Robert G. Gish, MD Robert G. Gish Consultants LLC Professor Consultant Stanford University Stanford, California

Increasing Knowledge of Molecular Pathways in Hepatocellular Carcinoma: Implications for Diagnosis, Staging, Treatment,

and Improved Patient Outcomes

PROGRAM OVERVIEW This case-based live activity will cover the diagnosis, treatment and management of patients with liver cancer and liver diseases.

TARGET AUDIENCE

This activity is intended for oncologists, hepatologists, gastroenterologists, and healthcare

professionals who manage patients with liver cancer and liver diseases.

LEARNING OBJECTIVES

Upon completion of the program, attendees should be able to:

Describe evidence-based guidelines for the diagnosis, staging, and management of

HCC, with an emphasis on assessing patient co-morbidities and concurrent medicines,

conducting appropriate laboratory and imaging work-ups, and developing BCLC

algorithm-compliant treatment plans

Identify the key molecular pathways involved in the pathogenesis of HCC, including

the molecular dysregulation attributable to alcoholic liver disease and the metabolic

syndrome

Describe the mechanisms of action underlying the safety and efficacy of current and

emerging targeted treatment options for advanced HCC

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FACULTY

Course Chair

Robert G. Gish, MD Robert G. Gish Consultants LLC Professor Consultant Stanford University Stanford, California Presenter

Robert G. Gish, MD Robert G. Gish Consultants LLC Professor Consultant Stanford University Stanford, California

MLG Course Reviewer

Ronald Simon, MD Adjunct Member Department of Experimental and Molecular Medicine The Scripps Research Institute Head, Division of Allergy, Asthma & Immunology Scripps Clinics La Jolla, California CCM/UMA Lead Nurse Planner Lynnsey Grzybowski, RN, BSN Oncology Nurse Sky Ridge Medical Center Lone Tree, CO

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Course Chair and Presenter - - Dr. Gish has received consultant fees and serves on the

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Increasing Knowledge of Molecular Pathways in Hepatocellular Carcinoma: Implications for Diagnosis, Staging, Treatment, and

Improved Patient Outcomes

Robert G. Gish, MD Robert G. Gish Consultants LLC

Professor Consultant Stanford University Stanford, California

Agenda

I. Introduction

II. The Role of Treatment Guidelines in HCCDoes it Matter Which Guideline We Use?

III. Signaling Pathways, Molecular Targets, and New Targeted Agents Under

Development in HCC

IV. Conclusions

V. Questions and Answers

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Increasing Knowledge of Molecular Pathways in Hepatocellular Carcinoma:

Implications for Diagnosis, Staging, Treatment, and Improved Patient

OutcomesRobert G. Gish, MDRobert G. Gish Consultants LLCProfessor ConsultantStanford UniversityStanford, California

Disclosure of PotentialConflicts of Interest

During the course of this lecture, Dr. Gish may mention the use of medications for both FDA-approved and non-approved indications

Dr Gish has received served on the Speakers Bureau and received consulting fees Bayer Pharmaceuticals Corporation and Onyx Pharmaceuticals, Inc.

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Agenda Introduction The role of treatment guidelines in HCC

does it matter which guideline we use? Signaling pathways, molecular targets, and

new targeted agents under development in HCC

Questions and answers, wrap-up, and evaluation

HCC = Hepatocellular carcinoma.

Learning Objectives

Upon completion of this activity, participants should be better able to:

Describe evidence-based guidelines for the diagnosis, staging, and management of HCC, with an emphasis on assessing patient co-morbidities and concurrent medicines, conducting appropriate laboratory and imaging work-ups, and developing BCLC algorithm-compliant treatment plans

Identify the key molecular pathways involved in the pathogenesis of HCC, including the molecular dysregulation attributable to alcoholic liver disease and the metabolic syndrome

Describe the mechanisms of action underlying the safety and efficacy of current and emerging targeted treatment options for advanced HCC

BCLC = Barcelona Clinic Liver Cancer.

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The Role of Treatment Guidelines in HCC

Does it Matter Which Guideline We Use?

Hepatocellular Carcinoma (HCC) 5th most common cancer in men; 7th in women worldwide 2rd leading cause of death from cancer worldwide Incidence and death rate rising whereas many other cancer

mortality rates are decreasing Worldwide: Primarily due to Hepatitis B, C

In the US due to HCV and non-alcoholic steatohepatitis (NASH) Global HCC: Every 30 seconds, one person in the world dies from

liver cancer. > 80% of HCC cases occur in people from sub-Saharan Africa, S-E

Asia and eastern Mediterranean Recent therapeutic advances and continually updated expert

guidelines have improved the prognosis of HCC from a death sentence to a cancer that can be detected and treated at an early stage for good outcomes

Monsour HP et al. Transl Cancer Res. 2013;2(6):492-506; Venook AP et al. The Oncologist. 2010;15:5-13; Bruix and Sherman. Hepatol. 2011;53:1020-122.

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Age-adjusted HCC Incidence in SEER, 2000-2010

SEER = Surveillance, Epidemiology and End Results cancer registries.

