advanced hcc: management strategies for emerging targeted therapies (powerpoint)

o Sign-In Sheets:– Your attendance counts– Please sign-in

o Assessments and Research– Practice Patterns and Trends Survey Questions– Pre-/Post-Assessment Questions

Please Respond to Questions on the Scantron Sheet Provided

Your Input is Very Important!

DISCLAIMERParticipants have an implied responsibility to use the newly acquired information

to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for

patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by

clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s

product information, and comparison with recommendations of other authorities.

This activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not

recommend the use of any agent outside of the labeled indications. 

The opinions expressed in the activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information

for each product for discussion of approved indications, contraindications, and warnings.

DISCLOSURE OF UNLABELED USE

Disclosure of Conflicts of InterestRobert G. Gish, MD

Reported a financial interest/relationship or affiliation in the form of: Consulting Fee, Bayer Pharmaceuticals Corporation, Onyx Pharmaceuticals, Inc.; Speakers’ Bureau, Bayer Pharmaceuticals Corporation, Onyx Pharmaceuticals, Inc.

Activity Agenda

o Introduction – 5 minso Overview of Epidemiology and Diagnosis of HCC – 10 minso Current and Emerging Management of HCC: Surgical

Management, Loco-Regional Therapy, and Targeted Therapy Development – 30 mins

o Practical Application Cases – 15 mins

Learning ObjectivesUpon completion of this activity, participants

should be better able to:o Identify risk factors associated with HCC, including underlying liver

disease, and to thoroughly assess patients upon presentationo Implement appropriate treatment plans for patients with HCC

according to patient and tumor characteristics and evidence-based clinical guidelines

o Evaluate recent trial data targeting novel agents being evaluated for the treatment of patients with advanced HCC and the potential impact these therapies may have on the current standard of care

o Devise strategies to integrate novel targeted agents into treatment plans for patients with advanced HCC

o Implement a more successful multidisciplinary approach for treating HCC based on expert and evidence-based recommendations

Demographic Question 1

If you are a physician, what is your primary specialty?1. Medical oncology

2. Surgical oncology

3. Radiation oncology

4. Radiation (non-oncology)

5. Internal medicine/primary care

6. Gastroenterology

7. Hepatology

8. Pathology

9. Medical oncology fellow

10. Other physician

Demographic Question 2

If you are not a physician, what is your primary specialty?1. Pharmacy

2. Nurse

3. Nurse practitioner

4. Physician assistant

5. Research

6. Data monitoring

7. Industry

8. Academic

9. Other

Demographic Question 3

In a typical month, how many patients with hepatocellular carcinoma do you treat?1. 1–5

2. 6–10

3. 11–15

4. 16–20

5. > 20

6. I do not treat patients with hepatocellular carcinoma

Practice Patterns and Trends Survey Question 1

What treatment do you utilize most often for a patient with unresectable HCC who is not a transplant candidate?1. Sorafenib

2. Clinical trial

3. Ablation

4. TAE

5. TACE

6. Radioembolization with Yttrium-90 microspheres

7. Stereotactic body radiation therapy

8. Other

Practice Patterns and Trends Survey Question 2

Please rate your level of knowledge regarding sorafenib for the treatment of HCC.1. No knowledge

2. Limited knowledge

3. Somewhat knowledgeable

4. Very knowledgeable

Practice Patterns and Trends Survey Question 3

Please rate your level of knowledge regarding novel targeted agents for the treatment of HCC.1. No knowledge

2. Limited knowledge

3. Somewhat knowledgeable

4. Very knowledgeable

Practice Patterns and Trends Survey Question 4

Please rate your level of knowledge regarding the mechanism of action of ramucirumab.1. No knowledge

2. Limited knowledge

3. Somewhat knowledgeable

4. Very knowledgeable

Overview of Epidemiology and Diagnosis of HCC

Pre-Assessment Question 1

Which of the following regarding LI-RADS is true?1. A system of standardized terminology and criteria to

interpret and report imaging examinations of the liver

2. Currently applies to patients with cirrhosis or at risk for HCC

3. Categorizes observations from LR1 to LR5, reflecting probability of benignity or HCC in at-risk patients

4. 1 and 2 only

5. 2 and 3 only

6. All of the above

Hepatocellular Carcinoma (HCC)

o 5th most common cancer in men; 7th in women worldwideo 3rd leading cause of death from cancer worldwideo Incidence and death rate rising whereas many other

cancer mortality rates are decreasingo Primarily due to Hepatitis B, C and non-alcoholic

steatohepatitis (NASH)o Global HCC: Every 30 seconds, one person in the world

dies from liver cancer. These deaths are preventable!o > 80% of cases occur in people from sub-Saharan Africa,

S-E Asia and eastern Mediterraneano This geography makes up 45% of world’s population

Monsour et al, 2013.

Johannes Brahms

Ray Charles

Édith Piaf

Victims of HCC

Siegel et al, 2014.

Incidence: 33,190

Deaths: 23,000

24,600 8,590

15,870 7,130

Epidemiology: USA 2014 Estimations

US Burden of Diseases, 1990-2010

YLL YLL Rank 1990 2010

Deaths (in thousands)1990 2010

DALY1990 2010

HIV/AIDS 64.5% 7 23 28.6 12.1( 57.7%)

11 33

Cirrhosis 38% 14 8 35.5 49.5( 43.3%)

21 16

Liver Cancer

125.5%

39 30 9.3 19.5( 118.4%)

- -

YLL = Years of Life Lost; DALY = Disability Adjusted Life Years.US Burden of Disease Collaborators, 2013.

Liver Cancer Mortality, US, 2000-2010

National Cancer Institute.

Mortality From CancerIn Obese Men

Calle et al, 2003.

