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Hepatocellular Carcinoma

Derek Jonker, MD FRCPCMedical Oncologist, The Ottawa Hospital

October 4, 2015

Conflict of Interest Disclosure

Remuneration: none Research support: none beyond direct costs

running trials. Indirect salary support: none

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Case Study

• 52 year old

• 2001 – Hematemesis; esophageal varices– Banding

– U/S liver – fatty liver, cirrhosis

– Hep B/C serology negative

• Dec 2012 – U/S – 5.9cm mass liver

• Jan 2013 – MRI liver– 6cm liver mass “HCC”

– Invasion of tumour into portal vein

• AFP 15,000

No contrast Arterial Venous/Delayed

Case Study

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Case Study

• March 2013 – Biopsy liver – hepatocellular ca

– Started sorafenib 400mg po bid

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AFP

Sorafenib x24 months

Baseline 18 months later

Case Study

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Case Study

• Sorafenib 400mg po bid

– Diarrhea, high blood pressure.  Dose reduction

– Unusually good response (PR), drop AFP

– Long control

• Jan 2015 – two angry skin lesions on leg

– Bx‐ keratoacanthoma

• Rising AFP

• Feb 2015 – stop Rx

Case Questions:

What surveillance should cirrhotic patients have for HCC?

How useful is AFP as a tumour marker? What is required to diagnose HCC?

What scan to order? What is LiRADS? What are the treatment options for

HCC?

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Worldwide variation in HCC

El–Serag, et al. Gastroenterology 132(7):2557-2576, 2007

Worldwide – 750,000 new cases annually5th most common cancer, 3rd leading cancer deathHot spots: sub‐Saharan Africa, East Asia9.2% of all cancersCase fatality ratio 96% in developing countries

• Aflatoxin is produced by the Aspergillus fungus

• Grows on food such as corn, peanuts, pistachios in warm damp conditions 

• Binds to DNA and can cause p53 mutation

• Synergistic with viral hepatitis, 60x risk if HBV infection

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Hepatitis B Virus

Responsible for 55% of HCC worldwide 400 million people infected Transmission

– 90% vertical transmission (maternal/newborn) in endemic areas

– In Canada is mostly sexual or parenteral

Responsible for 85% of HCC in ethnic Chinese

HCC in Canada

Men 3:1 Lifetime probability of developing liver

cancer is 0.8% for men, 0.3% for women

Predominantly age >60 yrs 5-year overall survival 20% (only lung,

esophagus and pancreas are worse)

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El–Serag, et al. Gastroenterology 132(7):2557-2576, 2007

Fastest increasing Incidence2.4% per year for 10 years

Canadian Cancer Statistics 2015. Toronto, ON: Canadian Cancer Society; 2015.

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HCC: Etiology Cirrhosis

– EtOH– HCV 65% of HCC in Canada– HBV

Remaining 35%?– NASH

Rare:– Hereditary hemochromatosis– A-1 anti-trypsin– Autoimmune hepatitis– Porphyria

Hepatitis C 170 million infected worldwide

– Vertical transmission

In Canada – immigrants, iv drug users, transfusion before 1992– 80,000 infected in BC

chronic infection leads to cirrhosis in 25% Interval infection to HCC – 20+ years Curable

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Harvoni®: Ledipasvir + Sofosbuvir

Afdhal et al, NEJM 370(20):1889‐1898, 2014

• Randomized trials

• 12 week treatment, once daily

• 99% sustained virologic response

• Covered in most provinces

– E.g. EAP in Ontario

• $1000 per pill  $84K

Holkira Pak®: Paritaprevir, ombiasvir, dasabuvir, ritonavir

3 pills per day 90-100% cure in genotype 1 Add ribavirin if genotype 1a or or 1b $56,000 for a 12 week course

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“Let me play the fool; With mirth and laughter let old wrinkles come, And let my liver rather heat with wine, than my heart cool with mortifying groans.”