Altekruze SF et al. Am J Gastroenterol. 2014;109:542-553.

Increasing Trends in HCC Incidence in United States, 2000-2010

Men Women

Altekruze SF et al. Am J Gastroenterol. 2014;109:542-553.

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Incidence rates by State, 2006-2010

El-Serag, et al. 2014

Liver Cancer Mortality, US, 20072011

AllNon-Hispanic

White Black API HispanicOverall 1 5.8 5.0 7.6 9.8 8.7

3539 years2 0.5 0.4 0.8 1.2 0.34044 years2 1.1 0.8 1.7 2.4 1.24549 years2 3.2 2.6 4.3 5.8 3.95054 years2 8.3 7.1 12.2 9.7 10.05559 years2 14.4 11.8 25.8 17.3 18.26064 years2 15.8 12.9 28.5 21.6 22.86569 years2 18.5 15.6 26.8 30.3 30.17074 years2 24.4 21.6 27.3 45.6 37.57579 years2 32.3 28.8 32.8 58.1 56.8

Mortality rates per 100,000

National Cancer Institute. 1. Howlader N et al (eds). SEER Cancer Statistics Review, 1975-2011, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2011: Table 14.15. 2. SEER data liver cancer mortality by age and race+ethnicity.xls

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HCC is Not One Disease

Cancer and underlying liver disease Clinically diverse cancer

physiological staging

anatomical staging

Molecularly diverse cancer Distinct molecular subtypes have begun to be characterized

At least 5 molecular drivers are known

Angiogenesis is a validated target in HCC

Finn RS. Clin Cancer Res. 2010;16:390-397.

Management of Hepatocellular Carcinoma Requires a Multidisciplinary Approach

Radiation Oncology

Pathology

Oncology

Radiology and Interventional Radiology

HepatobiliarySurgery

Hepatology/NP/RN/PA/CNS

Modified from Guy J et al. Clin Gastroenterol Hepatol. 2012;10:354-362.

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Stage 0PST 0,

Child-Turcotte-Pugh A

Stage DPST >2,

Child-Turcotte-Pugh C

Very early stage (0)Single

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What We Know About Treating HCC Staging patients is important

physiologic and anatomic

The only truly curative approach is surgery (resection or transplant). Most patients are not candidates for surgery

Chemoembolization (TACE/TABE) and microwave/radiofrequency ablation can improve survival in selected patients

Eventually most patients will require systemic/targeted treatment if they live long enough and their liver function remains stable

Cytotoxic chemotherapy has not had any impact on this disease

Sorafenib improves survival for patients with advanced HCC

Guy J et al. Clin Gastroenterol Hepatol. 2012;10:354-362. Bruix J, Sherman M. Hepatology. July, 2010.

Natural History and Prognosis of Untreated Liver Disease

Giannini EG et al. Hepatology. 2015;61:184-190.

Cum

ulat

ive

Surv

ival

Time (months)

1

.8

.6

.4

.2

0

0 12 24 36 48 60

BCLC 0BCLC ABCLC BBCLC CBCLC D

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Increasing Survival of Localized HCC, by Decade

Neji B et al. Hepatology. 2015;61:191-199.

Cum

ulat

ive

Surv

ival

Survival Time (months)

1

.8

.6

.4

.2

0

0 20 40 80 100 12060

p

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Case Study

Presentation and initial treatment

Case Study: Initial Presentation

35-year-old Korean man presents with elevated liver tests and is diagnosed with hepatitis B

Physical examination is normal Abdominal ultrasound shows a spleen of 13 cm and an

enlarged PV of 12 mm

Platelet count is 130,000 AFP blood level is 22

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Case Study: Presentation 5 Years Later 40-year-old Korean man presents with:

Abdominal fullness

5-lb weight loss

Fatigue

Laboratory tests: Albumin = 3 g/dL

INR = 1.5

Bilirubin = 3 mg/dL

ECOG PS 1

ECOG PS = Eastern Cooperative Oncology Group performance status.

Case Study: Results of CT Scan

4-phase CT scan reveals a 7-cm lesion between segments 1 and 4 near the portal vein, with classic arterial uptake and rapid washout consistent with HCC

Ascites was seen surrounding the liver; a small amount was seen in the pelvis.

CT = computed tomography; HCC = hepatocellular carcinoma.

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Case Study: Location of Tumor

Liver Transplantation for HCC:Milan Criteria (Stages 1 and 2)

Mazzaferro V et al. N Engl J Med. 1996;334:693-699.

+Absence of macroscopic vascular invasion,

absence of extrahepatic spread

Single tumor, not >5 cm Up to 3 tumors, none >3 cm

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Case Study Question 1

A. TACE

B. RFA

C. Liver transplantation

D. IV doxorubicin

E. Yttrium-90 microspheres

F. Oral therapy with a multi-targeted TKI

G. Other

What is the best next step to treat this patient?

Case Study Question 1: Decision

You decide to initiate treatment with TACE.