Pathogenesis of Hepatocellular Carcinoma

Adapted from Levrero, 2006.

15-40 yearsCH Cirrhosis

3-5% per yearHCC

pRb1 Pathway(pRb1 LOH, p27, p16 cyclin D1,

gankirin)

TGF-β1 Pathway

p53 familyP53 (mutations if aflatoxin exposure)

p73 altered expression

Wnt pathwayβ-catenin (axin>APC)

Early genetic alterations??

Epigenetic alterations

HBV e HCV

Diabetes Alcohol

NASH

Aflatoxins Inflammation Dysplastic Lesions Clonal Selection

Relevant Pathways in HCC Biology

Avila et al, 2006.

Probability

Survival (months)

P=4.31 x 10-5

Cluster B

Cluster A

Cluster A Pathways• Proliferation• Anti-apoptotic• Ubiquitination• Hypoxia-induced• DNA instability

Molecular Signatures: Etiology,Survival, Metastasis & Stem Cells

Lee et al, 2004.

Cell survivalBad

P70 S6K4E-BPI

Cell cycleprogression G1-S

Translation ofcell cycle

regulatory protein

PI3K

AKT

PDK1

mTOR

mLST8 raptor

mTOR Complex 1

PTEN

mTOR Complex 2

mTOR

mLST8 rictorSIN1

Actin cytoskeleton

Growth factor Growth factor receptorCell

membrane

P

PI3K/AKT/mTOR Pathway

Adapted from Llovet et al, 2008.

IntermediateHCC

Dysregulated GrowthPathways

Advanced/Metastatic HCC

AngiogenesisMetastasisPathways

Receptor Tyrosine Kinase Inhibitor

VEGF Inhibitor orAnti-VEGF Antibody

EarlyHCC

Targeted Therapy for HCC

Courtesy of Robert G. Gish, MD.

Burrel et al: MRI angiography (MRA) superior to helical CT for detection of HCC

Detection of main HCC and additional nodules pre-transplantation vs in explanted livers: Sensitivity of MRA and helical CT

Variables Pathology MRA (%)* CT (%)†

Per-patient basis (n=29)

Sensitivity (detection) 100 100

Sensitivity (characterization) 90 96

Specificity 95 NA

Accuracy 98 NA

Per-nodule basis (n=76), sensitivity analysis*

All HCC nodules 76 76 (58/76) 61 (43/70)

>20 mm 25 100 (25/25) 100 (24/24)

10–20 mm 28 89 (25/28) 65 (17/26)

<10 mm 23 34 (8/23) 10 (2/10)

CT = computed tomography; MRA = magnetic resonance angiography. Burrel et al, 2003.

*MRA was performed in 50 cirrhotic patients; 29 patients presented 76 nodules†Helical CT: Triphasic helical CT was performed in 26 of 29 HCC patients, presenting a total of 70 nodules

Liver-Specific MRI Contrast Agents

o Gadoxetate Disodium– T1 agent: extracellular + hepatocyte– Excretion: 50% renal, 50% liver– Hepatocyte phase: 20 minutes (in addition to dynamic

enhancement)– Lesions lacking hepatocytes have no uptake on

hepatocyte phase (cyst, metastases, most HCCs)– Can visualize the bile ducts

EOVIST® (gadoxetate disodium) Injection, bayerimaging.com.

Surveillance for HCC Reduces Mortality:A Randomized Controlled Trial

o Survival rate higher in screening vs control group (P < .01)

0

Time, Years

1 2 3 4 50.0

0.8

0.6

0.2

0.4

Screening

Su

rviv

al P

rob

abi

lity,

% Control

Zhang et al, 2004.

Percutaneous Ablative Therapies for Hepatocellular Carcinoma

Percutaneous ethanol injection

Acetic acid injection

Hot saline injection

Radiofrequency

Microwaves

Cryoablation

Laser

Irreversible electroporation

Light-activated drug therapy

Chemical ablation

Adapted from Lau et al, 2003.

Thermal ablation

New non chemical/non thermal

Survival Rates of Asian American PatientsWith HCC by Treatments

OLT = orthotopic liver transplantation; RFA = radiofrequency ablation; TACE = transcatheter arterial chemoembolization. Tong et al, 2010.

OLT all

Resection all

RFA only

TACE only

TACE RFA other

Supportive care

Patient Survival

Months of Follow Up0 30 60 90 120 150

0

20

40

60

80

100

Sur

viva

l, %

HCC Is Inhibited in HCV Patients With Sustained Viral Response and Sustained Biochemical

Response Following Treatment With IFN + RBV

CumulativeIncidence

of HCC(%)

AllPatients(N=420)

SVR(n=181)

Non-SVR(n=239)

Non-SVR,SBR

(n=131)

Non-SVR,Non-SBR(n=108)

3-year cumulative incidence

5-year cumulative incidence

SVR = sustained viral response; SBR = sustained biochemical response; IFN = interferon;RBV = ribavirin; HCV = hepatitis C virus.Nakajima et al, 2009.

AFP = alpha-fetoprotein; DCP = des-gamma-carboxy prothrombin;AFP-L3 = lens culinaris agglutinin A-reactive fraction of AFP.Toyoda et al, 2006.

AFP > 20 DCP > 40

AFP-L3% > 10

96 11093

153

45

14

15

159 (23%) all negative

Not All HCC Make All BiomarkersPatient number of AFP-L3%, DCP and AFP

in those with Known HCC (n=685)

AFP-L3%

DCP AFP

2 (0.5%)

3 (0.7%)

9 (2.2%)

15 (3.7%)

26 (6.5%)

81(20.2%)

True Negative

258 (64%)

7 (1.7%)

False PositiveAFP: 25%AFP-L3%: 7%DCP: 9%

N = 401

Utility When Biomarkers are Used in Combination in patients with no known HCC: False Positives

Sterling et al, 2009.

