Transcript Presentation Title

Multidisciplinary approach
to HCC
Moderator – Dr Sunil K Mathai
Panelists
Dr Sudhindran
Dr Sreekumar
Dr Prakash Zacharia
Dr Jose Francis
Case -1
• 45 year male who is known case of HBV related Cirrhosis on entacavir is
found to have a 4cm lesion in right lobe seument 6.
• How would you further evaluate this lesion- Dr PZ
4 cm lesion in HBV related
Cirrhotic liver
• Further Imaging
• 4Phase MDCT / MRI
 Diagnosis - Typical Characters of HCC
 Multifocal or not
 Vascular involvement
 Nodes
• Status of Liver & virus
• General Condition of patient
• Imaging modalities in HCC – Dr SM
– CT/MRI in HCC
– Kupffer specific imaging
Imaging in HCC
• Contrast Enhanced 4 phase MDCT
• Contrast MRI
• Contrast USG
• Would you biopsy the lesion– Dr Jose
• Indications for biopsy in suspected HCC
Would you biopsy the
lesion?
No
JF
Why?
• If curative therapeutic attempts are planned,
including surgery
- Biopsy is often contraindicated
Stigliano R et al Cancer Treat, Rev.2007; 33:437-447
• Avoid the risk of seeding (2.7%)
Perkins JD et al L. Hepatol. 1999;30: 472-478
JF
Why?
• Likelihood of HCC is > 90%
- If AFP is > 200 ng/ml
- Setting of a mass in a cirrhotic liver
Torzilli G et al Hepatology1999;30: 889-893
JF
Why?
• Diagnosis confidently established
- Presence of typical imaging features
• Four-phase multidetector CT (the four phases)
- Unenhanced,
- Arterial, hyperattenuating
- Venous, and hypoattenuating (washout)
- Delayed
• Dynamic contrast-enhanced MRI
JF
Algorithm
JF
Case continued ….
• Investigation were s/o HCC
• How will you stage the lesion – Dr PZ
Overview of staging systems
Investigations
• Liver lesion - assessment
• Child Status
• Portal Hypertension
• Platelet count (<1lakh) with splenomegaly
• OGD for varices, If no varices -?HVPG
• Evidence of dissemination
• Assessment of patient
• Other medical conditions
• Performance Status
BCLC Staging
• How will you assess the functional liver reserve – Dr Jose
– Scoring systems ( MELD,CTP ) versus
Role of HVPG
Role of ICG
Hepatic functional reserve
• Related to
- Quantity
- Quality of liver cells
• Assessment of remaining liver prior to hepatectomy
JF
Assess functional liver
reserve
•
•
•
•
MELD score
ICG Clearance
CT measurement of liver volume
Others
- HVPG
JF
MELD and HCC
• Increase priority of patients for Tx with HCC
- Assigned a higher score based on
staging
tumour
• Risk for ‘dropping out’ from the list because of cancer progression
JF
MELD and HCC
• T2 lesion
- 15% risk, score of 22
• 10% mortality bonus every 3 months
- Until they are Tx or
- No longer suitable for Tx
JF
Role of ICG
• Qin-Song Sheng,
• Hepatobiliary Pancreat Dis Int，Vol 8，No 1 • February 15，2009
• ICG-R15 (N= 3.5% to 10.6% )
• >14% precludes major liver resection
Role of HVPG
• MELD scores has been correlated with manifestations of liver
disease such as hepatic venous pressure gradiennts
•
Ripoll C et al Hepatology 2005;42(4);793-801
• Portal hypertension
- Independent factor in post-resection outcome
- Patients with Child–Pugh class A cirrhosis
and minimal portal hypertension
- Platelet count >100,000/mm3 and/or
- HVPG <10 mmHg)
- Are optimum resection candidates
JF
CT Measurement of the liver
volume
• The percentage of RLV (PRLV) was calculated using the
following formula:
• PRLV=RLV/predicted total liver volume ×100%
• RLV = Total liver tumor - (tumor volume + peri-tumor
volume)
• The predicted total liver volume (mL) = 121.75 + 16.49 ×
body mass (kg)
JF
Case continued….
• 4cm HCC. Child A CTP- 6/15 MELD- 8. No PV thrombus.
• What treatment would you advise here here – Dr
Sudhi
• Resection v/s Transplant
–
–
–
–
–
Indications for resection
Indications of transplant.