Gratiano, Merchant of Venice

Alcohol: Too much? Cirrhosis: Heavy for prolonged periods

– 50-70 g per day

5% x 341ml x3 = 51g

OR

13.5% x 750ml = 101g

X ½ bottle

• HCC only if cirrhosis, no independent carcinogenic effect• Synergistic effect if concomitant viral hepatits

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Obesity

Calle et al, NEJM 2003

Aside from immigration, the factor most responsible for the rise in HCC in Canada is obesity. Rise in obesity in NA has closely matched the rise in the incidence of HCC.Elevated BMI has a pronounced effect on relative risk of HCC in men.‐ BMI>30 doubles your risk and BMI>35 quadruples the risk.This effect is not seen nearly as much in women

Metabolic Syndrome in Canada, 2009-2011

Statistics Canada [http://www.statcan.gc.ca/pub/82-625-x/2012001/article/11735-eng.h

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ObesityMetabolic Syndrome

Non‐Alcoholic Fatty Liver Disease (NAFLD)

Non‐Alcoholic Steatohepatitis (NASH)

NASH cirrhosis

NASH associated HCC

• Accumulation of fatty acids and glucose in the liver increases TNF‐a, NFK‐b, EGF, leptin

• NASH associated HCC now as frequent as HCV‐HCC

New HCC: Evaluation for etiology

History:– iv drugs? Transfusion before 1992? EtOH?– Prior hepatitis?– Diabetic or metabolic syndrome

Lab:– anti-HCV Ab (prior infection)– HBsAg (ongoing infection), HBsAb (prior

infection/immunity)

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Rare causes: work‐up• Autoimmune hepatitis

– Female > male– Associated autoimmune disorders:

• Celiac, IBD, Graves’, Hashimoto’s, GN, SLE• sclerosing cholangitis, type I DM, RhA, Sjogren’s

– Anti‐smooth muscle Ab, anti‐nuclear Ab  

• Hereditary hemochromatosis– Fasting transferrin saturation 

• Evaluate further if >45% for males, >35% in women

– Ferritin – only specific if >1000ng/mL– Mutations: C282Y and H63D– Other: MRI to measure iron, liver biopsy

• Alpha‐1 antitrypsin deficiency– Lung disease (emphysema) by age 50– Often unrecognized; 1/3000 of European descent; rare in Asians– Genetic test – SERPINA1mutations

Screening in cirrhotics? U/S every 6 months

– Further evaluation of any lesion > 1cm with either triphasic CT or dynamic contrast enhanced MRI

– AASLD guidelines, Canadian Consensus Guideline– Meta-analysis [Aliment Pharmacol Ther. 2009 Jul;30(1):37-47]

Detect HCC at any stage– Pooled sensitivity 94%, specificity 94%

Detect HCC at early stage:– sensitivity 63%– higher sensitivity with U/S every 6 months (70%)

than annual (50%); P = 0.001

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AFP? Combining with U/S for screening does not

improve detection Sensitivity 60% at level of 20ng/mL

– But, 20% of cirrhotics have level >20ng/mL– 90% false positives

Sensitivity 22% at level of 200ng/mL Useful as surrogate for response to treatment if

>200 at baseline.– AFP response better predictor of survival than ORR,

ECOG PS, T-stage, or Childs-Pugh Riaz et al, JCO 2009

Diagnosis: Biopsy vs DI?

Biopsy – 2% risk of tumour seeding– 10% false negative rate

Non-invasive diagnostic standard: Li-RADs– Liver Imaging Reporting and Data System– 5 categories– “Li-RADS5” -100% specific

Forner et al Hepatology 2008» Sensitivity only 33% for lesions <2cm

– LiRAD4 – only 80%(?) HCC follow or biopsy

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Diagnosis of HCC – Li-RADs

By 4-phase CT or Dynamic contrast enhanced MRI Must record arterial and venous phases

Threshold growth def: >100% (>6mos), >50% (<6mos), or newCapsule: noted in portal venous or delayed images

What is Li-RADS5

Must have arterial enhancement Three additional factors:

– Growth– Venous washout– Capsule

Li-RAD5 if– 2cm+ and one of above– 1-2cm and two of above

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A

B

C

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Child‐Pugh Classification

• Score range 5 to 15

• Childs A = 5‐6 (ie maximum one risk)