How Do We Use AFP ?

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

o AFP is not a screening or surveillance tool for HCC

Wakodiagnostics.com

Months

AF

P: n

g/m

L

AF

P-L

3%

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

21 months

HCC diagnosisTumor size:

3-5 cm

Before HCC diagnosis

Tumor size: ≤ 2 cm

Sterling et al, 2012.

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

Liver Dedicated Surveillance

Ultrasound (US)+ HCC biomarkersα

in at-risk patients*

Poor/Fairquality US

Or abnormal 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

αblood 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, 2014.

Proposed Liver Ultrasound Algorithm

HCC Lesions Eligible for Automatic Priority Upgrade

Individual Class 5B and 5T Eligible for automatic priority

Single OPTN Class 5A nodule Corresponds to T1 stage HCC and does not qualify for automatic priority MELD points but must be considered towards the overall staging of the patient

Combinations of Class 5A nodules that meet stage T2 criteria

Eligible for automatic priority

For example, a candidate would be eligible for additional priority with:• Two 1.5 cm (5A) lesions; or• One 1.5 cm lesion (5A) and one 2.5 cm lesion (5B); or• One 3.5 cm lesion (5B); or• Two 2.1 cm lesions (5B)

OPTN Policies, 2013.

LI-RADS

o What is LI-RADS?– System of standardized terminology & criteria for imaging exams of liver– Supported and endorsed by ACR– Developed by radiologists with input from hepatobiliary surgeons, hepatologists,

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

o In what patient population does LI-RADS apply?– Patients at high risk for developing HCC

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

o Who can use LI-RADS? – Community and academic radiologists

o 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.American College of Radiology, version 2013.1.

DysplasticNodules

Large Cell Dysplasia

Small Cell Dysplasia

MacroregenerativeNodules

MacroregenerativeNodules

LI-RADS and Possible Premalignant Lesions

Courtesy of Robert G. Gish, MD.

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

American College of Radiology, version 2013.1.

Observation in high-risk patient

Apply ancillary features and then tie-breaking rules to adjust category

Untreated observation

Definitely benign

Probably benign

Neither definitely nor probably benign

LR-1 LR-2

Tumor in vein LR-5V

< 20

LR-3

≥ 20

LR-3

10-19

LR-3

≥ 20

LR-4

Arterial phase hypo- or iso-enhancement

< 10

Arterial phasehyper-

enhancement

LR-3

LR-3 LR-4 LR-4 LR-5LR-4

LR-4 LR-4 LR-5 LR-5LR-4

Diameter (mm):

•“Washout”

•Threshold growth

•“Capsule” One:

≥ Two:

None:

LR-MPossible non-HCC

malignancy

Treated observation

LR-Treated

LI-RADS: Algorithm

American College of Radiology.

LR-5

LR-5 LR-5OPTN5

American College of Radiology; OPTN Policies, 2013.

LI-RADS and OPTN

o LI-RADS: comprehensive system. Addresses entire spectrum of lesions & pseudolesions encountered in patients at high risk for developing HCC. Includes atlas and lexicon of standardized terminology.

o OPTN: focused system. Addresses definite HCC. Does not include atlas or lexicon of standardized terminology. Defers to LI-RADS all observations that do not meet imaging criteria for definite HCC.

o LR-5 and OPTN5: – both indicate 100% certainty for Dx of HCC– essentially equivalent (see Table next slide)

LR-5 OPTN Class 5

1-2cm HCC LR-5: 10-19mm•Arterial phase hyper-enhancement AND ≥ 2 of following:•Washout appearance•Capsule appearance•Threshold growth**

OPTN Class 5A: ≥ 1cm and < 2cm nodule•Increased contrast enhancement on late hepatic arterial phase AND both:•Washout during later contrast phases•Peripheral rim enhancement (capsule/pseudocapsule)

OPTN Class 5A-g: ≥ 1cm and < 2cm nodule•Increased contrast enhancement on late hepatic arterial phase AND the following:•Growth*

≥ 2cm HCC LR-5: ≥ 20mm•Arterial phase hyper-enhancement AND ≥ 1 of following:•Washout appearance•Capsule appearance•Threshold growth**

OPTN Class 5B: ≥ 2cm and ≤ 5cm nodule•Increased contrast enhancement on late hepatic arterial phase AND ≥ 1 of following:•Washout during later contrast phases•Peripheral rim enhancement (capsule/pseudocapsule)•Growth*

OPTN Class 5X: > 5cm nodule•Increased contrast enhancement on late hepatic arterial phase AND ≥ 1 of following:•Washout during later contrast phases.•Peripheral rim enhancement (capsule/pseudocapsule)

HCC with tumor in vein

LR-5V: HCC with tumor in vein•Definite enhancing soft tissue in vein

Imaging criteria not provided,

*OPTN requires growth by 50% or more in diameter during a greater than or equal to 6 month time interval.**LI-RADS defines threshold growth as 50% or more diameter increase during a greater then or equal to 6 month time intervalOr as 100% or more diameter increase during a greater than or equal to 6 month time interval.American College of Radiology.

