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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Purpose: This program would be beneficial for nurses involved the diagnosis and management
of patients with metastatic colorectal cancer.

CNE Credits: 1.00 ANCC Contact Hour(s).

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by the American Nurses Credentialing Centers Commission on Accreditation.

Awarded 1.00 contact hour(s) of continuing nursing education of RNs and APNs.

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
Speakers Bureau for from Bayer Pharmaceuticals Corporation and Onyx Pharmaceuticals, Inc.
MLG Course Reviewer - - Dr. Simon has disclosed no significant financial relationships.
CCM/UMA Lead Nurse Planner - - Lynnsey Grzybowski, RN, BSN has disclosed no
significant financial relationships.

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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.
II.

Introduction
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

3/23/2015

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

Disclosure of Potential
Conflicts of Interest
During the course of this lecture, Dr. Gish may mention
the use of medications for both FDA-approved and nonapproved indications
Dr Gish has received served on the Speakers Bureau and
received consulting fees Bayer Pharmaceuticals
Corporation and Onyx Pharmaceuticals, Inc.

3/23/2015

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 comorbidities and concurrent medicines, conducting appropriate
laboratory and imaging work-ups, and developing BCLC algorithmcompliant 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.

3/23/2015

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.

3/23/2015

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.

3/23/2015

Incidence rates by State, 2006-2010

El-Serag, et al. 2014

Liver Cancer Mortality, US, 20072011

All

Non-Hispanic
White

Black

API

Hispanic

5.8

5.0

7.6

9.8

8.7

3539

years2

0.5

0.4

0.8

1.2

0.3

4044

years2

1.1

0.8

1.7

2.4

1.2

4549 years2

3.2

2.6

4.3

5.8

3.9

5054

years2

8.3

7.1

12.2

9.7

10.0

5559

years2

14.4

11.8

25.8

17.3

18.2

6064 years2

15.8

12.9

28.5

21.6

22.8

6569 years2

18.5

15.6

26.8

30.3

30.1

7074

years2

24.4

21.6

27.3

45.6

37.5

7579

years2

32.3

28.8

32.8

58.1

56.8

Overall 1

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

3/23/2015

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
Hepatobiliary
Surgery
Hepatology
/NP/RN/PA/CNS

Pathology

Oncology

Radiology and Interventional

Radiology
Radiation
Oncology

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

3/23/2015

Hepatocellular Carcinoma Algorithm

(Modified from: Barcelona Clinic Liver Cancer (BCLC)
Llovet JM et al. J Natl Cancer Inst. 2008;100:698-711.)

Stage 0
PST 0,
Child-Turcotte-Pugh A

Stage A-C
PST 0-2,
Child-Turcotte-Pugh A or B

Very early stage (0)

Single <2 cm
carcinoma in situ

Intermediate stage (B)

Multinodular, PST 0

Early stage (A)

Single nodule <5 cm
or 3 nodules 3 cm,
PST 0

TAE or TACE
Local Chemo- or Radiotherapy
(Chemo or Bead
embolization,
Radioembolization)

3 nodules 3 cm

Single

Increased portal
pressure and elevated
bilirubin levels

Associated
diseases

Yes

Advanced stage (C)

Portal invasion,
N1, M1, PST 1-2

Terminal
stage (D)

Sorafenib
Chemo

Supportive Care

Median survival 11-20 months

*Sequence: TARE, TABE,
SBRT sorafenib?b

No

No

Yes

Resection

Liver transplantation
(CLT or LDLT)

RFA (PEIa)
Ablation (SBRT,
RF, TABE>
TARE,TACE)
< 3 tumors
< 5 cm

Salvage

Stage D
PST >2,
Child-Turcotte-Pugh C

Survival <3 months

*Combinations,
SBRT, TARE, TABE?b

Salvage

Downstage Bridge
5-year survival 40%-70%

Rarely used. b Confirmation required from RCTs.

SBRT = Stereotactic Body Radiation Therapy

Staging Treatment Algorithm

HCC

PST 0, Child-Pugh A

Very early stage 0

Single < 2 cm

PST 0-2, Child-Pugh A-B

Early stage A
Single or 3 nodules
3 cm, PST 0

Single

Resection

Advanced stage C
Portal invasion,
N1, M1, PST 1-2

Terminal
stage D

3 nodules 3 cm

Portal pressure/bilirubin
Increased
Normal

Intermediate stage B
Multinodular, PST 0

PST > 2, Child-Pugh C

No
OLT

Portal invasion,
N1, M1

Associated
diseases
Yes
RFA/MW
Down Stage

No

TACE/TABE
/TARE

Down Stage

Yes

TARE large Tumors

(PVT)
Sorafenib/
Clinical Trial/
Combination

Symptomatic/
Palliative

Adapted from: Llovet et al, 2008.