Expanding indications for resection
Expanding indications for transplant
Cytoreductive and salvage surgery
Treatment of HCC
• Main issues
– Survival
– Recurrence
HCC- resection
• Mainstay of treatment
– No Level I evidence
– Compelling data from cohort studies
• Ideal candidates
– Single nodule
Contraindication:
– Less than 5 cms
• Distant metastasis
– No vascular invasion
• Main portal vein thrombus
• IVC thrombus
Results
• 5 yr survival 35 to 70%
• Recurrence: 50 to 80%
Transplantation
• Theoretically the “best”:
– Widest possible resection margin
– Removes remnant liver at risk of cancer
– Restores liver function
• Advanced tumours
– High risk of recurrence
• Milan criteria
– 5 cm
UCSF
– 3 cm (X3)
• 6.5 cms
• 4.5 cm (X3)
No vascular invasion
Upto 7
Largest tumour
plus number
equals 7
AFP
Results of transplantation
• 5 year survival 60 to
75%
• 5 year recurrence
rate 30 to 40%
• No trial between resection and Tx
• If donor (LDLT or DDLT) available, Tx
• Suppose you plan for transplant. Would you advise a LDLT ? Dr PZ
– Ethics of LDLT in HCC patients
LDLT advantage
• LDLT – No or minimal waiting period
Issues
•
•
•
•
Hep B
Risk to the donor
Adverse tumor factors
Pressure to Expand the criteria (?)
• Would you consider RFA/TACE/TARE here. Dr SM
• Indications and clinical outcome of RFA
• Indications and clinical outcome of TACE/TARE
• RFA versus resection/Transplant
• RFA versus TACE/TARE
• 4cm HCC,Child A
• – RFA or TACE with RFA
Ablative therapy
• RFA/PEI
•
• Visiblity on USG or plain CT
• If visible, relationship with adjacent viscera and vessels
Ablative therapy indications
• Child Pugh A or B
• Single </= 3cm or 5cm
• Multiple nodules </= 3 in number each </= 3cm
Ablative therapy
• PEI and RFA complete response in 80% <3 cm
• complete response in 50% 3-5cm
• 40-70% 5 yr survival which is little less than resection
TACE
•
•
•
•
Care for Intermediate stage
Child A or B
Single ≥ 5cm and ≤ 8 cm
Multiple more than 3
• LESIONS WHICH ARE IDEAL FOR ABLATION BUT WITH POOR VISBILTY ON
USG /CT
TACE
• Contra indications
– Portal vein thrombosis
– Portal flow reversal
– Child C cirrhosis
TACE
• Partial response in 15-55%
• Significantly delays tumour progression
• Llovet etal*-Meta analysis
– 2yr survival in treated group 41% vs 27% in control group
– Llovet JM, Bruix J. Systematic review of randomized trials for
unresectable hepatocellular carcinoma: hemoembolization
improves survival. Hepatology 2003;37:429–42
TACE
• Doxorubicin.Mitomycin C,cisplatin
• Conventional TACE with lipiodol
• TACE with DEB(DC Beads)
TACE with lipiodol
• Efficacy of lipiodol not proven
• Lipiodol masks vascularity in follow up CT
•
• MRI is better than CT for follow up after TACE with lipiodol
TACE with DEB
• PVA particles with sulphonyl urea groups with ionically bound Doxo
molecules
• High tumour concentration and lower systemic concentration
• Less cardiac toxicity and less liver toxicity
• Our preference
• Expensive
TARE
•
•
•
•
•
•
•
•
Indications similar to TACE
Glass spheres(Thera spheres)
Resin spheres(SIR spheres)
No RCT
Only phase 2 clinical trials –encouraging results
Median survival from 9.4 months to 24 months
No increased risk from PVT
Very expensive
Combination
therapies
• TACE +RFA
– Increase tumour ablation volume
– Improves tumour free survival but does not improves overall survival
• Sorafenib +RFA/TACE/TARE
Case continued
• Planned for resection
• Role of PV embolization +/- TACE – Dr Sudhee
Role of portal vein
embolisation
• To increase the size of remnant liver
– To enable resection
• For very large tumours
• ? Feasibility in cirrhotics
– For want of nothing better to do
• Role of neoadjuvant therapy – Dr Jose
Neoadjuvant therapy before
resection
• To facilitate the surgical procedure
- By decreasing tumor vascularity
- Use agents to inhibit angiogenesis
- Downstaging the tumour
Preoperative TACE
• Controversial
• Preventing tumor recurrence & prolonging survival not proven
Problems faced:
• Perihepatic adhesions, liver resection more difficult
• Risk of liver failure
• Delay in definitive surgery
• Difficulty in future TACE for recurrent HCC
- Development of collateral vessels
• Tumour emboli during hepatic resection
• Two RCTs on TACE no impact on disease-free and overall survival
• Role of Laparoscopic liver resection – Dr Sudhee
Laparoscopic resection
• Ideal
– Smaller tumours
– Peripherally placed (eg left lateral segment)
• No randomised trials
• Probable decreased morbidity
Case continued
• Patient under goes resection. Post op Uneventful
• Role of Adjuvant therapy here. – Dr PZ
Adjuvant therapy
• Pre or post resection adjuvant therapy has no role at present
• Continue antiviral therapy
• How will you follow up post OP – Dr Jose
• Will you list him for elective transplant or wait for recurrence
Best option
Transplant
Why transplant?
