update to the management of patients with hcc€¦ · portal invasion, n1, m1, pst 1–2 end stage...
TRANSCRIPT
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UPDATE TO THE MANAGEMENT OF
PATIENTS WITH HCC
HUSSEIN K. MOHAMED MD, FACS.
Transplant and Hepato-biliary Surgery
Largo Medical Center
HCA
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DISCLOSURE
• I have no financial relationship(s) relevant to the
content of this CME activity.
• I will not discuss off-label use of medications.
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OBJECTIVES
• EPIDEMIOLOGY OF HCC
• ETIOLOGY AND PATHOGENISIS OF HCC
• DIAGNOSIS OF HCC
• ROLE OF SCREENING FOR HCC
• DIFFERENT MODALITIES OF TREATMENT
• ROLE OF MULTIDISCIPLINARY APPROACH IN
MANAGING OF PATIENT WITH HCC
• CONCLUSION AND ANSWERING QUESTIONS
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HCC IS A MAJOR HEALTH
PROBLEM
• It is the most common type of liver cancer.
• It is the sixth most common cancer worldwide
and It is the 5th most common malignancy in
men and the 8th in women.
• Hepatocellular carcinoma is now the third
leading cause of cancer-related deaths
worldwide, with over 600,000 death annually.
• It is 2-4 times higher in men than women.
• 80% of patients with HCC have underlying
cirrhosis
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GEOGRAPHIC DISTRIBUTION
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INCIDENCE AND TRENDS
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GLOBAL VARIATION IN HCC INCIDENCE RATE
Venook A P et al. The Oncologist 2010;15:5-13
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EPIDEMIOLOGY
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INCIDENCE IN THE U.S.
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ETIOLOGY & PATHOBIOLOGY
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STAGING OF HCC
Staging of HCC
American Joint Committee on Cancer-TNM System
Stage TNM Scheme
I T1N0M0 Single tumor <2cm
II T2N0M0 >2cm or single tumor <2cm + vascular invasion
IIIA T3N0M0 Single tumor >5cm or >2cm + vascular invasion
IIIB T1-3N1M0 Positive Regional Lymph Node
IVA T4N0-1M0 Multiple tumors involving major vessels/multiple lobes
IVB T1-4N0-1M1 Remote Metastasis
Vauthey et al., J Clin Oncol, 2002.
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DIAGNOSIS
• 1- Clinical presentation
• 2- Radiological testing:
A) US
B) CT
C) MRI
D) ANGIO
D) PET Scan
3- Laboratory
4- Pathology
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SYMPTOMS
• Abdominal pain and/or swelling
• Fatigue/weakness
• Yellowing of the skin and eyes (jaundice)
• Darkened urine
• Nausea/vomiting
• Unexplained weight loss
• Loss of appetite
• Fever
• Feeling very full after a small meal
• Itchy skin
• Enlarged veins under the skin
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DIAGNOSIS
• 1- Clinical presentation
• 2- Radiological testing:
A) US
B) CT
C) MRI
D) ANGIO
D) PET Scan
3- Tumor markers
4- Pathology
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ULTRASOUND
• Advantages:
• High availability
• Low cost
• Non-invasive
• High Specificity
• Vascular invasion can be adequately
evaluated
• Limitations:
• Operator experience
Obese patients
Low sensitivity
Limited differentiation of soft tissue
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ULTRASOUND
Our Patient: Screening Liver Ultrasound Transverse View
A hypoechoic rim is visible around the mass
PACS, BIDMC
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CT SCAN
ADVANTAGES:
1- It is a highly diagnostic test for HCC.
2- Arterial enhancement and venous
washout is highly diagnostic for HCC.
3- A 4-phase study is required for diagnosis.
DISADVANTAGES:
1- Limitation includes false negative imaging
2- Contrast toxicity.
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CT SCAN
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CT SCAN
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CT SCAN
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MRI
• Contrast-enhanced MRI is a highly diagnostic test
for HCC
• Advantages:
High sensitivity (82-96)%
High resolution
It has a better diagnostic capability in fatty liver.
