hepatocellular carcinoma in veterans: multidisciplinary approaches to a growing clinical challenge...

Hepatocellular Carcinoma in Veterans: Multidisciplinary Approaches to a Growing Clinical Challenge

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Program Chairs

Jorge A. Marrero, MD, MSProfessor of MedicineChief of HepatologyMedical Director, Liver TransplantationUT Southwestern Medical CenterDallas, Texas

Alan P. Venook, MDProfessor of Clinical Medicine Division of Medical OncologyUniversity of California, San FranciscoSan Francisco, California


Faculty

Adrian M. Di Bisceglie, MD, FACPProfessor of Internal MedicineChairman Department of Internal MedicineSaint Louis University School of MedicineChief, HepatologyDivision of Gastroenterology and HepatologySaint Louis University HospitalSt Louis, Missouri

Hashem B. El-Serag, MD, MPHChief, Gastroenterology and HepatologyChief, Clinical Epidemiology and OutcomesDepartment of MedicineBaylor College of MedicineHouston, Texas

Douglas Heuman, MD, FACP, FACG, AGAProfessor of Medicine Division of Gastroenterology, Hepatology and NutritionVirginia Commonwealth University School of Medicine Chief of Hepatology and Liver Transplantation Department of Medicine/Gastroenterology SectionHunter Holmes McGuire Department of Veterans Affairs Medical CenterRichmond, Virginia


Faculty

David Kaplan, MD, MSc Assistant Professor of Medicine Division of GastroenterologyUniversity of Pennsylvania Perelman School of MedicineDirector of HepatologyGastroenterology SectionPhiladelphia VA Medical CenterPhiladelphia, Pennsylvania

Paul Martin, MDProfessor of Medicine Chief, Division of HepatologyCenter for Liver DiseaseUniversity of Miami School of MedicineMiami, Florida

James A. Posey, III, MDAssociate ProfessorHematology/OncologyThe University of Alabama at BirminghamBirmingham, Alabama


Faculty

Stacey Stein, MDAssistant Professor of Medicine Yale University School of MedicineSection of Medical OncologyNew Haven, Connecticut

Tamar Taddei, MDAssociate Professor of Medicine Division of Digestive DiseasesDepartment of MedicineYale UniversityDirector, Liver Cancer ProgramsSmilow Cancer HospitalYale-New Haven HospitalVA ConnecticutWest Haven, Connecticut

Melanie B. Thomas, MD, MSAssociate ProfessorDivision of Hematology/OncologyHollings Cancer Center, Medical University- South CarolinaCharleston, South Carolina

Andrew X. Zhu, MD, PhD, FACPDirector, Liver Cancer ResearchMassachusetts General Hospital Cancer CenterBoston, Massachusetts


Faculty Disclosures

Adrian M. Di Bisceglie, MD, FACP, has disclosed that he has received funds for research support from Abbott, Bristol-Myers Squibb, Gilead Sciences, GlobeImmune, Idenix, Janssen, Roche/Genentech, Transgene, and Vertex and has received consulting fees from Bayer, Janssen, Novartis, Roche/Genentech, Salix, and Vertex.

Hashem B. El-Serag, MD, MPH, has disclosed that he has received consulting fees from Gilead Sciences and funds for research support from Aptalis.

Douglas Heuman, MD, FACP, FACG, AGAF, has disclosed that he has received consulting fees from Grifols and funds for research support from Astellas, Bayer, Bristol-Myers Squibb, Celgene, Centocor, Exelixis, Ikaria, Grifols, Millennium, Osiris, Otsuka, Salix, Scynexis, and UCB.

David Kaplan, MD, MSc, has disclosed that he has received funds for research support from Merck.

Jorge A. Marrero, MD, MS, has disclosed that he has received consulting fees from Bayer and Onyx.

Paul Martin, MD, has disclosed that he has received consulting fees from Abbott, Gilead Sciences, Janssen, and Vertex and funds for research support from Abbott and Vertex.


Faculty Disclosures

James A. Posey, III, MD, has no financial relationship(s) with commercial interests to disclose.