LR-5 and OPTN-5

LR-5 and OPTN-5o Equivalent with the following exceptions:o LR-5 uses more precisely defined terminologyo LR-5 is simpler

– OPTN uses -A, -B, -X designations, reflecting nodule size– LI-RADS (as of 2014) omits designations (unnecessary complexity).– LI-RADS requires size to be reported conversion to OPTN is easy

o 10-19mm growing arterial phase hyperenhancing nodules without “washout” or “capsule”

– OPTN categorizes these as definite HCC (OPTN 5A-g)– LI-RADS categorizes these as probable HCC (LR-4), because the differential

diagnosis includes intrahepatic cholangiocarcinoma

o Growth assessment if imaging exams are performed ≥ 6 months apart– OPTN does not allow assessment of growth in such cases– LI-RADS does allow assessment of growth in such cases

o Macrovasculoinvasive HCC– LI-RADS has LR-5V category for HCCs with tumor in vein– OPTN does not have category for macrovasculoinvasive HCC

American College of Radiology.

Post-Assessment Question 1

Which of the following regarding LI-RADS is true?1. A system of standardized terminology and criteria to

interpret and report imaging examinations of the liver

2. Currently applies to patients with cirrhosis or at risk for HCC

3. Categorizes observations from LR1 to LR5, reflecting probability of benignity or HCC in at-risk patients

4. 1 and 2 only

5. 2 and 3 only

6. All of the above

7. None of the above

Current and Emerging Management of HCC:

Surgical Management, Loco-Regional Therapy, and Targeted Therapy Development

Pre-Assessment Question 2

Which of the following phase III trials did not reach its primary endpoint?1. Brivanib in the BRISK-FL trial

2. Everolimus in the EVOLVE-1 trial

3. Ramucirumab in the REACH trial

4. Regorafenib in the RESORCE trial

5. 1 and 2 only

6. 3 and 4 only

Barcelona Clinic Liver Cancer (BCLC) Staging Classification and Treatment Schedule: proposed modifications/additions*

Stage 0PST 0,

Child-Turcotte-Pugh A

Stage A-CPST 0-2,

Child-Turcotte-Pugh A or B

Stage DPST >2,

Child-Turcotte-Pugh C

Very early stage (0)Single <2 cm

carcinoma in situ

Early stage (A)Single nodule <5 cmor 3 nodules ≤3 cm,

PST 0

Intermediate stage (B)Multinodular, PST 0

Advanced stage (C)Portal invasion,

N1, M1, PST 1-2

Terminal stage (D)

Hepatocellular carcinoma(Modified from: Llovet JM et al. J Natl Cancer Inst.

2008;100:698-711.)

Single 3 nodules ≤3 cm

Increased portalpressure and elevated

bilirubin levels

Yes

Associated diseases

No YesNo

Resection Liver transplantation(CLT or LDLT)

RFA (PEIa)

TAE or TACE Sorafenib

Supportive Care

Survival <3 months

Median survival 11-20 months

5-year survival 40%-70%

*Sequence: TARE, TABE ±

sorafenib?b

*Combinations,TARE, TABE?b

a Rarely used. b Confirmation required from RCTs.

HCC is Not ‘One Disease’

o Cancer and underlying liver diseaseo Clinically diverse cancer

– physiological staging– anatomical staging

o Molecularly diverse cancer– distinct molecular ‘subtypes’ have begun to be

identified– molecular ‘drivers’ still largely unknown– angiogenesis is a validated target in HCC

Finn, 2010.

Management of Hepatocellular Carcinoma Requires a Multidisciplinary Approach

Radiation Oncology

Pathology

Oncology

Radiology

Hepatobiliary Surgery

Hepatology

Guy et al, 2012.

What We Know About Treating HCC:

o Staging patients is important– physiologic and anatomic

o The only curative approach is surgery (resection or transplant)– Most patients are not candidates for above

o Chemoembolization (TACE) and radiofrequency ablation can improve survival– In selected patients

o Eventually most patients will require systemic treatment if they live long enough

o Cytotoxic chemotherapy has not had any impact on this diseaseo Sorafenib improves survival for patients with advanced HCC

Geographic Variations in Receipt of Potentially Curative Therapy in the Elderly Adjusting for time period, age, sex, comorbidity,

liver disease severity, tumor size, risk factors for HCC

El-Serag et al, 2006.

Adjusted odds ratio 95% confidence interval P-value

San Jose 1.00 - Reference

Utah 3.65 1.41-9.42 0.008

Connecticut 2.41 1.12-5.18 0.024

Detroit 1.77 0.86-3.61 0.119

Hawaii 2.02 0.94-4.36 0.072

Iowa 2.15 1.01-4.55 0.047

Los Angeles 2.47 1.28-4.74 0.007

New Mexico 2.85 1.29-6.29 0.010

San Francisco 1.47 0.73-3.00 0.287

Atlanta 3.24 1.46-7.19 0.004

Seattle 1.24 0.60-2.59 0.565

Llovet et al, 1999.

Survival After SurgicalResection for HCC

Adapted from Colombo et al, 2003.

Hepatic Resection

Percentage of HCCs deemedresectable at diagnosis

30% resectable

70% unresectable

Radiofrequency Ablation

High frequency

alternating current

Ionic vibration &

heat generation

45°C: Protein

denaturation

70°C: Thermal

coagulation

100°C: Tissue

desiccation

Adapted from Minami et al, 2011; Courtesy of Robert G. Gish, MD.

Early HCC Treated with RFAo 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%

o Tateishi et al, 2005:- 1000 RFA procedures in >700 patients:- Survival: 94, 77, and 54% (1-, 3-, and 5-year)

RFA in small resectable lesions?

Lencioni et al, 2005; Tateishi et al, 2005.

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

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

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

o Rate of local recurrence: RFA > surgical resection

Hong et al, 2005.

Treatment: Chemoembolizationo Normal liver gets 75% of blood

supply from portal vein and 25% of blood supply from hepatic artery

o Tumor receives most of its blood supply from the hepatic artery

o Injection into the hepatic artery spares most of the normal liver

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

Tumor

Hepaticartery

Catheter placement forchemoembolization

Ramsey et al, 2004.