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Percutaneous Ablative Therapies for HCC

Thermal ablation

Hot saline injection (rarely used)RadiofrequencyMicrowaveCryoablation (rarely used)Laser (clinical trials)

New non chemical/non thermalIrreversible electroporationLight-activated drug therapy

Chemical ablationPercutaneous ethanol injectionAcetic acid injection (rarely used)

Lau WY et al. Ann Surg. 2003;237:171-179. Lencioni R et al. J Hepatobiliary Pancreat Sci. 2010;17:399-403.

Survival Rates of Asian American PatientsWith HCC by Treatments

OLT = orthotopic liver transplantation; RFA = radiofrequency ablation; TACE = transcatheter arterial chemoembolization.

OLT all

Resection all

RFA only

TACE only

TACE RFA other

Supportive care

Patient Survival

Months of Follow Up

0 30 60 90 120 1500

20

40

60

80

100

Surv

ival

, %

Tong MJ et al. J Clin Gastroenterol. 2010;44:e63-e70.

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How Do We Use AFP ?

AFP is a useful biomarker of a patient's increased future RISK for HCC.

AFP is not a screening or surveillance tool for HCC. AFP is not used to diagnose HCC. A high AFP or rising AFP is used to modify imaging algorithms. AFP can now be used in conjunction with lectin-reactive

alpha-fetoprotein (AFP-L3) and Des-gamma-carboxyprothrombin (DCP).

Bruix J, Sherman M. Hepatology. July, 2010. www.wakodiagnostics.com/hccbiomarkers.html.

AFP = alpha-fetoprotein; DCP = des-gamma-carboxyprothrombin;AFP-L3 = lens culinaris agglutinin A-reactive fraction of AFP.

AFP >20 ng/dL

DCP >40 mAU/mL

AFP-L3% >10% of total AFP

96 11093

15345

14

15

159 (23%) all negative

Not All HCC Patients Have All Biomarkers

Toyoda H et al. Clin Gastroenterol Hepatol. 2006;4:111-117.

Incidence of AFP, DCP, and AFP-L3% in 685 patients with known HCC

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Months

AFP

: ng/

mL

AFP

-L3%

AFP conc. AFP-L3 conc. AFP-L3%

21 months

HCC diagnosisTumor size:

3-5 cm

Before HCC diagnosis

Tumor size: 2 cm

AFP L3% Rises before AFP in TypicalCourse of HCC Occurrence Case

Sterling RK et al. Am J Gastroenterol. 2012;197:64-74.

Liver Dedicated Surveillance

Ultrasound (US)+ HCC biomarkersin at-risk patients*

Poor/Fairquality US

Orabnormal

biomarkers

Good/Excellent quality US and

normal HCC biomarkers

gadoxetate disodium MRI (Or dynamic CT)

US surveillance q6 months with biomarkers

Negative MRI

Abnormal US or

increasing biomarkers

blood tests AFP-L3%/DCP (HCC serum biomarkers); *AASLD Guidelines 2009; # see LI-RADS.AASLD = American Association for the Study of Liver Diseases; AFP = alpha-fetoprotein; CT = computed tomography;DCP = des-gamma-carboxy prothrombin; HCC = hepatocellular carcinoma; LI-RADS = Liver Imaging Reporting and Data System;MRI = magnetic resonance imaging; US = ultrasound.

Proposed Imaging Liver HCC Surveillance Algorithm use FDA Cleared Biomarkers

Gish RG. Gastroenterol Hepatol. 2014;10:121-123.

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Elastography (Liver Stiffness Measurement [LSM]) and Predictors of HCC

Feier D et al. J Gastrointestin Liver Dis. 2013;22:283-289.

Parameters Independently Associated with the Presence of HCC

Main predictorsOdds ratio* 95% CI Coefficient

Standarderror P-value

Liver stiffness 8.27 2.5826.46 1.92 0.018 0.0001

Interquartilerange 1.16 1.041.29 1.49 0.055 0.0001

ALT 1.01 0.960.99 0.02 0.009 0.004AFP 1.04 1.011.08 0.04 0.01 0.009

CI = confidence interval; AFP = alpha-fetoprotein.

*Odds ratio for the independent variables gives the relative amount by which the oddsof HCC increase or decrease when the value of the independent variable is increased by 1 unit.

Management ?Post surgery biomarkers: ~6 weeks post resection

173 patients with curative resectionTumor markers assessed: AFP, AFP-L3, DCP

Toyoda H et al. J Hepatol. 2012;57:1251-1257.

AFP = alpha-fetoprotein; DCP = des-gamma-carboxyprothrombin;AFP-L3 = lens culinaris agglutinin A-reactive fraction of AFP.

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LI-RADS What is LI-RADS?

System of standardized terminology and criteria for imaging exams of liver Supported and endorsed by ACR Developed by radiologists with input from hepatobiliary surgeons, hepatologists,

hepatopathologists, and interventionalists LI-RADS is dynamic; it will be expanded and refined as knowledge accrues

In what patient population does LI-RADS apply? Patients with cirrhosis or at high risk for developing HCC

What imaging modalities are addressed by LI-RADS? LI-RADS v2013: CT and MRI performed with extracellular contrast agents LI-RADS v2014: was expanded to apply to hepatobiliary contrast agents, imaging

technique, management, and reporting Who can use LI-RADS?