Stacey Stein, MD, has disclosed that she has received consulting fees from Onyx-Bayer.

Tamar Taddei, MD, has disclosed that she has received funds for research support from Bayer Health.

Melanie B. Thomas, MD, MS, has disclosed that she has received consulting fees from Celgene and Genentech and fees for non-CME/CE services received directly from a commercial interest of their agents (eg, speaker bureaus) from Onyx-Bayer.

Alan P. Venook, MD, has disclosed that he has received funds for research support from Bayer, Genentech, Genomic Health, and Onyx.

Andrew X. Zhu, MD, PhD, FACP, has disclosed that he has received funds for research support from Bayer and Eli Lilly and Company and consulting fees from Daiichi-Sankyo, Eisai, Exelixis, and sanofi-aventis.


Overview

Reasons behind the rapid increase in HCC in the US

Importance of early detection and the guidelines for surveillance in patients at risk

Factors that affect prognosis and treatment options for HCC, including anatomic stage, biological grade, and cirrhosis severity

Curative and palliative treatments

Multidisciplinary collaboration to design the best treatment strategy for the individual patient

Epidemiology


Jemal A, et al. CA Cancer J Clin. 2009;59:225-249.

Trends in Mortality for HCC vs Other Cancers At a time when most

cancer mortality is decreasing, deaths from HCC in the US are increasing

Deaths from HCC are increasing faster than deaths from any other form of cancer

Hodgkin’s lymphomaStomachProstate

ColorectalOropharynx

LarynxLung

GallbladderNon-Hodgkin’s lymphoma

Small intestineBrain

LeukemiaMyeloma

SarcomasBladderKidney

Pancreas

MelanomaEsophagus

Liver

All malignant cancers

-60 -40 -20 0 20 40 60Percent Change

US Cancer Mortality Trends in Men, 1990-2005

Better Worse


National Cancer Institute. SEER fast stats.

Adjusted Incidence of HCC 1975-2009

Between 1975 and 2009, the adjusted incidence of HCC tripled in the US

The trend is continuing

0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

Yr of Diagnosis

Rat

e p

er 1

00,0

00

1975 1980 1985 1990 1995 2000 2005 2009


2013 Estimated US Cancer Deaths

Liver cancer in 2013 estimated as:

– The #5 cancer killer in men (up from #7 in 2005)

– The #9 cancer killer in women (not among top 10 in 2005)

Men 306,920Lung& bronchus

28%Prostate

10%Colon & rectum

9%Pancreas

6%Liver & intraheptic bile duct

5%Leukemia

4%Esophagus

4%Urinary bladder

4%Non-Hodgkin’s lymphoma

3%Kidney & renal pelvis

3%All other sites

24%

Women 273,43026% Lung & bronchus14% Breast

9% Colon & rectum7% Pancreas

5% Ovary4% Leukemia3% Non-Hodgkin’s lymphoma3% Uterine corpus2% Liver & intrahepatic bile duct2% Brain/other nervous system

25% All other sites

Siegel R, et al. CA Cancer J Clin. 2013;63:11-30.


Who Gets HCC?

People with liver cirrhosis of any cause

People with chronic hepatitis B or hepatitis C

Risk increases with

– Male gender

– Age

– Diabetes


Why Is Liver Cancer Increasing?

Liver cancer is increasing because cirrhosis is increasing

Cirrhosis is increasing because

– There are a lot of baby boomers

– They have a high prevalence of hepatitis C

– They are getting older

– They are getting fatter


HCV Among Baby Boomers in the VA

Most HCV infected veterans

– Were born in the baby boom

– Served in Vietnam war era

– Were infected in their 20s

Average duration of infection is now 30-40 yrs

Veterans in this cohort account for ~ 1/3 of all veterans in care and as many as 1 in 8 is seropositive for HCV

Vietnam

Korea & WWII

Gulf

Iraq

Age distribution of veterans in care, DVAMC Richmond, fiscal 2007.

Dominitz JA, et al. Hepatology. 2005;41:88-96.