Liver

Portal vein

Chemoembolization: Randomized Trials (Nearly Identical Techniques)

TechniqueSurvival, %

Year 1 Year 2 Year 3

TACE 57 31 26

Supportive care 32 11 3

TechniqueSurvival, %

Year 1 Year 2

TACE 82 63

Supportive 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.Lo et al, 2002; Llovet et al, 2002.

Largest Prospective Study of TACE for Unresectable HCC to Date

o N = 8510 patientso Primary endpoint: OSo Multivariate analysis conducted for factors affecting

survivalo OS

– Year 1: 82%; Year 3: 47%; Year 5: 26%; Year 7: 16%– OS better with lesser degree of liver damage

o Factors affecting survival– Child-Pugh stage– TNM stage (OS better with stage I, increasingly worse

progressing toward stage IV)– Alpha-fetoprotein level

OS = overall survival; TACE = transcatheter arterial chemoembolization; TNM = tumor, node, metastasis.Takayasu et al, 2006.

TACE vs Surgical Resection: A Case-Control Prospective Study

TechniqueSurvival, %

Year 1 Year 2 Year 3 Year 5

TACE 96 80 56 30

Surgical resection 90 80 70 52

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

o 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 (27%)

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

CLIP = Cancer of the Liver Italian Program; HBV = hepatitis B virus; TACE = transcatheter arterial chemoembolization. Lee et al, 2002.

Transplanted

All patients

TACE nonresponders

o Overall 5-year survival: 51.9%– Highly significant difference in

5-year survival between downstaged (transplanted) patients and patients not responding to TACE (P < .0001)

o Survival calculated from the beginning of TACE treatment

Su

rviv

al

0

0.2

0.4

0.6

0.8

1.0

0 365 730 1095 1460 1825

Days

80.9%

51.9%

0%

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

LT = liver transplantation; TACE = transcatheter arterial chemoembolization.Otto et al, 2006.

TACE nonrespondersTACE responders

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

0

Fre

edo

m F

rom

Rec

urr

ence

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 et al, 2006.

o Dose: – Main PVT were treated with > 1

cycle (p = 0.0296 with cirrhosis; p = 0.0077 without cirrhosis)

– No significant difference in the median first dose or accumulated radiation dose (Gy)

o Tumor Response:– WHO criteria: 42.2%– EASL (necrosis >50%): 70%– Stable Disease: 34.7%– Progression: 23.1%

Cirrhosis No PVT

N =52

N (%)

Branch

PVT

N = 19

N (%)

Main

PVT

N =11

N (%)

P value

Bilirubin 18 (35) 8 (42) 7 (64) 0.2003

Ascites 8 (15) 1 (5) 6 (55) 0.0042

HE 2 (4) 1 (5) 0 1.0000

EASL = European Association for the Study of the Liver; ECOG, Eastern Cooperative Oncology Group; PVT = portal vein thrombosis; WHO = World Health Organization.Kulik et al, 2008.

Without Cirrhosis

No PVT

N =19

N (%)

Branch

PVT

N =6

(N %)

Main

PVT

N =1

N (%)

P value

Bilirubin 1 (5) 0 0 1.0000

Ascites 0 1 (17) 0 0.2692

HE 0 0 0 -

Adverse Events:

Results

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

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

o Yttrium-90 microspheres– Average diameter: 20-30 µm – 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 et al, 2006.

o Phase II study: N = 108 (37 with PVT, 71 without PVT)

o Stratified by toxicity: Child-Pugh score (in cirrhotics), dose, location of PVT

o Median dose: 134 Gy

o Partial response rate: 42% (WHO), 70% (EASL)

o Adverse event rate highest in patients with main PVT and cirrhosis

o Median survival, main PVT: 133.5 days

– Branch PVT: 304 days

– No PVT: 467 days

Yttrium-90 Radiotherapy for HCC Patients With and Without PVT

EASL = European Association for the Study of the Liver; WHO = World Health Organization; PVT = portal vein thrombosis.Kulik et al, 2008.

PRECISION TACE with DC Bead™Addressing the challenge of improved survival

in hepatocellular carcinoma

Courtesy of Dr. David Brophy, St. Vincent’s University Hospital, 2013.

Assessing Response in HCCWHO RECIST

Complete Response (CR)

Disappearance of lesion(s)

Disappearance of lesion(s)

Partial Response (PR)

≥ 50% decrease ≥ 30% decrease

Stable Disease (SD)

Neither PR or PD Neither PR ≥or PD

Progressive Disease (PD)

≥ 25% increase; no CR,PR or SD

documented before increase

≥ 20% increase; no CR,PR or SD

documented before increase

EASL Criteria

CR Disappearance of intratumoral arterial enhancement

PR ≥ 50% decrease of arterial enhancement

SD Neither PR or PD

PD ≥ 25% increase of arterial enhancement

Therasse et al, 2000; Bruix et al, 2001.

Milan Criteria

o No evidence of extrahepatic spread

o Based on pre-transplant imaging

o 4 year survival – 74%o Recurrence rate -

<10%o Validated in several

studies with > 1000 patients– 5 yr survival >70%– Recurrence < 15%

3 lesions, none > 3 cm

1 lesion < 5 cm

Mazzaferro et al, 1996.

0

10

20

30

40

50

0 1 2 3

Rec

urr

ence

(%

)

Post transplant years

Milan No (n=172)

Milan Yes (n=137)

Cumulative Recurrence Rate

Todo et al, 2004.

Current MELD Upgrade for HCC

o Patients outside Milan criteria – Listed without MELD upgrade– Transplanted at discretion of individual transplant

centers on patient’s calculated MELD

o Patients downstaged with liver directed therapy– Special case to the Regional Review Board (RRB) for

MELD upgrade to 22 with upgrade q 3 months as a special case

MELD = Model for End-Stage Liver Disease.Kamath et al, 2007.