Community and academic radiologists How does LI-RADS work?

LI-RADS categorizes lesions, reflecting probability of benignity or HCC

www.acr.org/~/media/ACR/Documents/PDF/QualitySafety/Resources/LIRADS/lirads%20v20131%20w%20note.pdf. www.acr.org/quality-safety/resources/LIRADS

LI-RADS = Liver Imaging Reporting And Data System; ACR = American College of Radiology.

Definitely benignLR-1

Probably benignLR-2

Intermediate probability for HCCLR-3

Probably HCCLR-4

Definitely HCCLR-5

Definitely HCC with Tumor in VeinLR-5V

LR-M Malignant, not necessarily HCC

LI-RADS: Categories

http://nrdr.acr.org/lirads/

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Liver-specific Contrast Agents for Tumor Measurement

Development of hepatocyte-specific contrast agent improves tumor-to-liver contrast in MRIs

Gadolimium ethoxybenzyldimeglumine(Primovist/Eovist) can improve assessment of tumor size for accurate staging

Hypointense nodules indicate2 small HCCs

Van Beers BE et al. J Hepatol. 2012;57:421-429.

VEGF Levels as Prognostic Marker for Tumor Characteristics

Zhang W et al. Liver Transpl. 2015;21:101-111.

Parameters Independently Associated with Vascular Invasion

VariableOdds ratio 95% CI P-value

Plasma VEGF: >44 pg/mL vs. 44 pg/mL 5.57 2.4812.53

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Case Study

Assessment and further treatment

Case Study: Evolution

5 weeks later, a 4-phase CT is performed and shows no residual lipiodol

Tumor is now 8 cm without evidence of significant necrosis

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Case Study: Post-TABE MRI

TABE = transarterial bead embolization; MRI = magnetic resonance imaging.

Case Study Question 2

A. TACE

B. RFA

C. Liver transplantation

D. IV doxorubicin

E. Yttrium-90 microspheres

F. Oral therapy with a multitargeted TKI

G. Other

What is the best next step to treat this patient?

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Case Study Decision

You decide to initiate treatment with the multitargeted TKI sorafenib.

Case Study Question 3

A. 100 mg orally twice daily

B. 200 mg orally twice daily

C. 400 mg orally twice daily

What is the optimal sorafenib dosage for this patient?

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Case Study: Decision and Evolution

The patient was started on sorafenib 400 mg orally twice daily taken without food.

A painful red palmer rash developed 2 weeks after starting sorafenib therapy. This was scored as a grade 2 reaction.

Signaling Pathways, Molecular Targets, and New Targeted Agents Under

Development in HCC

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Sustainingproliferative signaling

Evading growth suppressors

Activating invasion and metastasis

Enabling replicativeimmortality

Inducingangiogenesis

Resistingcell death

Hallmarks of Cancer

Adapted from Hanahan D, Weinberg RA. Cell. 2011;144:646-674.

Pathogenesis of Hepatocellular Carcinoma

1540 yearsChronic

hepatitisCirrhosis

35% per year

HCC

HBV or HCV

Diabetes Alcohol

AflatoxinsInflammation Dysplastic lesions Clonal selection

Adapted from Levrero M. Oncogene. 2006;25:3834-3847.

NASH

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Frequent Mutations Associated with HCC

Signaling pathways Wnt pathway: AXIN, APC, -

catenin (CTNNB1) PI3K/RAS: KRAS, PIK3CA TGF-1 NOTCH: NOTCH1, NOTCH3 Hedgehog pathway: SHH,

SMO, HHIP

Cell-cycle control p53: IRF2, p53, CDKN2A pRB1: pRB1 LOH, p16, cyclin

D1, gankyrin c-MET

Avila MA et al. Oncogene. 2006;25:3866-3884. Moeini A et al. Liver Cancer. 2012;1:83-93. Guichard C et al. Nat Genet.2012;44:694-698.

Signaling pathways in HCC carcinogenesis

Avila MA et al. Oncogene. 2006;25:3866-3884. Moeini A et al. Liver Cancer. 2012;1:8393

Cellmembrane

Growth factor

Receptor tyrosinekinase

Integrins

Wnt

Extracellular Matrix

Notch

AngiogenesisSurvival and proliferation

Cell adhesionImmortalization

Metastasis

HedgehogVEGF

Cytokines

-catenin

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Growth factor Receptor tyrosinekinase

Cellmembrane

P

GRBSOS Ras

c-Raf

MAPK/Erk1/2P

c-fos/c-jun

Cell growth

EGFTGFHB-EGFIGF-1/IRSFGFHGFPDGFVEGFcMET

Receptor Tyrosine Kinase Signaling

mLST8 rictor

Cell survivalBad

P70 S6K4E-BPI

Cell cycleprogression G1-S

Translation ofcell cycle

regulatory protein

PI3K

AKT

PDK1

mTOR mTORComplex 1

PTENmTOR

Complex 2

Actin cytoskeleton

Growth factor Growth factor receptorCell

membrane

P

PI3K/AKT/mTOR Pathway

mLST8 SIN1 rictor

mTOR

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Proliferation and migration

Tumorcell

Endothelial cell

PDGF

VEGF

VEGF

Pericyte/Stellate

cell

Angiogenic Signaling in Cancer

Hepatic Resection

Percentage of HCCs deemedresectable at diagnosis

30% resectable

70% unresectable

Adapted from Colombo M, Sangiovanni A. Antiviral Res. 2003;60:145-150.

