Hepatocellular Carcinoma

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Hepatocellular Carcinoma

• Bilal Hameed
• 4/21/09

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What is Cancer?

• All cancers begin in cells, the bodys basic unit
  of life
• Cells make up tissues and tissues make up the
  organs of the body
• The uncontrolled, abnormal growth of cells
• Cancer may spread to other parts of the body

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What is the Liver?

• Makes chemicals that your body needs to stay
  healthy
• Removes waste products and other harmful
  substances from your blood
• Guards against infection

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The Liver is a Factory

• Builds and converts proteins and sugars
• Stores vitamins, sugars, fats and other nutrients
  
• Releases chemicals and nutrients into the body
  when needed

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What is the Function of the Liver?

• Largest internal organ in the body
• Two main parts a right lobe and a smaller left
  lobe
• Vital to the digestion of food
• Collects and filters blood from the intestine
• Produces important proteins and some of the
  bodys blood clotting factors
• Removes toxic wastes from the body
• Helps maintain proper sugar level in the body

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What Are Liver Enzymes?

• Chemicals that your liver uses to do its work
• Healthy liver
• the level of enzymes in your blood is normal
• Unhealthy liver
• the level of enzymes can be higher than normal

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Cirrhosis

• Pronounced sir-o-sis
• Means scarring of the liver
• At risk for liver failure and liver cancer
• Requires close medical follow-up

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What is Liver Cancer?

• An estimated 21,370 people diagnosed in the
  United States in 2008
• Fifth most frequent cause of cancer-related death
  among men
• A disease in which normal liver cells grow
  uncontrollably and form a tumor or tentacle-like
  growth
• Primary liver cancer is cancer that begins in the
  liver

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Hepatocellular Carcinoma Epidemiology Worldwide

• HCC accounts for 85 of primary liver cancers
• 5th most common cancer in men and 8th most common
  in women
• HCC results in 250,000 to one million deaths
  per annum and is the 3rd leading cause of cancer
  related deaths
• gt 600,000 cases diagnosed yearly

Leong TY-M, et al. HPB (Oxford). 200575-15.
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The Rising Incidence of Hepatocellular Carcinoma
in the United States
SEER Database Confirmed Histologic Cases
El-Serag NEJM 1999, 2004 update.
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The HCC Increase in the USA has Affected all
Ethnic Groups
Number of cases
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What Are Factors that Increase the Risk for
Hepatocellular Carcinoma?

• Chronic viral hepatitis (two common types are
  hepatitis B and hepatitis C)
• Cirrhosis of the liver
• Age
• Gender
• Chemical exposure (less common in the United
  States)
• Eating foods contaminated with the mold aflatoxin
  (less common in the United States)

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Risk factors
HCC develops mostly in pre-existing liver
cirrhosis, HCC is associated with chronic liver
disease. (e.g. perinatal HBV Infection) HCC-
rise in pre-existing liver cirrhosis 3/year-
USA 7/year - Japan
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What Happens to People With Hepatitis C Virus?
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Diagnosis unspecific symptoms

• Tumor specific symptoms (pain, fever, loss of
  weight, reduced liver function) occur late in
  advanced HCC

unspecific symptoms of advanced liver disease
fatigue Reduced activity sickness flatulence pain
Loss of weight vomiting pruritus splenomegaly
Spider naevi petechiae ascites icterus Portal
hypertension gt Bleeding of varices Hepatic
encephalopathy etc....
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Hepatocellular Carcinoma Prevention and Early
Detection

• Vaccination for hepatitis B
• Avoid intravenous (IV) drug use (commonly
  associated with the transmission of hepatitis C)
• Avoid alcohol abuse (increases the risk of
  cirrhosis)
• Certain medications may control hepatitis B or C
  infection, decreasing the risk of HCC
• People with cirrhosis of the liver or chronic
  viral hepatitis may need to be screened for liver
  cancer

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How is Hepatocellular Carcinoma Diagnosed?

• Diagnosis is often confirmed with a biopsy
• Diagnosis can sometimes be confirmed with blood
  or imaging tests
• Physical examination
• Blood test for alpha-fetoprotein (AFP) 50-70
  of people with primary liver cancer have elevated
  levels
• Ultrasound of the abdomen
• Computed tomography (CT or CAT) scan
• Magnetic resonance imaging (MRI)

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AASLD Practice Guidelines on Screening for
Hepatocellular Carcinoma
Hepatitis B carriers Asian males gt40 years, Asian
females gt 50 years All cirrhotic hepatitis B
carriers Family history of HCC Africans over age
20 Patients with high Hepatitis B viral load or
ongoing inflammatory activity Non-hepatitis B
cirrhosis Hepatitis C Genetic hemochromatosis Prim
ary biliary cirrhosis Alpha1-antitrypsin
deficiency Non-alcoholic steatohepatitis Autoimmun
e hepatitis
Bruix J and Sherman M. Hepatology 42 (5)
1208-1236, Nov 2005.
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Ultrasound