Survival estimate by preoperativeimaging assessment

Survival estimate bypathologic explant examination

Duffy et al, 2007.

(n=109)

(n=185)

(n=173)

79%

64%

41%

86%

71%

32%

(n=208)

(n=133)

(n=126)

UCLA Experience: 467 HCC Patients

Molecular Targeted Therapies Assessed in Phase II Clinical Trials in HCC

Adapted from Shin et al, 2013 and Zhu, 2013.

sorafenib

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

Su

rviv

al P

rob

abil

ity

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)

Placebo

(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

*O’Brien-Fleming threshold for statistical significance was P=0.0077.

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

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

Llovet et al, 2008.

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

Pro

gre

ssio

n-Fre

e P

rob

abil

ity

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

Pro

gre

ssio

n-Fre

e P

rob

abil

ity

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

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

Llovet et al, 2008.

sorafenibn=299

%

Placebon=303

%

Overall response

Complete response 0 0

Partial response 2 1

Stable disease 71 67

Progressive disease 18 24

Progression-free rate at 4 mo 62 42

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

*Not assessable: sorafenib (8.7%), placebo (8.3%).RECIST=Response Evaluation Criteria in Solid Tumors.Llovet et al, 2008.

Phase II SPACE Trial: Sorafenib orPlacebo in Combination With TACE for

Intermediate-Stage HCCo Phase 2, randomized, double-blind, placebo-controlled study of

sorafenib or placebo in combination with TACE with DEBDOX for intermediate-stage HCC

TACE = transarterial chemoembolization; DEBDOX = doxorubicin-eluting beads; EHS = extrahepatic spread; MVI = macroscopic vascular invasion; TTP = time to radiologic progression.Lencioni et al, 2012.

Selected EligibilityCriteria

• Unresectable HCC• Multinodular HCC• Child-Pugh A without

ascites or encephalopathy

• ECOG PS 0

Selected ExclusionCriteria

• EHS/MVI• Contraindication to

TACE

RANDOMIZE

TACE with DEBDOX + sorafenib 400 mg bid

TACE with DEBDOX +

placebo

Primary Endpoint• TTP

Secondary Endpoints• OS• Safety• Time to untreatable

progression• Time to vascular

invasion/EHS• Biomarker analysis• Patient-reported

outcomes

1:1 (n = 307)

Phase II SPACE Trial: Results

o 307 were randomized– Sorafenib (n=154)– placebo (n=153)

o Median TTP (50th percentile) was 169 days in the sorafenib group; 166 days in the placebo groups

o TTP at the 25th and 75th percentiles (preplanned) was 112/88 days and 285/224 days in the sorafenib and placebo groups, respectively

Assessment*

TTP OS*** Time to VI/EHS***

TTUP

HR 0.797 0.898 0.621 1.586

95% CI 0.588, 1.080 0.606, 1.330 0.321, 1.200 1.200, 2.096

P value (1-sided)**

0.072 0.295 0.076 0.999

* = ITT population (all randomized patients; ** = predefined alpha = 0.15; *** = median was not reached in either group.EHS = extrahepatic spread; VI = vascular invasion; TTP = time to radiologic progression; TTUP = time to untreatable progression.Lencioni et al, 2012.

Unmet Needs in Advanced HCC

o First-line therapies that improve clinical outcomes relative to treatment with sorafenib (the standard of care)1,2 with regard to– efficacy1

– safety and tolerability1

• (options also needed for patients who are ineligible)

– quality of life (QoL)3

o Second-line therapies for patients who progress on or do not tolerate sorafenib1

– What is the natural history of this population after sorafenib?

1. Finn et al, 2010; 2. Llovet et al, 2008; 3. Fan et al, 2010.

Phase III Trials of First-Line Therapy in Advanced HCC

Study drug(trial acronym) Mechanism

Control NPrimary endpoint

Data expected

Sorafenib + doxorubicin(CALGB-80802)1

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

Doxorubicin: cytotoxic

Sorafenib 480 OSOn hold

Sorafenib + erlotinib (SEARCH)2

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

Erlotinib: RTKI of EGFR-1

Sorafenib 720 OSnegative

Linifanib3 Multikinase inhibitor (VEGFR, PDGFR, others) Sorafenib

1035 OSnegative

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.

*Per Central Imaging

Toh et al, 2013.NR = not reached; ORR = objective response rate; OS = overall survival; PFR = progression-free rate; TTP = time to disease progression;TTPr = time to disease progression-radiographic.

aRadiographic progression only.Data available August 2010.

Responses confirmed on 2 visits>4 weeks apart.

010.5 [2.9, 24.8]9.1 [2.5, 21.7]ORR% [95% CI]

2.5 [1.0, 4.5]10.4 [8.4, 14.3]9.7 [6.4, 12.2]OS, medianmo [95% CI]

NR [3.7, NR]5.4 [3.6, 9.2]5.4 [3.6, 7.3]TTPra, medianmo [95% CI]

Secondary

16.7 [0.4, 64.1]34.2 [19.6, 51.4]31.8 [18.6, 47.6]PFR at 16 Weeks% [95% CI]

Primary

Child-Pugh Bn=6

Child-Pugh A n=38

All Patients n=44

Endpoints

010.5 [2.9, 24.8]9.1 [2.5, 21.7]ORR% [95% CI]

2.5 [1.0, 4.5]10.4 [8.4, 14.3]9.7 [6.4, 12.2]OS, medianmo [95% CI]