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Survival After SurgicalResection for HCC

Llovet JM et al. Hepatology. 1999;30:1434-1440.

High frequencyalternating current

Ionic vibration &heat generation

45C: Proteindenaturation

70C: Thermalcoagulation

100C: Tissuedesiccation

Radiofrequency Ablation

Adapted from Minami Y, Kudo M. Int J Hepatol. 2011;doi:10.4061/2011/104685. Courtesy of Robert G. Gish, MD.

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Early HCC Treated with RFA Lencioni et al, 2005:

206 patients with early stage unresectable HCC treated with RFAFavorable 5 year survival

3yr Survival 5yr SurvivalChild A with single lesion 89% 61%Child A 76% 51%Child B 46% 31%

Tateishi et al, 2005:1000 RFA procedures in 664 patients:Survival: 94, 77, and 54% (1-, 3-, and 5-year)

RFA in small resectable lesions?

1. Lencioni R et al. Radiology. 2005;234:961-967. 2. Tateishi R et al. Cancer. 2005;103:1201-1209.

Is RFA Better Than Surgical Resection?Surgery considered better, but...

148 patients Child A; case control RFA vs. Surgical resection

1yr Survival 3yr Survival Recurrence

Surgery (n=93)

97.9% 83.9% 45.2%

RFAn=55)

100.0% 72.7% 58.2%

P=0.24 P=0.54

Overall survival + recurrence-free survival: RFA = surgicalresection for single small HCC with good hepatic reserve

Rate of local recurrence: RFA > surgical resection

Hong SN et al. J Clin Gastroenterol. 2005;39:247-252.

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Treatment: Chemoembolization

Normal liver gets 75% of blood supply from portal vein and 25% of blood supply from hepatic artery

Tumor receives most of its blood supply from the hepatic artery

Injection into the hepatic artery spares most of the normal liver

Embolization of the hepatic artery prevents systemic absorption of chemotherapy agents and induces ischemic necrosis of tumor

Tumor

Hepaticartery

Catheter placement forchemoembolization

Liver

Portal vein

Ramsey DE, Geschwind J-F. Appl Radiol. 2004;33. Available at www.medscape.com/viewarticle/474054_3.

Chemoembolization: Randomized Trials (Nearly Identical Techniques)

TechniqueSurvival, %

Year 1 Year 2 Year 3TACE 57 31 26Supportive care 32 11 3

TechniqueSurvival, %

Year 1 Year 2TACE 82 63Supportive care 63 27

Llovet et al[2]: N = 112 with unresectable HCC, 80% to 90% HCV positive, 5-cm tumors (~ 70% multifocal)

Lo et al[1]: N = 80 with newly diagnosed unresectable HCC, 80% HBV positive, 7-cm tumors (60% multifocal)

HBV = hepatitis B virus; HCV = hepatitis C virus; TACE = transcatheter arterial chemoembolization.

1. Lo C-M et al. Hepatology. 2002;35:1164-1171. 2. Llovet JM et al. Lancet. 2002;359:1734-1739.

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TACE vs Surgical Resection: A Case-Control Prospective Study

TechniqueSurvival, %

Year 1 Year 2 Year 3 Year 5TACE 96 80 56 30Surgical resection 90 80 70 52

N = 182, ~ 70% HBV positive, 99% Okuda stage I, 76% with tumors < 3 cm

Surgery superior to TACE for tumors smaller than 2 cm and/or CLIP stage 0 BUT for tumors > 3 cm and/or CLIP stage 1-2, 5-year survival identical

for both groups

Median OS (P = .1529) Resection: 65.1 months TACE: 50.4 months

CLIP = Cancer of the Liver Italian Program; HBV = hepatitis B virus; TACE = transcatheter arterial chemoembolization.

Lee H-S et al. J Clin Oncol. 2002;20:4459-4465.

Combined RFA and TACEFor Recurrent HCC

Treatment Response Recurrence 1-yr Surv 5-yr SurvRFA 92% 43% 74% 28%

TACE 69% 57% 66% 20%

RFA + TACE 94% 21% 89% 44%

N=103Treated with 1) RFA, 2) TACE, 3) both

Yang W et al. Hepatol Res. 2009;39:231-240.

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100% 80%

*confirmed by 4w interval**one point in EASL/ 6mo interval in JSHCC

20% Which is the best surrogate criteria for survival ?

Neovascularization in blue

TACE

Validation of evaluation criteria for TACE Multi institutional study (JIVROSG-0602)

Reduction: 0% Response: SD

orig.WHO*

80%PR

mod.WHO*

0%SD

orig.RECIST*

25%SD

mod.RECIST*

80%PR

EASL/JSHCC **

Sato Y et al. Ups J Med Sci. 2013;118:16-22.