B = 7‐9

C = 10‐15 (end stage liver disease)

1 point 2 points 3 pointsINR <1.7 1.7-2.3 >2.3

Albumin (g/L) >35 28-35 <28

Bilirubin (mol/L) <34 34-50 >50

Ascites (clinical) Absent Slight or diuretic controlled

Moderate

Encephalopathy None Mild Moderate

HCC Management

Adapted from the Barcelona-clinic liver cancer staging system

FitAge <70

ComorbiditiesAge >70

Liver limited,Childs A/B

Childs-Pugh AN+ or M+Portal v inv

Resect (or RFA) Transplant RFA TACE Sorafenib Palliation

Solitary <2cm, Childs A

1-3 nodules<3cm(Milan Criteria)

Larger or >3 nodules

Childs-Pugh CPS >2

TACETACE

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Milan criteria Score to predict risk of

recurrence of HCC following liver transplant

Criteria:– single tumors ≤5 cm in

diameter or no more than three tumors ≤3 cm in diameter

83% RFS at 26months 75% OS at 4 years

Mazzaferro, NEJM 1996

Priority for Transplant: The MELD score

• Model for End‐Stage Liver Disease (MELD) system 

– Score from 6 (less ill) to 40 (gravely ill)

– determines how urgently patient needs liver transplant within next 3 months

• MELD calculation:– MELD = 3.78×ln[ min(1,Bili/17.2)] + 11.2×ln[min(1,INR)] + 9.57×ln[min(1,Cr/ 88.4)] + 6.43

• MELD and mortality

• Time on wait‐list?– Some transplant prioritization schemes also 

include 3 points for each 3 months 

a patient is on the wait list

• While you wait….– TACE

– More TACE

MELD score 3 month mortality

≥40 71%

30‐39 53%

20‐29 20%

10‐19 6%

<10 1.9%

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RFA (Radiofrequency Ablation) Heat 57oC coagulative necrosis Percutaneous with local (conscious sedation),

outpatient Criteria:

– Unresectable <3cm– No extra-hepatic disease– No vascular inv– No adjacent loops bowel– Childs A-B

Post ablation zone is larger than initial lesion– radiologist needs to know about ablation to interpret scan

Post-ablation– Nausea + pain post-op, resolve in 4 hrs– flu-like symptoms x5d (fever, malaise)– Bleeding 1%, seeding <1%, abscess 1%, diaphragmatic

burn,… Local control 80%

Chemotherapy

Typically low response rates– Doxorubicin 0-15%– Doxo/5FU/Methyl-CCNU 19%– Doxo/bleo 16%– Etoposide 13-18%– Cisplatin 1%

Absence of benefit in randomized trials

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TACE: Arterial Chemoembolization

HCC single blood supply – hepatic artery

Rest of liver protected– Dual supply

Chemotherapy agent– Cisplatin (Not available)– Doxorubicin 60-

75mg/m2 Embolizing agent

– Lipiodol, gelfoam

• 70% Childs A, 30% Childs B• Average 3 sessions of TACE

HR 0.4755 vs 25% 2yOS

Llovet et al, Lancet 2

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TACE: Toxicities

Pain, fever, fatigue acute liver failure, 7.5% (range 0-49%)

– encephalopathy, 1.8% (0-16%)– ascites, 8.3% (0-52%)

acute renal failure, 1.8% (0-13%) upper gastrointestinal bleeding; 3% (0-22%) hepatic or splenic abscess, 1.3% (0-2.5%) treatment-related mortality 2.4% (0-9.5%)

mainly due to acute liver failure.

TACE: Doxo vs Drug Eluting-Beads?