• Ultrasound uses sound waves that cannot be heard
  by humans
• Sound waves produce pattern of echoes as they
  bounce off internal organs
• These create a picture of the liver and other
  organs in the abdomen
• Completely painless and takes 15-20 mins

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Ultrasound
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Computed Tomography CT scan

• An xray machine linked to a computer takes a
  series of pictures of the liver ( 3 dimensional
  pictures)
• Patients receive an injection of special dye so
  the liver shows up clearly in the pictures
• Painless and takes abt 30mins

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MRI

• A powerful magnet linked to a computer is used to
  make detailed pictures of area inside the body
• During the scan you will be asked to lie very
  still inside a metal cylinder
• Painless but can take upto an hour
• Let the doctor if you have claustrophobia

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Liver Biopsy

• Only way to be sure of the diagnosis is to take
  some cells or tissue and look under the
  microscope ( called biopsy)
• Fine needle is passed under the skin ( using US
  or CT scan)

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Screening guidelines

• AFP and US every 6 months
• AFP elevated (gt200 ng/ml), no TU gt further
  imaging (CT, MRI)
• TU lt 1 cm, AFP normal gt control in 3 months
• TU 1-2 cm, AFP normal gt histology, control in 3
  months
• AFP not elevated , TU gt 2cm gt hypervascularizatio
  n in 2 imaging techniques
• AFP elevated, TU gt2 cm gt hypervascularization in
  single imaging procedure
• diagnosis

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Treatment

• Choice of treatment depends on
• Condition of the liver
• Number of tumors
• Size of tumor
• Location of tumor
• Whether cancer had spread outside the liver
• Age, kidney function etc..

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HCC Treatment Options
Curative
Non-Curative

• Trans-Arterial Chemo-Embolization (TACE)
• Sorafenib

• Transplantation
• Surgical Resection
• Ablative Therapy
• RadioFrequency Ablation (RFA)
• Cryoablation
• Percutaneous ETOH ablation

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• MELD score
• INR
• Bilirubin
• Creatinine

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Percutaneous Ablation
Radiofrequency (RFA)

• Radiofrequency thermal energy applied to the
  tumor causes local temp to exceed 60 degrees C
• For patients who do not meet resection criteria
  and are Child-Pugh A or B
• Best for tumors less than 4cm
• KM estimates of 3-and 5-year survival 78 and
  54

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Chemoembolization
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• Thank you

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• Questions or comments

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Transarterial Chemoembolization in HCC

• Median tumor size 5 - 7 cm
• Improves 2 yr survival from 20 to 60

Llovet JM, et al. Hepatology. 2003 Feb37429
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Why its difficult to treat HCC by systemic
therapy?

• Liver cancers typically retain active
  drug-metabolizing systems that contribute to an
  intrinsic resistance to chemotherapy drugs
• Liver cancers also have enhanced expression of
  transporters of the multidrug resistance protein
  family
• Many drugs have intrinsic hepatotoxicity that may
  exacerbate the underlying liver disease
• Leukopenia and thrombocytopenia that are caused
  by splenic sequestration from portal hypertension
  compromise therapy with agents that induce bone
  marrow suppression

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New Frontier!!Targeted Therapies

• Attack pathways that are critical for cancer
  survival and progression and minimize off-target
  toxicity
• Molecular pathogenesis of HCC have demonstrated
  the critical importance of activation of growth
  signaling pathways, including multiple receptor
  tyrosine kinase pathways
• The highly vascular nature of HCC reflects
  profound activation of angiogenic signaling
  pathways, many of which are activated through
  receptor tyrosine kinases
• These targeted agents do not induce the tumor
  involution and radiologic remission typical of
  the cytotoxic chemotherapies but rather result in
  disease stabilization and prolongation of
  survival, a new paradigm in cancer therapeutics

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Molecular Pathogenesis for HCC
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Sorafenib Targets Both Tumor Cell and Vascular
Compartments
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Sorafenib A Unique Multiple Kinase Inhibitor for
HCC
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The SHARP Trial

• (Sorafenib HCC Assesment Randomized Protocol)

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SHARP TRIAL Study Design

• Primary End Point
• Overall survival (randomization until date of
  death)
• Time to symptomatic progression (quality of life
  assesment)
• Secondary End point
• Time to radiological progression (RECIST
  criteria), safety and disease-control rate

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Symptomatic Progression

• Defined as either a decrease of 4 or more points
  from the baseline score on patients' responses to
  the FHSI8 questionnaire
• A change that was confirmed 3 weeks later
• A deterioration in ECOG performance status to 4,
  or death

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Disease Control Rate

• Defined as the percentage of patients who had
  a best-response rating of complete response,
  partial response, or stable disease (according to
  RECIST) that was maintained for at least 28 days
  after the first demonstration of that rating on
  the basis of independent radiologic review