3/23/2015

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

Cumulative Survival

1
BCLC 0
BCLC A
BCLC B
BCLC C
BCLC D

.8
.6
.4
.2
0
0

12

24

36

48

60

Time (months)

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

3/23/2015

Increasing Survival of Localized HCC, by Decade

Cumulative Survival

1
p<0.001

.8

Decade
2000s
1990s
1980s
1970s

.6
.4
.2
0
0

20

40

60

80

100

120

Survival Time (months)

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

Real-world Deviations from BCLC Guidelines Can

Adversely Affect Patients
Real-world data indicate frequent deviations in
treatment strategies from BCLC recommendations
Deviations adversely affected patients with earlystage HCC
BCLC 0/A patients treated with downstream (non-curative)
therapies had lower survival than those treated by
convention
More aggressive upstream treatments for advanced
(BCLC C/D) HCC did not show survival benefit compared
with conventional management
Alkhatib Z et al. Hepatology. 2014;60(4 Suppl):836A (Abstract 1325).

3/23/2015

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

10

3/23/2015

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.

11

3/23/2015

Case Study: Location of Tumor

Liver Transplantation for HCC:

Milan Criteria (Stages 1 and 2)
Single tumor, not >5 cm

Up to 3 tumors, none >3 cm

+
Absence of macroscopic vascular invasion,
absence of extrahepatic spread
Mazzaferro V et al. N Engl J Med. 1996;334:693-699.

12

3/23/2015

Case Study Question 1

What is the best next step to treat this patient?
A. TACE
B. RFA
C. Liver transplantation
D. IV doxorubicin
E. Yttrium-90 microspheres
F. Oral therapy with a multi-targeted TKI
G. Other

Case Study Question 1: Decision

You decide to initiate treatment with TACE.

13

3/23/2015

Percutaneous Ablative Therapies for HCC

Percutaneous ethanol injection
Acetic acid injection (rarely used)

Chemical ablation

Hot saline injection (rarely used)

Radiofrequency
Microwave
Cryoablation (rarely used)
Laser (clinical trials)

Thermal ablation

Irreversible electroporation
Light-activated drug therapy

New non chemical/non thermal

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 Patients

With HCC by Treatments
Patient Survival

OLT all
Resection all
RFA only

100

TACE only
Survival, %

80

TACE RFA other

Supportive care

60
40
20
0
0

30

60
90
120
Months of Follow
OLT = orthotopic liver transplantation; RFA = radiofrequency ablation; TACE =Up
transcatheter arterial chemoembolization.

150

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

14

3/23/2015

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-carboxy
prothrombin (DCP).

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

Not All HCC Patients Have All Biomarkers

Incidence of AFP, DCP, and AFP-L3%
in 685 patients with known HCC
AFP
>20 ng/dL

DCP
>40 mAU/mL
93

96

110
153
45

15

14
AFP-L3%
>10% of total AFP

159 (23%)

all negative

AFP = alpha-fetoprotein; DCP = des-gamma-carboxyprothrombin;

AFP-L3 = lens culinaris agglutinin A-reactive fraction of AFP.

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

15

3/23/2015

AFP L3% Rises before AFP in Typical

Course of HCC Occurrence Case

AFP: ng/mL

AFP-L3%

HCC diagnosis
Tumor size:
3-5 cm

Before HCC
diagnosis
Tumor size:
2 cm

21 months

Months
AFP conc.

AFP-L3 conc.

AFP-L3%

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

Proposed Imaging Liver HCC Surveillance

Algorithm use FDA Cleared Biomarkers
Poor/Fair
quality US
Or
abnormal
biomarkers

gadoxetate disodium MRI

(Or dynamic CT)

Negative MRI

Liver Dedicated
Surveillance
Ultrasound (US)
+ HCC biomarkers
in at-risk patients*
Good/Excellent
quality US and
normal HCC
biomarkers

US surveillance q6
months with
biomarkers

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

16

3/23/2015

Elastography (Liver Stiffness Measurement

[LSM]) and Predictors of HCC
Parameters Independently Associated with the Presence of HCC
Odds
ratio*

95% CI

Coefficient

Standard
error

P-value

Liver stiffness

8.27

2.5826.46

1.92

0.018

0.0001

Interquartile
range

1.16

1.041.29

1.49

0.055

0.0001

ALT

1.01

0.960.99

0.02

0.009

0.004

AFP

1.04

1.011.08

0.04

0.01

0.009

Main predictors

CI = confidence interval; AFP = alpha-fetoprotein.

