (HR)
— Future liver remnant (FLR)
— HR=FLR/total liver volume-Tu
— =>20 % if no cirrhosis
— =>30-40 % if cirrhosis

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 Surgery
— Liver Transplantation
— Potentially curative for early HCC.
— 4 y OS: 85% and 4-y RFS: 92%
— Removes detectable and undetectable lesions,
— treats underlying cirrhosis
— Avoids complications of small FLR.
— United Network for Organ Sharing (UNOS)/Milan criteria
— Patient has a tumor 5 cm in diameter or 2-3 tumors 3 cm each
— No macrovascular involvement
— No extrahepatic disease
— Child-Pugh B and C
— These patients may be resected if transplantation not feasible
Mazzaferro et al , N Engl J Med 1996;334(11):693-700.

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 Surgery
— Bridge therapy
— Locoregional treatment of HCC as a bridge to liver
transplantation in eligible patients waiting for the procedure.
— radiofrequency ablation (RFA),
— Chemoembolization
— radioembolization

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 Local Regional Therapy
— Aim: selective tumor necrosis,
— categories: ablation or embolization.
— They are not comparable to that of liver resection or
transplantation.
— should not be used in place of resection or transplantation for
eligible patients

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 Local Regional Therapy
— Ablation: inducing direct necrosis
— Chemical : ethanol (PEI), acetic acid
— Physical: radiofrequency ablation [RFA], microwave ablation,
cryoablation
— laparoscopic, percutaneous or open approaches.

— Indications: local disease only completely amenable to ablative

therapy according to the size and location of the tumor(s).
— Major complications 5%, mortality 0%
— Tumor necrosis is assessed by CT/MRI at intervals an no
contrast uptake

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 RFA: Needle and effect

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 PEI vs RFA
HCC <= 4cm
RCT
Complete tumor necrosis was defined as persistent hypoattenuation of the tumor
on helical CT 4 months after the most recent ablation therapy
Lim et al, Gastroenterology. 2004 Dec;127(6):1714-23.

Conventional PEI Higher dose PEI RFA

52 (64 tumors) 53 (56 T) 52 (61T)
Complete necrosis (NS) 88% 92% 96%
Sessions More More Fewer (S)
1,2,3 OS (S) 85%, 61%, 50% 88%, 63%, 55% 90%, 82%, 74%
1,2,3 DFS (S) 61%, 42%, 17% 63%, 45%, 20% 78%, 59%, 37%

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 PEI vs RFA
Cirrhosis, child A/B, 1-3 Tumors, 1.5-3 cm
RCT
Brunello et al, Scand J Gastroenterol. 2008;43(6):727-35.

Conventional PEI RFA

69 70
1-y CR (S) 36% 66%
HR OS (NS) 1 0.88

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 PEI Vs RFA
Cirrhosis, child A/B, 1-3 Tumors, <= 3 cm
RCT
Shiina et al, Gastroenterology. 2005 Jul;129(1):122-30.

Conventional PEI RFA

114 118
Sessions (S) 6.4 2.1
4-y OS (S) 57% 74%
Recurrence/progression (S) higher Lower

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 Resection Vs RFA
Cirrhosis, child A/B, solitary Tumors, <= 5 cm
RCT
Chen et al, Ann Surg. 2006;243:321-328.

Surgery resection RFA

90 71 (19 withdrew consent)
complications () More and severer
1,2,3,4-y OS (NS) 93.3%, 82.3%, 73.4%, 95.8%, 82.1%, 71.4%,
64.0% 67.9%
1,2,3,4-y DFS(NS) 85.9%, 69.3%, 64.1%, 86.6%, 76.8%, 69%,
46.4% 51.6%

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 Ablation limitations
— Dome
— Capsule
— Near major blood vessel or bile duct or abdominal organ

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 Embolization
— Aim: selective catheter-based infusion of particles targeted to the
arterial branch of the hepatic artery feeding the tumor leading to
ischemia. T:HA, NL: PV
— Types:
— bland embolization,
— chemoembolization
— radioembolization)
— Caution:
— arterial anatomy outlined
— embolization is limited to a segment, subsegment, or lobe
— Indications:
— All HCC tumors are embolizable if the arterial supply is isolated.
— Used in unresectable/inoperable tumors not amenable to ablation (>5cm),
alone or followed by ablation

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 A celiac angiogram showing the blood vessels of the
liver with multiple HCC tumors before (left) and after
(right) treatment showing loss of vascularity and
response to therapy.