DC-BEADs – bead loaded with doxorubicin– Bead trapped in capillary, slowly

releases doxo– Lower systemic release of chemo

Several small RCTs Less transaminitis, less abd pain No difference survival Cost driving choice of TACE

– Doxorubicin 100mg $420– DCBEADS $3000

Sacco et al, J Vasc Interven Radiol 2011Golferi et al, BJC 2014

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TACE vs TEA?(Transarterial Ethanol Ablation)

Lipiodol-ethanol mixture Ethanol causes arteriole endothelial damage

– Induces embolization

Small comparative trials No difference in survival No concerns for anthracycline systemic

toxicity (eg cardiac history) Very reasonable alternative Probably cheapest

Sorafenib Sorafenib (Nexavar®, Bayer HealthCare) Inhibits RAF, VEGRF, PDGR

Sorafenib 400mg bid Placebo

Advanced HCC, Child-Pugh A, 92% ECOG 0-1

SHARP Trial

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SHARP Trial97% Childs-Pugh AORR 2 vs 1%

mOS 10.7 vs 7.9 monthsHR 0.69, p<0.001

1yOS 44vs 33%

Llovet et al, NEJM 20

Sorafenib toxicity

• Toxicity:– Anorexia (14 vs 3%)

– Weight loss (9 vs 1%)

– Diarrhea (39 vs 11%

– Alopecia (14 vs 2%)

– Dry skin (8 vs 4%)

– Hand‐Foot reaction (21 vs 3%)

– Voice change (6 vs 1%)

– Hypertension (5 vs 2%)

– Abdominal pain (8 vs 3%)

– Rare: keratoacanthoma, SqCellCa

• Management

– Symptomatic (e.g. imodium), dose reduce (eg 400+200200 BID200 QD)

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Sorafenib for Childs-Pugh B?

No RTC evidence N=297 consecutive

patients, A+B Much worse

outcome for CP-B Toxicity no

different

Not fundable PCODR

mOS 10 vs 3.8 months(A vs B)

Sorafenib as an adjuvant?

• STORM trial evaluated post resection/ablation

• Sorafenib vs Placebo to maximum 4 years

• Results:

– No difference in                                                          RFS, OS

– More toxicity                                                           with sorafenib 

Bruix et al, ASCO 2014

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Special considerations

Thrombocytopenia– Some improvement with splenectomy or

splenic embolization. Value? Variceal bleeding

– Non cardio-selective beta-blocker (egpropranolol)

– banding Ascites control

– Diuretics– Pleurx catheter

What’s New? PD-1 cMET

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Nivolumab and Immune Checkpoint Inhibition

• Nivolumab is a fully human IgG4 anti‐PD‐1 monoclonal Ab that blocks interaction between PD‐1 and PD‐L1/PD‐L2, restoring T‐cell immune activity directed against the tumour cell.

Topailian et al, NEJM 2012

PD-1 / PD-L1 in HCC Upregulation of PD-1 and PD-L1 poor prognostic factors Phase I/II study HCC Inclusion:

– HCV, HBV and non-infected– Child-Pugh A+B (no ascites or encephalopathy)– Failed (68%) or refused sorafenib

RD2DL: Nivolumab 10mg/kg q2 weeks ORR 19% (14% PR, CR 5%)

– 75% of these ongoing

El-Koueiry, ASCO 2015

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Nivolumab in HCC

El-Koueiry, ASCO 2015

El-Koueiry, ASCO

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<br />MET as a Prognostic Factor

Presented By Ghassan Abou-Alfa at 2015 ASCO Annual Meeting

Presented By Ghassan Abou-Alfa at 2015 ASCO Annual Meeting

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Phase III Cabozantinib vs Placebo NCT01908426

Presented By Ghassan Abou-Alfa at 2015 ASCO Annual Meeting

High-cMET expressorsubgroup

Trivantinib

Placebo

7.2 vs 3.8 months mOSHR 0.38, p=0.01

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Phase III Tivantinib vs Placebo NCT01755767

Presented By Ghassan Abou-Alfa at 2015 ASCO Annual Meeting

HCC Management

Adapted from the Barcelona-clinic liver cancer staging system

FitAge <70

ComorbiditiesAge >70

Liver limited,Childs A/B

Childs-Pugh AN+ or M+Portal vein inv

Resect (or RFA) Transplant RFA TACE Sorafenib Palliation

Solitary <2cm, Childs A

1-3 nodules<3cm(Milan Criteria)

Larger or >3 nodules

Childs-Pugh CPS >2

TACETACE

Nivolumab, Tivantinib, Cabozantinib

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Questions