• Limitations:
Expensive
Contrast allergy
Patient Dependent
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MRI
Our Patient: 3 Phase Contrast Enhanced T1 MRI
PACS, BIDMC
Portal Venous PhaseArterial Phase Delayed Phase
Lesion demonstrates enhancement during the arterial phase
and washout during the venous phase
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ANGIOGRAM
• ANGIOGRAPHY:
1- It is both a diagnostic and
therapeutic test.
2- It has been replaced largely by
cross-sectional imaging for
diagnostic purposes.
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IMAGING
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PET SCAN Our Patient: Normal RN Bone Scan
“No evidence of MDP avid osseous metastases.”
PACS, BIDMC
Anterior Posterior
Bone Scintigraphy: Technetium, 99Tcm
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ALPHAFETOPROTEIN
• Alphafetoprotein (AFP):
1- It is insufficiently sensitive or specific
by itself for diagnosis or
surveillance.
2- It is useful in conjunction with
imaging for follow up and for
screening.
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SURVEILLANCE
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HIGH RISK GROUP FOR HCC
• 1- Hepatitis C cirrhosis.
• 2- Hepatitis B cirrhosis.
• 3- African Americans with hepatitis B.
• 4- Hepatitis B carrier with family history of HCC.
• 5- Asian male hepatitis B carriers over age 40.
• 6- Asian female hepatitis B carriers over age 50.
• 7- Stage 4 primary biliary cirrhosis.
• 8- Genetic hemochromatosis and cirrhosis.
• 9- Alpha 1-antitrypsin deficiency and cirrhosis.
• 10- Other cirrhosis.
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DIAGNOSTIC ALGORITHM FOR HCC
From Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology
2005;42:1208–36; with permission.)
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TREATMENT
• 1- Surgical Resection
• 2- Liver Transplantation
• 3- Loco-regional treatment:
- Trans-arterial Chemo-Embolization
- Trans-arterial Radio- Embolization
- Ablation by RFA or Microwave
- Cyberknife
- Cryoablation
- Percutaneous Alcohol Injection
• 6- Chemotherapy
• 7- Combination
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SURGICAL RESECTION
• It is the treatment of choice for HCC in non-
cirrhotic patients.
• It can be offered for cirrhotic patients with
preserved liver function.
• The 5-year survival after resection can exceed
50%.
• Pre or post-resection adjuvant therapy is not
recommended.
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SURGICAL ANATOMY
Anatomy: Couinaud Classification
http://ourworld.compuserve.com/homepages/sbrillant
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SURGICAL ANATOMY
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SURGICAL RESECTION
• The Patient is a surgical candidate
– General condition
– Liver condition.
• The tumor is resectable
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Child-Pugh score
Measure 1 point 2 point 3 point
Total bilirubin <2 2-3 >3
Serum albumin >3.5 2.8-3.5 <2.8
INR <1.7 1.7-2.3 >2.3
Ascites none mild Moderate
to sever
Hepatic encephalopathy none Grade I-II Grade III-
IV
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Interpretation OF Child-Pugh score
Point Class One year
survival
Two year
survival
5-6 A 100% 85%
7-9 B 81% 57%
10-15 C 45% 35%
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Child-Pugh score
Measure 1 point 2 point 3 point
Total bilirubin <2 2-3 >3
Serum albumin >3.5 2.8-3.5 <2.8
INR <1.7 1.7-2.3 >2.3
Ascites none mild Moderate
to sever
Hepatic encephalopathy none Grade I-II Grade III-
IV
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MELD SCORE
• Serum Bilirubin, Creatinine and INR
• 0.957X Log (serum creatinine)
• + 0.378 X Log (serum bilirubin)
• +1.120 X Log ( INR)
• X10
• Round to the nearest whole number
USE OF MELD SCORE:
• Survival of patients with variceal hemorrhage (TIPS)
• General surgery outcome
• Liver transplantation
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MELD SCORE
• MELD score is a reliable index in the preoperative
evaluation of liver function in cirrhotic patients
undergoing partial hepatectomy for hepatocellular
carcinoma (HCC)
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PORTAL HYPERTENTION
• According to international guidelines [European
Association for the Study of the Liver (EASL) and the
American Association for the Study of Liver Diseases
(AASLD)], portal hypertension (PHTN) is considered a
contraindication for liver resection for hepatocellular
carcinoma (HCC), and patients should be referred for
other treatments
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PORTAL HYPERTENTION
• Indeed, the presence of esophageal varices as
determined by endoscopy or significant splenomegaly
(major diameter >12 cm) with a platelet count of <100
000/mm3 are considered surrogate markers of clinically
significant PHTN.