• Offers
- Curative
- Improved survival
- Cost savings
- Minimised risk of recurrence
- Prevent complications of cirrhosis
• Resection and lesion ablation not addressed the above
issues
Surveillance
• Is a must
• A curative intervention
- Reducing morbidity & mortality
Alpha Feto protein / USG
• Cut off level of 20 ng/ml
- Sensitivities 41 to 60%
- Specificities 80 to 94%
- Frequency of 6 months
• Ultrasonography
- Sensitivity of 65%
- Specificity > 90% for early detection
- Every 6 months
Practice guidelines American Association for the Study of Liver Diseases
Bruix J et al Hepatology 2005;42:1208-36
• Inadequate marker
AFP
- High false-positive rate in active hepatitis
AFP begins to rise - vascular invasion
• Insensitive for detection
- Early lesions at a curable stage
• The AASLD guidelines eliminated - screening test
-
CT / MRI as surveillance
• Not generally recommended
• Associated
- High cost
- Harm
- Radiation
- Allergic reaction to contrast medium
- Nephrotoxicity with CT
- Nephrogenic fibrosing dermopathy
- Use of gadolinium renal failure
Follow up post OP
• HCC recurs
- 70% of patients within 5 years
- Most occurrences after 2 years
• Chang CH et al Arch Surg 2004,139:320-5
• Poon RT et al Ann of Surg2002,235:373-82
• Kumada T et al Hepatology 1997;25:87-92
Follow up post OP
• Assess risk factors for recurrence
• Before going for any modality of treatment
High risk groups for HCC
• Hepatitis B carriers
- Asian men >40 years
- Presence of cirrhosis
• Annual incidence rate of HCC
- HBV cirrhosis 2.2 to 4.3%
* FattovichG. Et al Gastroenterology 2004;127:S35-50
• Other factors
- F/H of HCC
- Viral Genotype
- Dual infections
- Alcohol/ smoking
- Tumour histology
•
Chemoprevention after
resection
Retinoid derivatives - vitamin A (retinol)
* Polyprenoic acid is a synthetic acyclic retinoid
- Inhibits experimental carcinogenesis
- Induces apoptosis in human HCC cell lines
• Menatetrenone, a Vit. K2 analogue
- Suppressive effect on recurrence
Interferon
- Direct antiviral effect
- Immunomodulatory effect
- Direct and indirect antiproliferative effects
• Benefits:
- Delayed recurrence
- Decreased severity of recurrence
- Secondary local ablative/resection possible
TARE
• Role in micrometastasis
Case continued
• 2 years later patient comes with recurrence. He is in CHILD B Cirrhosis. CTP
9/15.
• How would you proceed now – Dr Sudhee
Management of recurrence
Types of recurrence
(theoretical)
• Metastasis from original
tumour
– Vascular invasion to
portal vein

Multicentric
carcinogenesis (new
tumour)

Early recurrence (1 yr)
Extrahepatic recurrence
Worse prognosis
Cirrhosis (Hep C, Alcohol)
Later recurrence
Confined to liver
??Better prognosis
Cannot distinguish clinically or radiologically
Risk factors for recurrence
• Tumour factors:
– Vascular invasion
• Satellite nodules, size and AFP are surrogate clinical markers
– Presence of capsule
– Tumour differentiation
Host factors
– Hepatitis C
• Higher incidence of
multicentric recurrence
– Chronic active hepatitis
Not very conclusive
Surgical factors




Margin of resection: 1 cm
Extent of resection (anatomic vs
nonanatomic)
Perioperative blood transfusion ?
Manipulation of tumour ?
•
Management:Difficult
Too many variablesdecision!
– Status of liver?
• Cirrhotic or not
– Primary treatment?
• Tx, Resection or Local ablative treatment
– Time of recurrence
• Less than 1 year or not
– Tumour characterestics
• Multicentric or not
• Site and size
A-la- carte
Options available
•
•
•
•
•
Transplantation
Repeat hepatectomy
Radio Frequency Ablation (RFA)
Trans Arterial Chemo Embolisation (TACE)
Palliative Chemotherapy
First option in HCC
Best surgical excision - Transplantation
Case Continued …..