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 Bland embolization (TAE)
chemoembolization (TACE)
— Particles to block arterial flow. :
— Gelatin sponge,
— polyvinyl alcohol, and
— polyacrylamide microspheres
— Chemotherapeutic agents:
— Doxorubicin and/or Cisplatin
— Containdications to TACE:
— Child C
— Portal v thrombosis
— Bilirubin > 3 mg/ml: liver abscess
— Biliary enteric bypass: liver abscess

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 Bland embolization (TAE)
chemoembolization (TACE)
— Complications:
— acute portal vein thrombosis,
— cholecystitis, and
— bone marrow suppression,
— post-embolization syndrome
— fever,
— abdominal pain,
— and intestinal ileus
— Mortality: <5 %

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 TAE Vs TACE Vs BSC
Unresectable HCC, Child A and B, Okuda I and II
RCT
HR of death for TACE vs BSC =0.47 (S)
Terminated early
TAE Vs TACE ??
Llovet et al, Lancet. 2002;359:1734-1739.
BSC TAE TACE
35 37 40
1,2-y OS (S) 63% and 27% 75% and 50% 82% and 63%*S
RR 34%

PortalV inasion Less

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 TACE Vs BSC
Unresectable HCC,
RCT
TACE q 2-3 months
HR of death for TACE vs BSC =0.49 (S)
Lo et al, Hepatology. 2002;35:1164-1171.

BSC TACE (Cisplatin)

40 40
1,2, 3-y OS (S) 32, 11, 3% 57, 31, 26%
Death from liver failure more

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 Radioembolization
— Agents:
— Microspheres embedded with yttrium-90 (beta radiation
emitter)
— tumor necrosis is more likely to be induced by radiation
rather than ischemia.
— PRR: 42%
— Complications:
— cholecystitis and
— abscess formation.

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 Combinations of local therapies
TAE then RFA
— Aim: focused heat delivery of RFA may be enhanced by vessel
occlusion by TAE
— Use 3-5 cm tumors who are not eligible for liver resection or
transplantation

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 TAE-> RFA Vs resection
Retrospective
1-3 lesions, size ,<= 3 cm, or single tumor ,<= 5cm
Child A, no vascular invasion, no mets,
Yamakado et al, Radiology. 2008;247:260-266

TAE/RFA Resection
104 62
1,2, 5-y OS (NS) 98%, 94%, 75% 97%, 93%, 81%
1,2, 5-y DFS (NS) 92%, 64%, 27% 89%, 69%, 26%

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 TAE-> RFA/PEI Vs resection
Retrospective , single author experience
single tumor ,<= 7cm
Yamakado et al, Radiology. 2008;247:260-266

TAE/RFA/PEI Resection
33 40
1,2, 5-y OS (NS) 97%, 77%, 56% 81%, 70%, 58%

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 Radiotherapy!!
— Conformal or stereotactic
— Focused, thus limiting the risk of radiation-induced liver
damage
— unresectable/inoperable due to performance status or
comorbidity e.g. if PEI, RFA, TACE, TAE is not feasible

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 Systemic therapy

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 Doxorubicin: NO!
Combination: NO!
— Low RR
— No OS advantage
— Yeo et al, J Natl Cancer Inst. 2005;97:1532-1538.
— Unresectable HCC

doxo Cisp-INF-Doxo-FU
PIAF
MOS (NS) 6.8 m 8.7m
RR 10% 20%
Toxicity higher

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 Tamoxifen!!!
— ???

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 Sorafinib (NEXAVAR)

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 Sorafinib mechanism of action
oral multikinase inhibitor which suppresses
tumor cell proliferation and angiogenesis,

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 SHARP trial
— Llovet et al, N Engl J Med. 2008;359:378-390.
— Patient inclusion criteria included
— Histologically proven HCC
— Advanced HCC
— (ECOG PS) 0-2
— ≥1 measurable untreated lesions
— Child-Pugh class A (mild hepatic impairment)
— No prior systemic treatment

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 COST
— One box(m)$ 5000 = 5000 x 5.5 = 27,500 LE
— Duration of therapy
— Until no longer clinically benefiting from therapy
or until unacceptable toxicity occurs
— For OS of 10.7 m:
— 10.7 x 27, 500= 294, 250
— For PFS of 5.5 m
— 5.5 x 27, 500= 151, 250

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 Sharp trial summary
Sorafinib BSC
MOS (S) 10.7 m 7.9 m
TTP (S) 5.5 m 2.8 m
Toxicity Hand-foot
diarrhea
Cost 150-294, 000 LE

Child A >90% *
PS 0-1 >90%*

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 Asia-Pacific Sorafinib trial
Sorafinib BSC
150 76
MOS (S) 6.2 m 4.1 m
MTTP (S) 2.8m 1.4 m

Child A >97% *
PS 0-1 >90%*
Cheng et al., J Clin Oncol 26: 2008 (May 20 suppl; abstr 4509)

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 Take home message
— Risk factors for HCC
— Screen high-risk subjects by US and AFP
— Classic appearance in CT, MRI, tri-US: arterial uptake and
venous washout
— Liver function assessment and reserve
— Patient, liver, tumor
— Surgery: resection and transplant
— Local regional therapy: ablation, emobolization
— Systemic therapy = sorafinib

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