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SURGICAL RESECTION
• The Patient is a surgical candidate
– General condition
– Liver condition.
• The tumor is resectable
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HEPATIC RESECTION
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HEPATIC RESECTION
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HEPATIC RESECTION
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HEPATIC RESECTION
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HEPATIC RESECTION
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HEPATIC RESECTION
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HEPATIC RESECTION
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HEPATIC RESECTION
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HEPATIC RESECTION
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HEPATIC RESECTION
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HEPATIC RESECTION
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Liver Transplantation
• It is an effective treatment for HCC under the
following selection criteria:
1- Within Milan Criteria (solitary HCC <5 cm or
with up to 3 nodules smaller than 3 cm each).
2- No extra-hepatic malignancy.
3- No vascular invasion.
• The 5-year survival of these early stage
patients exceeds 70%.
• Pre-transplant TACE/ablation is recommended
while the patient on the waiting list.
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DOWN STAGING PROTOCOL
• Inclusion Criteria: – One tumor above 5 cm and up to 6.5 cm in size
– Multiple tumors not exceeding total tumor size of 8 cm
– No vascular invasion
– No extra-hepatic spread.
• Down Staging Definition: – Tumor shrink to within Milan Criteria or
– No viable tumor seen on imaging
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DOWN STAGING PROTOCOL
• Listing Criteria:
– Tumor must be within successful down stage
definition.
– Must be maintained within the down stage definition
for at least 3 month.
– The AFP must be either decreasing and maintained
at a level < 400 ng/mi at the time of listing.
– No evidence of extra-hepatic disease.
– Imaging and AFP to be done at 3 month intervals
while on the list.
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CHEMOEMBOLIZATION
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CHEMOEMBOLIZATION
• Beads block the capillaries and chemo leaks out
causing more regional cell death.
• Doxorubicin cell death increases with hypoxia,
embolization cuts off arterial supply and oxygen
and they have a SYNERGISTIC effect.
• 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.
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CHEMOEMBOLIZATION
• Pre embolization, HCC Post embolization, HCC
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RADIOFREQUENCY ABLATION
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HOW IT WORKS
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RADIOFREQUENCY ABLATION
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RADIOFREQUENCY ABLATION
To combat the physical limitations of a single probe several
designs have been constructed.
Leveen RF probe with umbrella shaped array
RITA probe also has umbrella shaped array and allows infusion
of saline through 4 tines
Triangular shaped configuration
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RADIOFREQUENCY ABLATION
• Local ablation is safe and effective therapy for
patients who cannot undergo resection, or as a
bridge to transplantation.
• Patients with HCC lesions < 2 cm subject to
RFA showed a 5-year survival of 70%,
comparable to that of surgical resection in
optimal candidates.
• It is not recommended for subscapsular location
and poor tumor differentiation.
