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 tumour staging

• Risk for ‘dropping out’ from the list because of cancer progressionJF

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– Less than 5 cms– No vascular invasion

Contraindication:•Distant metastasis•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– 3 cm (X3) UCSF

•6.5 cms•4.5 cm (X3)

Upto 7Largest tumour

plus number equals 7

No vascular invasion 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 DiseasesBruix J et al Hepatology 2005;42:1208-36

AFP• Inadequate marker

- 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) Cirrhosis (Hep C, Alcohol)

Early recurrence (1 yr)Extrahepatic recurrenceWorse prognosis

Later recurrenceConfined 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

Not very conclusive

Host factors– Hepatitis C

• Higher incidence of multicentric recurrence

– Chronic active hepatitis

Surgical factorsMargin of resection: 1 cmExtent of resection (anatomic vs nonanatomic)Perioperative blood transfusion ?Manipulation of tumour ?

Management:Difficult decision!• Too many variables

– 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

• Surgical

excision

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) 50%- Disease-free survival 16 % to 27.4 %- Recurrence rate 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 FactorsAfter Surgical Resection

• Co-existing liver diseaseInflammation activity [15]ALT, GGTviral load, serum HBeAgGenotype C HBV [16]Liver functional reserve [17]

• Pathological features of tumorpTNM stage[18-21]Size, number, capsule, differentiationVenous invasion; Intrahepatic metastasis (IM)Inflammatory cell infiltration (favorable factor)

• Tumor-associated antigens and detection of circulating cancer cellsSerum AFP level (protein, mRNA) [22-25]; AFP-L3)Serum MAGE [26], hTERT [27] mRNA ;

• Invasion and metastasis-related markersOsteopontin (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 profilingGenomic aberrations

16q [41]; 8p [42, 43]Changed restriction landmark genomic scanning (RLGS) spots [45]

Gene expression profiling90 genes associated with intrahepatic metastasis [46]153 genes predicting signature for metastases and outcome [29].12 genes predictive system [47]

Proteomics analysisCK19 [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 Therapy• Sorafenib

- 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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