Response to TACE as a Biological Selection Criterion for LT in HCC

TACE nonrespondersTACE responders

0

Free

dom

Fro

m R

ecur

renc

e

0

0.2

0.4

0.6

0.8

1.0

365 730 1095 1460 1825Days

35.4%

94.5%

P = .0017

LT = liver transplantation; TACE = transcatheter arterial chemoembolization.

Otto G et al. Liver Transpl. 2006;12:1260-1267.

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Intra-arterial Radioembolization With Yttrium-90: Rationale and History

Radioembolization: Use of intra-arterially delivered yttrium-90 microspheres emitting high-dose radiation for the treatment of liver tumors

Yttrium-90 microspheres Average diameter: 20-30 m

100% pure beta emitter (0.9367 MeV)

Physical half-life: 64.2 hours

Irradiates tissue with average path length of 2.5 mm (maximum: 11 mm)

Murthy R et al. Biomed Imaging Interv J. 2006;2:e43.

PRECISION TACE with DC BeadAddressing the challenge of improved survival in

hepatocellular carcinoma

Courtesy of Dr. David Brophy, St. Vincents University Hospital, 2013.1. Malagari K et al. Abdom Imaging. 2008;33:512-519. 2. Valera M et al. J Hepatol. 2007;46:474-481. 3. Llovet JM et al. Lancet.2002;359:1734-1739. 4. Pelletier G et al. J Hepatol. 1998;29:129-134. 5. Lo C-M et al. Hepatology. 2002;35:1164-1171.

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75% Reduction in SAEs at the same institution

Complications SAE Comparison: Conventional TACE vs PRECISION TACE

Courtesy of Dr. David Brophy, St. Vincents University Hospital, 2013.

TACE = transcatheter arterial chemoembolization.

Milan Criteria

3 lesions, none >3 cm

1 lesion 70% Recurrence is

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35

0

10

20

30

40

50

0 1 2 3

Recu

rren

ce (%

)

Post transplant years

Milan No (n=172)

Milan Yes (n=137)

HCC Cumulative Recurrence Rate after Liver Transplant

Todo S et al. Ann Surg. 2004;240:451-461.

Prognostic Factors for Survival after Liver Transplantation

Zhang W et al. Liver Transpl. 2015;21:101-111.

Parameters Independently Associated with Survival after Liver Transplantation

VariableHazard ratio 95% CI P-value

Overall survival

Vascular invasion 3.82 1.808.10 44 pg/mL) before liver transplant

Total tumor diameter (5 cm)

2.12

2.63

1.084.14

1.335.18

0.03

0.005

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36

sorafenib

(95% CI, 40.9-57.9)Median: 46.3 weeks (10.7 months)

Surv

ival

Pro

babi

lity

Time (weeks)

Hazard ratio in sorafenib group: 0.69(95% CI, 0.55-0.87)P =0.00058*

placeboMedian: 34.4 weeks (7.9 months)(95% CI, 29.4-39.4)

1.00

0

0.75

0.50

0.25

1.00

0

0.75

0.50

0.25

0 808 16 24 32 40 48 56 64 72

274 241 205 161 108 67 38 12 0Patients at risk

276 224 179 126 78 47 25 7 2299303

274 241 205 161 108 67 38 12 0Patients at risk

sorafenib276 224 179 126 78 47 25 7 2placebo

299303

Sorafenib: Phase III SHARP Trial: Overall Survival Intent-to-Treat Population

*OBrien-Fleming threshold for statistical significance: P=0.0077 Llovet JM et al. N Engl J Med. 2008;359:378-390.

196 126 80 50 28 14 8 2192 101 57 31 12 8 2 1196 126 80 50 28 14 8 2192 101 57 31 12 8 2 1

Prog

ress

ion

-Fre

e Pr

obab

ility

Hazard ratio: 0.58(95% CI, 0.45 0.74)P=0.000007

546 12 18 24 30 36 42 480Time (weeks)

sorafenibMedian: 24.0 weeks (5.5 months)(95% CI, 18.0 30.0)placeboMedian: 12.3 weeks (2.8 months)(95% CI, 11.7 17.1)

1.00

0

0.75

0.50

0.25

Prog

ress

ion

-Fre

e Pr

obab

ility

546 12 18 24 30 36 42 480 546 12 18 24 30 36 42 480Time (weeks)

1.00

0

0.75

0.50

0.25

1.00

0

0.75

0.50

0.25

Patients at risksorafenib:placebo:

299303

Sorafenib: Phase III SHARP Trial: Time to Tumor Progression (Independent Review)

Llovet JM et al. N Engl J Med. 2008;359:378-390.

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Sorafenib: Phase III SHARP Trial: Best Response by RECIST (Independent Review)

Sorafenibn=299

%

Placebon=303

%Overall response

Complete response 0 0Partial response 2 1Stable disease 71 67Progressive disease 18 24

Progression-free rate at 4 mo 62 42

*Not assessable: sorafenib (8.7%), placebo (8.3%).