• Planned for transplant. Placed on waiting list
• Bridge to transplant. –
Dr SK
Bridge to transplant
• RFA/TACE/TARE
Case continued …..
• On waiting list 6 months later found to have portal vein thrombosis.
• Imaging for PV thrombus … Dr SM
Imaging for portal vein
thrombosis
• Screening USG
• CT
• MR
• Serologic markers indicative of PVT – Dr PZ
Markers for PV Thrombosis
• Des Gamma Carboxy Prothrombin (Prothrombin induced by vitamin K
absence)
• AFP ( ?higher levels)
Case Continued….
• Recurrence of HCC. PVT Child B
• What are the options now. Dr Jose
The BCLC staging system for HCC
Should we consider !
• Young patient
• Child’s B status
• Questions to be answered:- How much of PV is thrombosed?
• Can we offer something?
•
After curative resection of
HCC
The 5-year
- Overall survival (OS)
- Disease-free survival
- Recurrence rate
•
•
•
•
50%
16 % to 27.4 %
38 % to 61.5 %
Ercolani G, Ann Surg 2003; 237:536-43.
Takayama T, Lancet 2000;356:802-7
Tang ZY, J Cancer Res Clin Oncol 2004;130:187-96.
Poon RT, Liver Transpl 2004;10:S39-45
Portal vein Thrombosis
• Not an absolute contraindication
• Relative contraindication
• Poor prognostic indicator for postop. graft dysfunction
• Superior mesenteric vein - survival rate after Tx
• ? thrombectomy
Summary of Risk Factors
After Surgical Resection
•
•
•
Co-existing liver disease
Inflammation activity [15]
ALT, GGT
viral load, serum HBeAg
Genotype C HBV [16]
Liver functional reserve [17]
Pathological features of tumor
pTNM stage[18-21]
Size, number, capsule, differentiation
Venous invasion; Intrahepatic metastasis (IM)
Inflammatory cell infiltration (favorable factor)
Tumor-associated antigens and detection of circulating cancer cells
Serum AFP level (protein, mRNA) [22-25]; AFP-L3)
Serum MAGE [26], hTERT [27] mRNA ;
•
Invasion and metastasis-related markers
Osteopontin (OPN) (tissue and serum) [28, 29]
Intratumor microvessel density (MVD) level [30-32]
VEGF level (tissue and serum) [33, 34]
p53 gene mutation [36]
Reduced expression of p27 [37], E-cadherin [38]
Overexpressions of Lminin-5[39], MMP-2, MMP-9, MT1-MMP [40]
•
Genomic aberrations and expression profiling
Genomic aberrations
16q [41]; 8p [42, 43]
Changed restriction landmark genomic scanning (RLGS) spots [45]
Gene expression profiling
90 genes associated with intrahepatic metastasis [46]
153 genes predicting signature for metastases and outcome [29].
12 genes predictive system [47]
Proteomics analysis
CK19 [48,
• Treatment has evolved in recent years because of :- Better screening
- Improved surgical techniques
- Alternative treatments
• Treatment is multidisciplinary and involves
- Surgeons
- Hepatologist
- Oncologist
- Interventional radiologists
Cytotoxic chemotherapy
• To date, there is no first-line systemic treatment for unresectable HCC
• No impact on patient survival
TACE
• A metaanalysis of RCTs
- Assessing TAE, TACE or both
- As primary palliative treatment
• Improved 2-year survival rate
• Compared with conservative treatment
Yttrium-90 microspheres
• Radioembolization
• Palliative treatment
- For Child–Pugh class A cirrhosis
- Intermediate-stage HCC
Surgery
• Macroscopic vascular invasion
- Strong risk factor for recurrence
• Selected cases
- With normal liver function
- No portal hypertension
- Unilateral intraportal tumor
- Does not occlude the portal bifurcation
• Resection and portal tumor extraction
- Increase survival rate
• Targetted therapies in HCC
•
Targeted Molecular
Sorafenib
Therapy
- Use alone or in combination (e.g. TACE)
• Others
- Brivanib and erlotinib,
• Monoclonal antibodies
- Bevacizumab
- Cetuximab
• Role of Sorafenib in HCC - Dr PZ
Sorafenib
• Multikinase inhibitor
• Used in advanced HCC
Available data
SHARP trial
• 602patients with HCC ( 299 sorafenib & 303 placebo)
• 31% decrease in risk of death
• Median survival 10.7months vs 7.9mths for placebo
• Significant benefit in time to progression 5.5mths vs 2.8
Issues
• Data available for Child A
• High cost
• Side Effects
• Diarrhea
• Hand foot skin reaction
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