0

500

1000

1500

2000

Age

Fre

qu

ency

20 40 60 80 100


Others: 38%

HBV:10%

NAFLD:7%

Alcohol alone: 45%

1976-1990

Others: 46%

HBV: 4%

Alcohol alone: 25%

Alcohol and HCV: 7%

HCV alone: 18%

1991-2000

Others: 21%

HBV: 4%

NAFLD: 11%

Alcohol alone: 19%

Alcohol and HCV: 17%

HCV alone: 28%

2001-2008

Trends in HCC Etiology

~50% increase in HCV-related HCC between 1991-2008

Yang JD, et al. Mayo Clin Proc. 2012;87:9-16.


Cirrhosis and HCC in Veterans: A Perfect Storm

Davison J, et al. Public Health Matters. 2009;4:2-4.

Over an 8-yr period (2000-2007) , the number of veterans in care in the VA system with diagnosed cirrhosis increased 2.5-fold, whereas the number of cases of HCC in care increased 5-fold

Patients with HCC

Patients with cirrhosis

Patients (n)

60,00045,00030,00015,000

2007

2006

2005

2004

2003

2002

2001

2000

336955,093

276151,436

232047,914

195344,049

163539,878

131634,693

101328,352

67719,905

0

Detection and Surveillance


HCC Carries a High Mortality Compared With Other Common Cancers 5-yr survival from

diagnosis of liver cancer overall is 15%

The only common cancer with worse overall prognosis is pancreatic cancer (6%)

Siegel R, et al. CA Cancer J Clin. 2013;63:11-30.


Why Is HCC So Lethal?

Cirrhosis is often not diagnosed

Evolves silently, often in multiple foci

Progresses to invade vessels

Spreads via both blood and lymph

Rarely produces symptoms until advanced stage

Most are diagnosed late


Survival by HCC Tumor Stage: VCU/McGuire VA Experience, 1997-2005 Survival of HCC is

strongly related to stage at diagnosis

Earlier detection of HCC could improve outcome

Stravitz RT, et al. Am J Med. 2008;121:119-126.

II

III

IV

I

0

0.2

0.6

0.4

0.8

1.0

0 1 2 3 4 5Yrs

Su

rviv

al


Surveillance Imaging for HCC

Ultrasound is the usual modality for HCC surveillance and detection

Advantages: cheap, safe, supported by data

Drawbacks: operator dependent, limited sensitivity, difficult in obese patients

Masses detected by ultrasound typically require further characterization with other modalities (CT, MRI)

Sonogram shows a smallhypoechoic mass

Wilson SR, et al. Radiology. 2010;257:24-39.


Ultrasound Surveillance in Early HCC: Systematic Review

AFP improves detection to 70%

Every 6 mos significantly better than 12 mos

Study Sensitivity (95% CI) % WeightPateron 1994 0.58 (0.37-0.84) 6.45Kobayashi 1985 0.40 (0.31-0.78) 5.10Arrigoni 1988 0.69 (0.49-0.89) 9.60Oka 1990 0.68 (0.54-0.81) 11.56Cottone 1994 0.87 (0.77-0.96) 12.81Zoli 1996 0.91 (0.84-0.98) 13.41Tradati 1998 0.33 (-0.11 to 0.78) 4.30Henrion 2000 0.67 (0.38-0.96) 7.16Bolondi 2001 0.82 (0.73-0.91) 13.03Tong 2001 0.58 (0.41-0.75) 10.47Santa 2003 0.25 (0.62-0.82) 4.93 Subtotal 0.63 (0.52-0.82) 87.27

0 1.0

Singal A, et al. Aliment Pharmacol Ther. 2009;30:37-47.