RECIST=Response Evaluation Criteria in Solid Tumors.

Llovet JM et al. N Engl J Med. 2008;359:378-390.

Case Study

Management of hand-foot skin reaction

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Case Study: Multitargeted TKI ToxicityHand-Foot Skin Reaction

In one study, >90% of patients may experience skin reactions on multitargeted TKI therapy1

Incidence of hand-foot skin reaction was 21% in SHARP trial (all grades)2

Subsequent prospective clinical trials have found the incidence of reported hand-foot skin reaction as high as 60%1

1. Autier J et al. Arch Dermatol. 2008;144:886-892. 2. Llovet JM et al. N Engl J Med. 2008;359:378-390.

Case Study Question 4

A. Immediate sorafenib discontinuation plus supportive care to address skin reaction

B. Sorafenib dose interruption for 1 week plus supportive care

C. Sorafenib dose reduction by 50% plus supportive care

D. Sorafenib dose reduction by 75% plus supportive care

E. Use supportive care to address skin reaction; alter dose after 1 week if no improvement

What is the next best step for treatment?

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Case Study: Multitargeted TKI Toxicity Hand-Foot Skin Reaction

Typically develops within first 24 weeks of treatment and no later than day 45

Characterized by tender lesions that are scaling and have halo of erythema at pressure or flexure points

Later, areas of thickened skin develop

Lacouture ME et al. Oncologist. 2008;13:1001-1011.

Case Study: Grading and Management of Hand-Foot Skin Reaction

Grade Characteristics Management

1

Minimal skin changes or dermatitis

(eg, erythema)without pain

Avoid hot water Use moisturizing cream Consider keratolytics Wear cotton gloves/socks at night No dose reduction needed; follow-up within 2 weeks

2

Skin changes (eg, peeling,

blisters, bleeding, edema)

and/or pain, not interfering with daily activities

Employ grade 1 strategies Apply clobetasol ointment BID Use topical analgesics; use systematic analgesics only

after evaluating bleeding/kidney function If needed, consider 50% dose reduction for 728 days

until hand-foot skin reaction is grade 1/0, then full dose

3 Skin changes with

pain, interfering with daily activities

Employ grade 1/2 strategies Treatment interruption for 7 days until grade 1/0;

resume 50% of full dose and, if possible, escalate to full dose

Lacouture ME et al. Oncologist. 2008;13:1001-1011.

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Case Study: Multitargeted TKI vs. Chemotherapy Dermal Toxicity

Characteristic Multitargeted TKI Chemotherapy

Palm and soleinvolvement

Localized withhyperkeratotic plaque or

blistersDiffuse tender erythema

Area oferuption

Plantar surfaces in addition to nonpressure-bearing

areas Plantar surfaces

PathologyVacuolar degeneration in the stratum malpighii with

epidermal acanthosis

Dermal-epidermal interface dermatitis and vacuolar degeneration of basilar

keratinocytes

Lacouture ME et al. Oncologist. 2008;13:1001-1011.

Chemotherapy-induced and TKI-induced acral erythema differ in several aspects

Case Study: Prophylactic Options for Hand-Foot Skin Reaction

Perform full-body skin exam before initiation of therapy Emphasis on palms and soles

Pedicures to remove calluses and/or hyperkeratotic regions

Use of orthotic devices in patients with abnormal weight-bearing

Reduce hand/foot exposure to hot water

Encourage rest, avoidance of traumatic activity during early stages of therapy Avoid vigorous exercise during this time

Avoid constrictive footwear, friction to skin

Lacouture ME et al. Oncologist. 2008;13:1001-1011.

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Strategies for Managing Other Adverse Effects Diarrhea (39% of patients in SHARP trial1) (usually occurs by month 4)

Consider dietary changes2.3

Antidiarrheal agents if severe2.3

Fatigue (22% of patients in SHARP trial1)

Consult dietitian if nutrition intake is a concern2

Consider growth factors if anemia is found2

Consider modafinil or methylphenidate if severe3

Correct sleep disorder and hepatic encephalopathy3

Hypertension (5% of patients in SHARP trial1)

Encourage healthy lifestyle practices (diet, exercise)2

Start or adjust antihypertensives2.3

Hypophosphatemia

Replacement therapy

1. Llovet JM et al. N Engl J Med. 2008;359:378-390. 2. Wood LS. Commun Oncol. 2006;3:558-562. 3. Eisen T et al. J NatlCancer Inst. 2012;104:93-113.

Case Study: Key Roles of Mid-Level Providers in Patient Care With Oral Therapies

Educating patients regarding potential adverse effects before initiating therapy

Encouraging patients to notify them promptly when adverse effects emerge to allow for early intervention

Educating patients on the potential treatments for adverse effects, their expected efficacy, and alternative options

Encouraging patient compliance through open communication, referrals to support groups

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Case Study Question 5

A. Imodium

B. Vitamin B6

C. Hydrocodone bitartrate

D. Dolasetron mesylate

E. Other

F. None

What therapies would you initiate before starting sorafenib?