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

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

Management ?
Post surgery biomarkers: ~6 weeks post resection

173 patients with curative resection

Tumor markers assessed: AFP, AFP-L3, DCP
AFP = alpha-fetoprotein; DCP = des-gamma-carboxyprothrombin;
AFP-L3 = lens culinaris agglutinin A-reactive fraction of AFP.

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

17

3/23/2015

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
LI-RADS = Liver Imaging Reporting And Data System; ACR = American College of Radiology.
www.acr.org/~/media/ACR/Documents/PDF/QualitySafety/Resources/LIRADS/lirads%20v20131%20w%20note.pdf.
www.acr.org/quality-safety/resources/LIRADS

LI-RADS: Categories
LR-1

Definitely benign

LR-2

Probably benign

LR-3

Intermediate probability for HCC

LR-4

Probably HCC

LR-5

Definitely HCC

LR-5V

Definitely HCC with Tumor in Vein

LR-M

Malignant, not necessarily HCC

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

18

3/23/2015

Liver-specific Contrast Agents for Tumor

Measurement
Development of
hepatocyte-specific contrast
agent improves tumor-toliver contrast in MRIs
Gadolimium ethoxybenzyl
dimeglumine
(Primovist/Eovist) can
improve assessment of
tumor size for accurate
staging

Hypointense nodules indicate

2 small HCCs

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

VEGF Levels as Prognostic Marker

for Tumor Characteristics
Parameters Independently Associated with Vascular Invasion
Variable

Odds
ratio

95% CI

P-value

5.57

2.4812.53

<0.001

4.17

1.869.35

0.001

14.34

1.74117.97

0.013

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

Total tumor diameter:

5 cm vs. <5 cm

Tumor differentiation:
Poor/moderate vs. well-differentiated

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

19

3/23/2015

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

20

3/23/2015

Case Study: Post-TABE MRI

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

Case Study Question 2

What is the best next step to treat this patient?
A. TACE
B. RFA
C. Liver transplantation
D. IV doxorubicin
E. Yttrium-90 microspheres
F. Oral therapy with a multitargeted TKI
G. Other

21

3/23/2015

Case Study Decision

You decide to initiate treatment with the multitargeted TKI
sorafenib.

Case Study Question 3

What is the optimal sorafenib dosage
for this patient?
A. 100 mg orally twice daily
B. 200 mg orally twice daily
C. 400 mg orally twice daily

22

3/23/2015

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

23

3/23/2015

Hallmarks of Cancer
Sustaining
proliferative signaling

Resisting
cell death

Evading growth
suppressors

Activating invasion
and metastasis

Inducing
angiogenesis

Enabling replicative
immortality

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

Pathogenesis of Hepatocellular Carcinoma

HBV or HCV
Diabetes

Alcohol

NASH

Aflatoxins
Inflammation Dysplastic lesions

1540
Chronic years
hepatitis

Cirrhosis

Clonal selection

35%
per year

HCC

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

24

3/23/2015

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

Extracellular
Matrix
Notch

Growth
factor

Wnt
Hedgehog

VEGF

Integrins
Cell
membrane

Cytokines

Receptor
tyrosine
kinase

-catenin

Angiogenesis
Survival and proliferation
Cell adhesion
Immortalization
Metastasis

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

25

3/23/2015

Receptor Tyrosine Kinase Signaling

Receptor tyrosine
kinase

Growth factor
Cell
membrane
P
GRB
EGF
TGF
HB-EGF
IGF-1/IRS
FGF
HGF
PDGF
VEGF
cMET

SOS

Ras
c-Raf

MAPK/Erk1/2

c-fos/c-jun

Cell growth

PI3K/AKT/mTOR Pathway
Growth factor receptor

Growth factor
Cell
membrane

P
PI3K
PTEN

mTOR
Complex 2

PDK1
mTOR

mLST8

SIN1

AKT

Bad

mTOR

mTOR
Complex 1

rictor

Actin cytoskeleton

Cell cycle
progression G1-S

mLST8
P70 S6K
4E-BPI

rictor

Cell survival

Translation of
cell cycle
regulatory protein

26

3/23/2015

Angiogenic Signaling in Cancer

Tumor
cell
Pericyte/
Stellate
cell
PDGF
VEGF
VEGF

Endothelial
cell

Proliferation and migration

Hepatic Resection
Percentage of HCCs deemed
resectable at diagnosis

30% resectable

70% unresectable

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

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3/23/2015

Survival After Surgical

Resection for HCC

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

Radiofrequency Ablation
High frequency
alternating current
Ionic vibration &
heat generation
45C: Protein
denaturation
70C: Thermal
coagulation
100C: Tissue
desiccation