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RADIOFREQUENCY ABLATION
Cons
Grounding pads necessary (which can cause skin
burns)
Destroys tissue planes in heat field
Not recommended for subcapsular lesions or close to
skin
Painful, usually requiring general anesthesia
Very susceptible to heat sink
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MICROWAVE ABLATION
Principles of tissue heating and cell death are
exactly the same as RF
Probes are needle shaped and radiate MW away from the probe
Size of burn is dependent on probe size
Larger burns (6-7 cm) require very large probes… up to 1 cm in diameter
Probe technology is not perfected, early probes made teardrop shaped burns due to deflection from needle and wave-wave interactions
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MICROWAVE ABLATION
When a proper probe is used the burn is very consistent and has very little, maybe no, heat sink effect due to high energy deposition in short amount of time
Shorter burn times
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ADVANTAGES OF MICROWAVE ABLATION
Does not require grounding pads
No gas tanks required (cryo)
Has great potential and will likely replace
RF if probe size can be decreased
eventually… sorry LeVeen
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SORAFENIB
• Sorafenib is recommended by the NCCN for the following patients with unresectable HCC and have Child-Pugh A or B diseasea,b
– Not transplant candidates
– Inoperable by performance status or comorbidity, local disease only
– Metastatic disease
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Sorafenib Targets Tumor Cell
Proliferation and Angiogenesis
RAS
Endothelial Cell or Pericyte
Proliferation
Migration
Angiogenesis:
Tubule formation
PDGF-b
VEGF
VEGFR-2 PDGFR-b
Paracrine
stimulation
Differentiation
Mitochondria
Apoptosis
Tumor Cell
PDGF
VEGF Proliferation
Survival
Mitochondria
HIF
Nucleus
Apoptosis
ERK
RAS
MEK
RAF
Nucleus
ERK
MEK
RAF Mcl-1
Avila MA, et al. Oncogene. 2006;25:3866-3884; Liu L, et al. Cancer Res. 2006;66:11851-11858;
Semela D, et al. J Hepatol. 2004;41:864-880; Wilhelm SM, et al. Cancer Res. 2004;64:7099-7109.
HGF
HGF
Autocrine
loop
Sorafenib
Sorafenib
HGF = hepatocyte growth factor.
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CLINICAL TRIAL
• Data from Llovet JM, et al. N Engl J Med. 2008;359: 378-390
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Sorafenib in HCC – Overall Conclusions
Sorafenib prolonged OS vs. placebo in advanced
HCC1,2,3
- 44% increase in OS in the SHARP trial
- 47% increase in OS in the Asia Pacific Trial
Sorafenib prolonged TTP vs placebo1,2,3
- 73% prolongation in TTP in the SHARP trial
- 74% prolongation in TTP in the Asia Pacific Trial
In both SHARP & AP phase III trials the AEs reported
in patients on Sorafenib were predominantly grade 1
and 2 in severity and gastrointestinal, constitutional,
and dermatologic in nature2,3
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PEI/RFA Sorafenib
Stage 0 PST 0, Child–Pugh A
Very early stage (0)
1 HCC <2cm
Carcinoma in situ
Early stage (A)
1 HCC or 3 nodules
<3cm, PST 0
Advanced stage (C)
Portal invasion,
N1, M1, PST 1–2
End stage (D)
Liver transplantation TACE Resection Symptomatic
treatment Curative treatments Randomised controlled trials
Associated diseases
Yes No
3 nodules ≤3cm
Increased
Normal
1 HCC
Portal pressure/
bilirubin
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698–711.
Stage D PST >2, Child–Pugh C
HCC
Intermediate stage (B)
Multinodular,
PST 0
Stage A–C PST 0–2, Child–Pugh A–B
BCLC Staging System and Treatment Strategy
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KEYS FOR SUCCESSFUL
TREATMENT OF HCC
• Screening and early detection
• Early referral
• Early implication of the the most
appropriate treatment
• Treatment using multidisciplinary
approach
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MULTIDISCIPLINARY APPROACH
CENTER
• Radiology
• Oncology
• Hepatology
• Hepatobiliary surgery
• Coordinator
• Pathology
• Hospitalist
• PCP/GI
• Transplantation surgery
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CONCLUSION
• HCC has become a cancer that can be prevented,
detected at early stage, and effectively treated.
• Patients who are at high risk for developing HCC should
be entered into surveillance programs.
• The BCLC staging system is effective and widely used
both for staging and treatment allocation.
• Even though we are getting better results from TACE,
RFA,MICROWAIVE ablation and PEI, individually or in
combinations. Surgical resection and liver
transplantation remains as the only curative modalities
for treating HCC.
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CONCLUSION
• Sorafenib is recommended as first line option in
patients who can not benefit from resection,
transplantation, ablation or TACE and still have
preserved liver function.
• The best results can be achieved for patients
with HCC when their management carried by a
MULTI-DISCIPLINARY TEAM USING A MULTI-
DISCIPLINARY APPROACH .
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THANK YOU
?
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WAITING TIME ON THE LIVER
TRANSPLANT LIST BY REGION