Phase III Trials of First-Line Therapy in Advanced HCC

Study drug(trial acronym) Mechanism Control N

Primary endpoint

Data expected

Sorafenib + doxorubicin(CALGB-80802)1

Sorafenib: multikinaseinhibitor (VEGFR, PDGFR, Raf, others)Doxorubicin: cytotoxic

Sorafenib 480 OS On hold

Sorafenib + erlotinib(SEARCH)2

Sorafenib: multikinaseinhibitor (VEGFR, PDGFR, Raf, others)Erlotinib: RTKI of EGFR-1

Sorafenib 720 OS Negative

Linifanib3 Multikinase inhibitor (VEGFR, PDGFR, others) Sorafenib 1035 OS Negative

Brivanib(BRISK-FL)4

Selective inhibitor of FGFR + VEGFR Sorafenib 1050 OS Negative

Sunitinib5 Oral multitargeted tyrosine kinase inhibitor Sorafenib 1075 OS Negative

Lenvatinib6 Multikinase inhibitor of (VEGFR, FGFR, others) Sorafenib 940 OS 2015

1 NCT01015833; 2 NCT00901901; 3 NCT01009593; 4 NCT00858871; 5 NCT00699374; 6 NCT01761266.

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Study drug(trial acronym) Mechanism Control N

Primary endpoint

Data expected

Brivanib(BRISK-PS)1

Selective inhibitorof FGFR + VEGFR Placebo 395 OS

Negative

Everolimus(EVOLVE-1)2 mTOR inhibitor Placebo 546 OS Negative

Ramucirumab(REACH)3 MAb to VEGFR-2 Placebo 544 OS

Negative

Brivanib(BRISK-APS)4

Selective inhibitorof FGFR + VEGFR Placebo 252 OS

Study Terminated

Tivantinib(METIV-HCC)5 cMET inhibitor Placebo 303 OS 2015

Regorafenib(RESORCE)6 VEGFR inhibitor Placebo 530 OS 2016

Cabozantinib(CELESTIAL)7

cMET, VEGFR2, RET Placebo 760 OS 2016

ADI-PEG-208 Arginine-deiminase Placebo 633 OS 2015

Phase III Trials of Second-LineTherapy in Advanced HCC

1 Llovet JM et al. J Clin Oncol. 2013;31:3509-3516. 2 Zhu AX et al. J Clin Oncol. 2014;32(suppl3): abstract 172. 3 NCT01140347;4 NCT01108705; 5 NCT01755767; 6 NCT01774344; 7 NCT01908426; 8 NCT01287585.

Max

imum

Tum

or C

hang

e fr

om B

asel

ine

(%)

Patients with both baseline and on-study tumor assessment, N = 311

Brivanib Placebo

N = 210 N = 101

Brivanib: Can We Find the Subset of Patients Who Will Benefit? Change in Target Tumor from Baseline

Llovet JM et al. J Clin Oncol. 2013;31:3509-3516.

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HGF/ c-MET and HCC

HGF/ cMET signaling plays a role in liver regeneration1

cMET expression is reported increased in HCC2,3,4

Prognostic value is unclear

HGF expression and cMET activation in models can induce tumor growth5

HGF expression reported to be decreased in HCC

cMET overexpression by IHC correlates with poor prognostic features and poor outcomes6,7,8

Elevated plasma HGF associated with decreased benefit to sorafenib in SHARP9

1. Borowiak M et al. Proc Natl Acad Sci USA. 2004;101:10608-10613 2. Kiss A et al. Clin Cancer Res. 1997;3:1059-1066. 3. Selden C et al. J Hepatol. 1994;21:227-234. 4.Tavian D et al. Int J Cancer. 2000;87:644-649. 5. Horiguchi N et al. Oncogene. 2002;21:1791-1799. 6. Ueki T et al. Hepatology. 1997;25:619-623. 7. Llovet JM et al. Clin Cancer Res. 2012;18:2290-2300.

HGF = hepatocyte growth factor; ICH = immunohistochemistry

Improved OS in METDiagnostic-High Group

Santoro A et al. Lancet Oncol. 2013;14:55-63.

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Conclusions Use of evidence-based treatment guidelines improves patient

outcomes.

Molecular targeted therapeutics will play a role in the future of HCC management.

Sorafenib has established a benchmark for front-line studies. Great unmet need for patients who are ineligible for, intolerant

to, and progress on sorafenib

Randomized Phase II trials are needed to better assess activity for moving agents into Phase III

Characterize promising new targets for therapy To better identify patients who will receive benefit

Optimizing Multidisciplinary Management of HCC

Treatment decision

Patientcall

Treatment

Hepatology Surgery Oncology

Current standard

All relevant specialistsTreatment decision

Patient communication

What we want

Interv. radiology Pathology

Courtesy of Carrie Frenette, MD, CPMC integrated HCC clinic.

ON-19L_HCC Program Overview_2.6.pdfThis activity is intended for oncologists, hepatologists, gastroenterologists, and healthcare professionals who manage patients with liver cancer and liver diseases.LEARNING OBJECTIVESMethod of ParticipationParticipation Statement