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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3/23/2015

Early HCC Treated with RFA

Lencioni et al, 2005:
206 patients with early stage unresectable HCC treated with RFA
Favorable 5 year survival
3yr Survival

5yr Survival

Child 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...
1yr Survival

3yr Survival

Recurrence

Surgery
(n=93)

97.9%

83.9%

45.2%

RFA
n=55)

100.0%

72.7%

58.2%

P=0.24

P=0.54

Overall survival + recurrence-free survival: RFA = surgical

resection for single small HCC with good hepatic reserve
Rate of local recurrence: RFA > surgical resection
148 patients Child A; case control RFA vs. Surgical resection

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

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3/23/2015

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

Tumor

Catheter placement for

chemoembolization

Tumor receives most of its blood

supply from the hepatic artery
Hepatic
artery

Injection into the hepatic artery

spares most of the normal liver

Liver

Embolization of the hepatic artery

prevents systemic absorption of
chemotherapy agents and induces
ischemic necrosis of tumor

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

Year 1

Survival, %
Year 2

TACE

57

31

26

Supportive
care

32

11

Technique

Year 3

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

Technique

Survival, %
Year 1

Year 2

TACE

82

63

Supportive care

63

27

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.

30

3/23/2015

TACE vs Surgical Resection: A Case-Control

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

Survival, %
Year 1

Year 2

Year 3

Year 5

TACE

96

80

56

30

Surgical
resection

90

80

70

52

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 TACE

For Recurrent HCC
N=103
Treated with 1) RFA, 2) TACE, 3) both
Treatment

Response

Recurrence

1-yr Surv

5-yr Surv

RFA

92%

43%

74%

28%

TACE

69%

57%

66%

20%

RFA + TACE

94%

21%

89%

44%

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

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3/23/2015

Validation of evaluation criteria for TACE Multi

institutional study (JIVROSG-0602)
TACE

Which is the best surrogate

criteria for survival ?

20%

80%

100%

orig.WHO*

mod.WHO*

orig.RECIST*

Reduction: 0%
Response: SD

80%
PR

0%
SD

mod.RECIST*

25%
SD

EASL/JSHCC **

80%
PR

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

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

Response to TACE as a Biological Selection

Criterion for LT in HCC
94.5%

Freedom From Recurrence

1.0
0.8

P = .0017

TACE responders
TACE nonresponders

0.6
0.4
35.4%
0.2
0
0

365

730

1095
Days

1460

1825

LT = liver transplantation; TACE = transcatheter arterial chemoembolization.

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

32

3/23/2015

Intra-arterial Radioembolization With Yttrium-90:

Rationale and History
Radioembolization: Use of intra-arterially delivered yttrium90 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 Bead

Addressing 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.

33

3/23/2015

Complications SAE Comparison: Conventional

TACE vs PRECISION TACE
75% Reduction in SAEs at the
same institution

TACE = transcatheter arterial chemoembolization.

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

Milan Criteria
1 lesion <5 cm

3 lesions, none >3 cm

No evidence of
extrahepatic spread
Based on pre-transplant
imaging
4 year survival is 74%
Recurrence rate is <10%
Validated in several
studies with >1000
patients
5-year survival is >70%
Recurrence is <15%

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

34

3/23/2015

HCC Cumulative Recurrence Rate after Liver

Transplant

Recurrence (%)

50
40
Milan No (n=172)

30
20
10

Milan Yes (n=137)

0
0

Post transplant years

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

Prognostic Factors for Survival after

Liver Transplantation
Parameters Independently Associated with
Survival after Liver Transplantation
Hazard
ratio

95% CI

P-value

3.82

1.808.10

<0.001

Plasma VEGF (>44 pg/mL)

before liver transplant

2.12

1.084.14

0.03

Total tumor diameter (5 cm)

2.63

1.335.18

0.005

Variable
Overall survival
Vascular invasion
Recurrence-free survival

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

35

3/23/2015

Sorafenib: Phase III SHARP Trial: Overall Survival

Intent-to-Treat Population

Survival Probability

1.00
sorafenib
Median: 46.3 weeks (10.7 months)
(95% CI, 40.9-57.9)
placebo
Median: 34.4 weeks (7.9 months)
(95% CI, 29.4-39.4)