(I2 = 76.7%; P < .0001)


HCC Surveillance: Guideline Recommendations Who:

– Patients at risk due to cirrhosis or chronic hepatitis B

How:

– VA and NCCN: recommend AFP and liver ultrasound every 6-12 months

– AASLD and EASL: recommend liver ultrasound every 6 months

NCI and USPHS Task Force do not recommend surveillance for HCC

– Rationale:

– Benefit is has not been proven in cirrhosis

– Cost, risk

Prospective randomized study of surveillance is needed

Diagnosis and Staging


HCC Diagnosis: Dynamic Imaging

HCCs are hypervascular

Tumor blood supply:

– 100% hepatic artery

Liver parenchymal blood supply:

– 30% hepatic artery

– 70% portal vein

Dynamic imaging (MRI, CT) follows tumor density with time after IV contrast bolus

– Requires both arterial enhancement and washout

During early arterial phase on CT, an HCC appears brighter than surrounding liver

In later portal venous phase, the HCC appears darker than surrounding liver (washout)


Diagnosis of HCC: To Biopsy or Not?

Yes

– Positive biopsy provides

– Diagnostic certainty if imaging is inconsistent with HCC

– Prognostic information

– Avoids inappropriate treatment and misleading “cure”

– May be required for experimental treatments

– May permit personalized therapy based on tumor gene expression

No

– Not always feasible

– Not needed if high diagnostic certainty based on imaging

– Risk

– Hemorrhage

– Tumor seeding

– False negatives (up to 1/3 of biopsies) may delay treatment

Heuman DM, et al. Eur J Intern Med. 2012;23:37-39.


Staging of HCC: The ABCs

Prognosis of HCC and treatment options are determined by

– Anatomical extent of tumor (stage)

– Biological aggressiveness (grade)

– Cirrhosis severity and functional status

Staging tests typically include multiphase CT/MRI of abdomen, chest CT, and bone scan


Anatomic Staging: TNM

Goodman J, et al. Arch Surg. 2005;140:459-464.

Stage TNM

I Single tumor < 2 cm

II 1 tumor 2-5 cm or 2 or 3 tumors, largest < 3 cm

III 1 tumor > 5 cm or 2 or 3 tumors, largest > 3 cm

IV4 or more intrahepatic tumors or vascular invasion

or extrahepatic metastasis


AASLD Diagnostic Criteria for HCC

Adapted from Bruix J, et al. Hepatology. 2011;53:1020-1022.

Stable > 18-24 mos Enlarging

Return to surveillance

every 6-12 mos

Proceed according to lesion size

Nondiagnostic of HCC

Repeat imaging and/or biopsy + -

Other diagnosis

Diagnostic of HCC

Typical vascular pattern

Atypical vascular pattern with both

techniques

Atypical vascular pattern

Typical vascular pattern on dynamic

imaging

Treat as HCC

Biopsy

> 2 cm

1 dynamic imaging technique

< 1 cm

Repeat USevery 3-4 mos

1-2 cm

1 dynamic imaging study

Repeat biopsy or imaging follow-up

Change in size/profile

Mass on surveillance US or high AFP in a cirrhotic liver


Child-Pugh Classification of Severity of Liver Disease

Pugh RN, et al. Br J Surg. 1973;60:646-649. Lucey MR, et al. Liver Transpl Surg. 1997;3:628-637.

Measure 1 Point 2 Points 3 Points

Bilirubin, mg/dL < 2.0 2.0-3.0 > 3.0

Albumin, g/dL > 3.5 2.8-3.5 < 2.8

Prothrombin time, sec < 4.0 4.0-6.0 > 6.0

Ascites None Slight Moderate

Encephalopathy, grade None I-II III-IV

Grade Total Points Surgical Risk 2-Yr Survival, %

A (well-compensated disease) 1-6 Good 85

B (significant functional compromise) 7-9 Moderate 60

C (decompensated disease) 10-15 Poor 35


Liver transplantation RFA/PEI

Curative treatments (30%); 5-yr survival: 40%-70%

TACE

Single

Increased Associateddiseases

Normal No Yes

Sorafenib

Portal pressure/bilirubin

3 nodules ≤ 3 cm

Resection Symptomatic (20%); survival

< 3 mosRCTs (50%); 3-yr survival: 10%-40%

Terminalstage (D)

Okuda 1-2, PS 0-2, Child-Pugh A-B

Intermediate stage (B)

Multinodular, PS 0

Okuda 3, PS > 2,Child-Pugh C

Very early stage (0)Single < 2 cm

Carcinoma in situ

Early stage (A)Single or 3 nodules

< 3 cm, PS 0

Advanced stage (C)Portal invasion, N1,

M1, PS 1-2

PS 0, Child-Pugh A

HCC

BCLC Staging and Treatment Strategy

Llovet JM, et al. Journal of the National Cancer Institute. 2008;100:698-711.