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Study Design
121 centers in 21 countries
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Study Design

• Some inclusion labs
• - Plts gt60
• - Hgb gt 8.5
• - INR lt2.3
• - ALT/AST lt 5 UNL
• - Creatinine lt1.5
• Tumor measurements were done at screening, every
  6 weeks and at the end of treatment by CT or MRI
• Patients visited clinic every 3 weeks and at end
  of treatment
• Compliance was assessed on the basis of pill
  counts and diary entries

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Baseline Characteristics
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Baseline Characteristics
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Baseline Characteristics
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Statistical Analysis

• The primary outcomes were assessed according to
  the intention-to-treat principle
• Two formal interim analyses after approximately
  170 and 300 deaths had occurred and one final
  analysis were planned for the survival outcome

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Statistical Analysis

• Assuming median overall survival of 7 months in
  the placebo group, it was estimated that 424
  deaths in the two groups combined, the study
  would have a power of 90 to detect a 40
  increase in overall survival in the sorafenib
  group
• On the basis of these calculations, authors
  estimated that approximately 560 patients needed
  to be enrolled

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Overall Survival ITT
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Overall Survival ITT

• Cox proportional-hazards model identified eight
  characteristics that were prognostic indicators
  for overall survival
• ECOG performance status, presence or absence of
  macroscopic vascular invasion, extent of tumor
  burden ChildPugh status, and baseline AFP,
  albumin, AP and total bilirubin
• After adjustment for these prognostic factors,
  the effect of sorafenib on overall survival
  remained significant (hazard ratio, 0.73 95 CI,
  0.58 to 0.92 P0.004)

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Time to Radiological Progression
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Size Does Not Matter!!

• Only 3 achieved a partial response and 71 had
  stable disease
• We rarely see significant tumour shrinkage as
  defined by RECIST criteria
• This makes it difficult to define not only a
  positive response but also a negative one
• In clinical praxis this is an argument in favor
  of not stopping therapy of HCC with sorafenib too
  early

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Targeted Therapies

• Improvement in survival occurred despite a
  surprisingly limited partial response rate of 2
• Survival was extended because the drug was able
  to retard tumor progression
• This represents an important first step in the
  application of targeted therapies for
  hepatocellular carcinoma

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Overall Survival of Selected Subgroups. According
to Baseline Prognostic Factors
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Subset Analysis Tumor Burden
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Adverse Reactions

• Hypertension was noted in 9 in sorafenib group
  as compared to 4 in placebo group
• Hemmorhage/bleeding was noticed in 18 in
  sorafenib patients vs 20 in placebo treated
  patients
• - Bleeding from esophageal varices was
  seen in 2.4 in sorafenib group and
  4 in placebo group
• Rate of adverse reactions resulting in permanent
  discontinuation was similar in both sorafenib
  and placebo groups, 32 and 35 respectively
• INR elevation were observed in 42 in sorafenib
  group and 34 in placebo treated patients

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Evidence Based Medicine

• Randomization
• Concealed allocation
• Follow up
• Intention to treat analysis
• Equal Co-intervention
• Blinding
• Compliance
• Primary outcomes well defined

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Limitations

• Child A only
• ? Blinding
• Cost of the drug
• Side effects ( long follow up needed)
• Less response in increase tumor burden
• Conflict of interest ( drug sponsored)

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SHARP Summary

• Sorafenib prolonged overall survival
• - Median 10.7 months versus 7.9 months
• - Hazard ratio 0.69 P 0.00058
• - ABI 2.8 months increase in overall
  survival
• - RBI 44 increase in overall survival
• Sorafenib prolonged time to progression
• - Median 5.6 months versus 2.8 months
• - Hazard ratio 0.58 P0.000007
• - ABI 2.8 months prolongation in time to
  progression
• - RBI 73 prolongation in time to
  progression
• Well tolerated with manageable side effects

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How to React?

• Nihilism
• Tested in incurable HCC
• Only 3 months
• Over excitement
• Use in everyone with HCC
• Cautious optimism
• Use it for current indication
• Great for HCC field (screening, risk factors)

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Cost and Affordability

• The pharmacy price of sorafenib is approximately
  5,400 per month in the United States, 3,562
  per month in France, 1,400 per month in Korea,
  and 7,300 per month in China

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Molecular Targeted Therapy Clinical Trials in HCC
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Sorafenib in Practice Who should use it?

• Knows how to diagnose HCC
• Knows potentially curative and palliative therapy
• Should not substitue OLT,resection,RFAor TACE
• Knows liver disease
• Knows indication of sorafenib (stick by current
  data)
• Knows side effects
• Knows end of life issues (hospice, pain control)
• Hepatologist,Oncologist, or best BOTH on the same
  team

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• Sorafenib in advanced hepatocellular carcinoma
• We have won a battle not the war