NR [3.7, NR]5.4 [3.6, 9.2]5.4 [3.6, 7.3]TTPra, medianmo [95% CI]

Secondary

16.7 [0.4, 64.1]34.2 [19.6, 51.4]31.8 [18.6, 47.6]PFR at 16 Weeks% [95% CI]

Primary

Child-Pugh Bn=6

Child-Pugh A n=38

All Patients n=44

Endpoints

Linifanib: Who benefited? What are predictive markers? Study M06-879: 1st or 2nd Line Advanced HCC Best Percentage Change from Baseline in Target Lesions

Study drug(trial acronym) Mechanism

Control NPrimary 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 2014

Brivanib(BRISK-APS)4

Selective inhibitorof FGFR + VEGFR Placebo 252 OS 2014

Tivantinib

(METIV-HCC)5 cMET inhibitor Placebo 303 OS 2014

Regorafenib

(RESORCE)6 VEGFR inhibitor Placebo 530 OS 2016

Cabozantinib

(CELESTIAL)7cMET, VEGFR2, RET Placebo 760 OS 2016

ADI-PEG-208

Arginine-deiminase Placebo 633 OS 2014

Phase III Trials of Second-LineTherapy in Advanced HCC

1 Llovet et al, 2012; 2 Zhu et al, 2014; 3 NCT01140347; 4 NCT01108705; 5 NCT01755767; 6 NCT01774344; 7 NCT01908426; 8 NCT01287585.

Number of Patients at Risk

Brivanib 263 144 92 37 20 9 3 2 1 0 0 0 0Placebo 132 45 21 6 5 2 1 1 1 1 1 1 0

Events / patients 151 / 263 75 / 132

Median TTP, mo 4.2 2.7

HR (95% CI) 0.56 (0.42 – 0.78)

P (log rank) 0.0001

Llovet et al, 2012.

BRISK-PS: Decreased Time to Progression (but no change in survival: data not shown)

Max

imu

m T

um

or

Ch

ang

e f

rom

Bas

elin

e (%

)

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 et al, 2012.

Ramucirumab

o VEGFR-2 and its ligands (including VEGF-A, -C, and -D) are important mediators of angiogenesis and angiogenesis is integral to HCC carcinogenesis and pathogenesis

o Ramucirumab is a recombinant human monoclonal antibody (MAb) of the immunoglobulin G, subclass 1 (IgG1) that binds to the extracellular domain of VEGFR-2 with high specificity and affinity

o Ramucirumab was well tolerated in 2 Phase 1 studies involving patients with advanced, refractory solid tumors; and 2 HCC patients (receiving doses of 10 mg/kg Q2W) had disease stabilization on-study for 9 and 14 months, respectively

VEGFR-2 = vascular endothelial growth factor receptor 2.Zhu et al, 2010.

Best Overall Response and Objective Response Rate

n   (%)  

Best Overall Response

Complete Response (CR) 0 (0%)

Partial Response (PR) 4 (10%)

Stable Disease (SD) 25 (60%)

Progressive Disease (PD) 9 (21%)

Not Evaluable (NE) 4 (10%)

Objective Response Rate

Response Rate (CR + PR) 9.5%

95% CI (3%-23%)

Dis. Control Rate (SD + RR) 69%

95% CI (53%-82%)

Zhu et al, 2013.

Ramucirumab: CP12-0710 Overall Survival

Zhu et al, 2013.

All Patients BCLC C - Child A BCLC C - Child B

OS

Median 12.0 18.0 4.4

95% CI 6.1-19.7 6.1-23.5 0.5-9.0

1 year OS

Rate 49.4%

95% CI 33.1-63.7

BCLC C

Child A

Child B

All Patients

HGF/ c-MET and HCC

o HGF/ cMET signaling plays a role in liver regeneration1

o cMET expression is reported increased in HCC2,3,4

– Prognostic value is unclear

o HGF expression and cMET activation in models can induce tumor growth5

– HGF expression reported to be decreased in HCC

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

o Elevated plasma HGF associated with decreased benefit to sorafenib in SHARP9

HGF = hepatocyte growth factor; ICH = immunohistochemistry1. Borowiak et al, 2004; 2. Kiss et al, 1997; 3. Selden et al, 1994; 4.Tavian et al, 2000; 5. Horiguchi et al, 2002; 6. Ueki et al, 1997;7. Wu et al, 2006; 8. Rimassa et al, 2012; 9. Lovett et al, 2012.

Rimassa et al, 2012; Santoro et al, 2013.

Improved OS in METDiagnostic High Group

Conclusions

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

o Sorafenib has established a benchmark for front-line studies

o Great unmet need for patients who are ineligible for, intolerant to, and who progress on sorafenib

o Integrating new clinical assessment tools into clinical trialso Randomized Phase II trials are needed to better assess

activity for moving agents into Phase IIIo Identify promising new targets for therapy

– 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.

Post-Assessment Question 2

Which of the following phase III trials did not reach its primary endpoint?1. Brivanib in the BRISK-FL trial

2. Everolimus in the EVOLVE-1 trial

3. Ramucirumab in the REACH trial

4. Regorafenib in the RESORCE trial

5. 1 and 2 only

6. 3 and 4 only

Practical Application Cases

Case Study 1

o 65 year old Asian man– Chronic HBV treated with tenofovir– No decompensation (MELD 6)– Good functional status

o HCC screening– CT: 2.6 cm (S6) enhancing mass with PV washout– AFP 15 ng/ml

o Referred for evaluation

HBV = hepatitis B virus; MELD = model for end-stage liver disease; PV = portal venous; AFP = alfa-fetoprotein.