Biologically Aggressive HCC

Features– Microvascular invasion

– Satellite nodules

– Diffuse infiltrating growth

– Poorly differentiated

– Mixed cholangio-carcinoma

– Bad molecular signature

– FDG-PET scan positive

– High AFP and AFP-L3%

– Rapid growth

Associated with– Early metastasis

– High risk of recurrence after resection or liver transplantation

– Failure of local control with RFA/TACE

– Poor prognosis

There is no consensus on how to incorporate biology into tumor staging


Importance of Cirrhosis Severity and Functional Status BCLC staging system combines anatomic

extent of disease with severity of liver failure (CTP class) and functional status

Patients with poor functional status or decompensated cirrhosis are stage D regardless of anatomical stage

BCLC stage D has poorest survival and few treatment options

Functional Status

0 Fully active, normal life; no symptoms

1 Minor symptoms; able to do light activity

2Capable of self-care but unable to carry out work activities; up for more than 50% waking hrs

3Limited self-care capacity; confined to bed or chair 50% waking hrs

4 Completely disabled; confined to bed or chair

Pts at Risk, nStage A 64 51 25 8Stage B 60 22 11 4Stage C 76 10 3 1Stage D 39 7 1 0

Log-Rank P ValueA vs B: < .0001

B vs C: .04C vs D: .01

B

A

D C

0

20

60

40

80

100

0 10 20 30 40 50Mos

Su

rviv

al P

rob

abil

ity

60 70

Marrero JA, et al. Hepatology. 2005;41:707-716.

Treatment


Treatment Options for HCC

Curative (stage I-II)

– Thermal ablation (radiofrequency, microwave)

– Resection (partial hepatectomy)

– Liver transplantation (total hepatectomy)

Palliative (stage III-IV)

– Transarterial therapies

– Targeted therapy (sorafenib)


Solitary Liver Cancers < 5 cm May Be Cured by Resection or Ablation

Normal bilirubin concentration, and the absence of clinically significant portal hypertension measured by hepatic vein catheterization (hepatic vein pressure gradient <10 mmHg) are predictors of excellent outcomes after surgery

Bruix J, Serman M. Hepatology. 2005;42:1208-1236.


Radiofrequency Ablation

B


RFA Candidacy

Unresectable, liver-dominant

Best: < 3 lesions < 3 cm

Location: not subcapsular, not subdiaphragmatic, not near major vessels

Visible by US/non-contrast CT

– Can lipiodol label in rare cases

Adequate clotting function


RF Ablation - Complications

Pain

Fever

Abnormal LAEs

Vasovagal/Hypotension

Pleural Effusion (0.6%)

Pneumothorax

Hemorrhage (0.5%)

Ascites

Cholangitis

Abscess

Hepatic Infarct

Biliary Stricture

Tumor Seeding

Skin burns


RFA for Very Early–Stage HCC

Author Child-Pugh Class

N Survival

1 Yr 3 Yrs 5 Yrs

Lencioni[1]AB

14443

10089

7646

5131

Tateishi[2]A

B/C22198

9690

8365

6331

Choi[3]AB

359160

NANA

7849

6438

1. Lencioni R, et al. Radiology. 2005;234:961-967. 2. Tateishi R, et al. Cancer. 2005;103:1201-1209. 3. Choi D, et al. Eur Radiol. 2007;17:684-692.


Simon CJ, et al. Radiographics. 2005;25(suppl 1):S69-S83.