0.75

0.50

0.25

Hazard ratio in sorafenib group: 0.69

(95% CI, 0.55-0.87)
P =0.00058*
0

Patients at risk
sorafenib 299
placebo 303

16

24

274
276

241
224

205
179

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

32
40
48
Time (weeks)

161
126

108
78

67
47

56

64

72

38
25

12
7

0
2

80

*OBrien-Fleming threshold for statistical significance: P=0.0077

Sorafenib: Phase III SHARP Trial: Time to Tumor

Progression (Independent Review)
Progression - Free Probability

1.00
sorafenib
Median: 24.0 weeks (5.5 months)
(95% CI, 18.0 30.0)
placebo
Median: 12.3 weeks (2.8 months)
(95% CI, 11.7 17.1)

0.75

0.50

0.25

Hazard ratio: 0.58

(95% CI, 0.45 0.74)
P=0.000007
0

Patients at risk
sorafenib: 299
placebo: 303

12

18

196
192

126
101

80
57

24
30
Time (weeks)
50
31

28
12

36

42

48

14
8

8
2

2
1

54

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

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3/23/2015

Sorafenib: Phase III SHARP Trial: Best Response by

RECIST (Independent Review)

Sorafenib
n=299
%

Placebo
n=303
%

Overall response
Complete response
Partial response

Stable disease

71

67

Progressive disease

18

24

62

42

Progression-free rate at 4 mo
*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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3/23/2015

Case Study: Multitargeted TKI Toxicity

Hand-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

What is the next best step for treatment?
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

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3/23/2015

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

Minimal skin
changes or
dermatitis
(eg, erythema)
without pain

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

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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3/23/2015

Case Study: Multitargeted TKI vs. Chemotherapy

Dermal Toxicity
Chemotherapy-induced and TKI-induced acral erythema differ
in several aspects
Characteristic

Multitargeted TKI

Chemotherapy

Palm and sole

involvement

Localized with
hyperkeratotic plaque or
blisters

Diffuse tender erythema

Plantar surfaces in addition

to nonpressure-bearing
areas

Plantar surfaces

Vacuolar degeneration in
the stratum malpighii with
epidermal acanthosis

Dermal-epidermal interface
dermatitis and vacuolar
degeneration of basilar
keratinocytes

Area of
eruption

Pathology

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

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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3/23/2015

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 Natl
Cancer 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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3/23/2015

Case Study Question 5

What therapies would you initiate before
starting sorafenib?
A. Imodium
B. Vitamin B6
C. Hydrocodone bitartrate
D. Dolasetron mesylate
E. Other
F. None

Phase III Trials of First-Line Therapy in Advanced

HCC
Study drug
(trial acronym)
Sorafenib +
doxorubicin
(CALGB-80802)1

Sorafenib + erlotinib
(SEARCH)2

Mechanism
Sorafenib: multikinase
inhibitor (VEGFR, PDGFR,
Raf, others)

Primary
Data
endpoint expected

Control

Sorafenib

480

OS

On hold

Sorafenib

720

OS

Negative

Doxorubicin: cytotoxic
Sorafenib: multikinase
inhibitor (VEGFR, PDGFR,
Raf, others)
Erlotinib: RTKI of EGFR-1

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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3/23/2015

Phase III Trials of Second-Line

Therapy in Advanced HCC
Study drug
(trial acronym)

Mechanism

Control

Primary
endpoint

Data
expected

Brivanib
(BRISK-PS)1

Selective inhibitor
of 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

Brivanib
(BRISK-APS)4

Selective inhibitor
of 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

Negative

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;
NCT01108705; 5 NCT01755767; 6 NCT01774344; 7 NCT01908426; 8 NCT01287585.

Maximum Tumor Change from Baseline (%)

Brivanib: Can We Find the Subset of Patients Who Will

Benefit? Change in Target Tumor from Baseline

Brivanib
N = 210

Placebo
N = 101

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

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

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3/23/2015

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
HGF = hepatocyte growth factor; ICH = immunohistochemistry
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.

Improved OS in MET
Diagnostic-High Group

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

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3/23/2015

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

Current standard
Interv.
radiology

Hepatology

Surgery

Oncology

Pathology

Treatment
decision
What we want
Patient
call

Treatment

All relevant specialists

Treatment decision
Patient communication

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

45