Case Study 1 (cont.)

o PE: anicteric, no stigmata– Liver / spleen not palpable, no ascites– No hepatic bruit

o Lab: bili 0.5, AP 75, AST 45 ALT 63– WBC 3.9 Hgb 16.5 PLT 189– PT 10.4 sec (INR 0.9)

Case Study 1: Imaging

portal venous phasearterial phase

3/13/19523/13/195259 YEAR59 YEARMM

Page: 112 of 768Page: 112 of 768

Acq no: 13Acq no: 13KVp: 120KVp: 120mA: 366mA: 366Tilt: 0Tilt: 0RD: 402RD: 402

CT ABDOMEN \T\ PELVIS W \T\ W/O CONTCT ABDOMEN \T\ PELVIS W \T\ W/O CONTARTERIALARTERIAL

9/13/2011 3:17:26 PM 9/13/2011 3:17:26 PM790477790477

APPLIEDAPPLIED LOC: -1081 LOC: -1081

THK: 2THK: 2FFSFFS

IM: 26 SE: 7IM: 26 SE: 7Compressed 11:1Compressed 11:1

DFOV:40.2x40.2cmDFOV:40.2x40.2cmW: 400W: 400

C: 40C: 40Z: 1Z: 1

RR LL

AA

PP cm cm

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Acq no: 14Acq no: 14KVp: 120KVp: 120mA: 297mA: 297Tilt: 0Tilt: 0RD: 402RD: 402

CT ABDOMEN \T\ PELVIS W \T\ W/O CONTCT ABDOMEN \T\ PELVIS W \T\ W/O CONTVENOUSVENOUS

9/13/2011 3:17:54 PM 9/13/2011 3:17:54 PM790477790477

APPLIEDAPPLIED LOC: -1093 LOC: -1093

THK: 2THK: 2FFSFFS

IM: 21 SE: 8IM: 21 SE: 8Compressed 11:1Compressed 11:1

DFOV:40.2x40.2cmDFOV:40.2x40.2cmW: 400W: 400

C: 40C: 40Z: 1Z: 1

RR LL

AA

PP cm cm

Case Study 1: CT / angiographyshowed a second lesion in the left lobe

Case Study 1 (cont.)now with two lesions

o More investigation ?– AFP-L3– Lesion biopsy

o Ablation ? Bridge to surgery or transplant?– PEI– RFA– TACE

o Primary resection – chemo-prevention

o MELD exemption / OLTx ?

PEI = percutaneous ethanol injection; RFA = radiofrequency ablation; TACE = transcatheter arterial chemoembolization;MELD = model for end-stage liver disease; OLTx = orthotopic liver transplantation.

Case Study 1 (continued)

o Options– Primary resection– Liver replacement?– RFA alone– TACE alone– RFA + TACE

o Chemo-prevention after treatment if no OLTx?

Case Study 2:Patient during a Follow-up visit 5 Years After

Diagnosis of HCVo 5 years after your initial evaluation for HCV genotype1,

patient declined INF based therapies historically, at age 40, the patient presents with abdominal fullness, a 5-lb weight loss, and fatigue

o Laboratory tests

– Albumin: 3.0 g/dL– INR: 1.5– Bilirubin: 3 mg/dL– ECOG PS 1

HCV = hepatitis C virus; INF = interferon; INR = international normalized ratio; Eastern Cooperative Oncology Group Performance Status.

Case Study 2:CT Scan Performed

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

o Ascites was seen surrounding the liver and a small amount in the pelvis

Case Study 2 (cont.)

Question 1

What is the best next step to treatthis patient?a) TACE

b) RFA

c) Liver transplantation

d) IV doxorubicin

e) Yttrium-90 microspheres

f) Oral therapy with a multitargeted TKI

g) Other

TKI = tyrosine kinase inhibitor.

Case Study 2: Decision

o You decide to initiate treatment with TACE

Case Study 2: Evolution

o 5 weeks later, a 4-phase CT is performed and shows no residual lipiodol, and now the tumor is 8 cm without evidence of significant necrosis

Question 2

What is the best next step to treatthis patient?a) TACE

b) RFA

c) Liver transplantation

d) IV doxorubicin

e) Yttrium-90 microspheres

f) Oral therapy with a multitargeted TKI sorafenib

g) Other

Case Study 2: Decision

o You decide to initiate treatment with sorafenib

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

Case Study 2:Decision and Evolution

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

o After sorafenib therapy was started, a painfulred palmar rash developed 2 weeks afterstarting therapy

o This was scored as a grade 2 reaction

Case Study 2: Multitargeted TKI Toxicity: Hand-Foot Skin Reaction

o More than 90% of patients experience skin reactions on multitargeted TKI therapy– Incidence of hand-foot skin reaction reported as high as 60%

• 21% in SHARP trial (all grades)

Yang et al, 2008; Autier et al, 2008; Llovet et al, 2008.

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

Question 5

What therapies would you initiate before starting sorafenib?a) Loperamide hydrochloride

b) Vitamin B6

c) Hydrocodone bitartrate

d) Dolasetron mesylate

e) Other

f) None

Question 6

What HCV therapies would you consider before or after starting sorafenib?a) INF + ribavirin

b) SOF + ribavirin for 24 weeks

c) INF + ribavirin + SOF

d) INF + ribavirin + SIM

e) SOF + SIM

f) None

INF = interferon; SOF = sofosbuvir; SIM = simeprevir.

Case Study 2: ProgressionQuestion 7

o The patient progresses after sorafenib

Which of the following would be an acceptable treatment option?

a) Ramucirumab in a clinical trial

b) Brivanib in a clinical trial

c) Regorafenib in a clinical trial

d) All of the above

Audience Q&A

Thank You

o Thank you for participating in this activity,Advanced Hepatocellular Carcinoma:Management Strategies for Emerging Targeted Therapies

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