Microwave Ablation

Kills tumor by heating tissue with microwaves

Approach, application similar to RFA

Advantages

– Easier targeting

– Less “heat sink” effect of adjacent vessels

– Less painful


Randomized Trial of RFA vs Resection: No Survival Difference N = 168

HCC < 4 cm and up to 2 nodules

85% positive for viral hepatitis (77% with HBV)

Feng K, et al. J Hepatol. 2012;57:794-802.

0

0.2

0.6

0.4

0.8

1.0

0 6 12 18 24 30Mos

Pro

bab

ility

of

Su

rviv

al

36

OS

Resection groupRadiofrequency ablation groupCensored

Pts at Risk, nRES group 84 75 70 66 63 55 52RFA group 84 73 67 64 58 50 46


Resection or Thermal Ablation for HCC: Pros and Cons Potentially curative

Best results with solitary small tumors

Some lesions may be untreatable due to location

Some patients may be untreatable due to severity of liver disease

Significant procedural morbidity

Does not cure cirrhosis

Does not eliminate risk of new HCCs


Total Hepatectomy With Liver Transplantation for Early-Stage HCC Transplantation

– Cures cancer

– Eliminates cirrhosis

Feasibility demonstrated in a landmark study by Mazzaferro in 1996

Inclusion criteria (N = 48)

– Unresectable HCC

– Staging criteria

– Single lesion < 5 cm or

– < 3 lesions, each < 3 cm

Following liver transplantation,

– Actuarial survival at 4 yrs: 75%

– Recurrence-free survival at 4 yrs: 83%Mazzaferro V, et al N Engl J Med. 1996;334:693-699.

Pts at Risk, n

0

20

60

40

80

100

0 6 12 18 24 36

Mos After Transplantation

OS

(%

)

4830 42

48 45 40 32 27 21 17 9 5


Effect of MELD Exceptions on Transplantation for HCC Since 2002

– Transplantation for HCC within Milan criteria has been given high priority (MELD exceptions)

– LT for HCC increased 6-fold: now > 20% of all LT’s performed

Ioannou GN, et al. Gastroenterology. 2008;134:1342-1351.

HCC, no exceptionHCC, MELD exception

Liv

er

Tran

spla

nta

tio

n R

eci

pie

nts

W

ith

HC

C (

%)

30

25

20

15

10

5

0

Pre-MELD Era MELD Era

1997 1998 1999 2000 2001 2002 2003 2006 20072004 2005


Transplantation for HCC: Expanding the Limits via “Downstaging” Extended stage criteria (3A)

– 1 lesion >5 cm and ≤ 8 cm or

– < 3 lesions, largest ≤ 5 cm or

– < 5 lesions, largest ≤ 3 cm

– Total sum ≤ 8 cm

– No vascular invasion

Required for downstaging

– Tumor ablation

– 3-mo follow-up showing lack of further progression

Downstaged HCC then listed and transplanted under MELD exception

In 61 patients exceeding Milan criteria

– 71% successfully downstaged

– 57% underwent LT

– 4-year survival post LT = 92%

– No posttransplant recurrence

Predictors of failure

– AFP > 1000

Yao FY, et al. Hepatology. 2008;48:819-827.


Limits of Liver Transplantation for HCC

Arithmetic: Only 1 in 10 patients with end-stage liver disease or HCC can receive liver transplantation because of the scarcity of donor livers

Transplantation can only be offered if there is good chance of long-term survival benefit

Considerations include

– Expected poor survival with alternative treatments

– Medical and surgical risk (comorbidities)

– Compliance and sobriety

– Social support


Palliation of HCC: Transarterial Chemoembolization Treatment strategy combines

– Selective arteriography (precise targeting)

– Chemotherapeutic drugs (produce necrosis)

– Adsorbent (release chemo drugs gradually)

– Embolization (produce ischemia, prevent washout)

Numerous technical variations


Palliative TACE Prolongs Survival in Unresectable HCC

Llovet J, et al. Lancet. 2002;359:1734-1739. Llovet J, et al. Hepatology. 2003;37:429-442.

40 29 14 4 235 19 7 3 0

0

20

60

40

80

100

0 12 24 36Mos Since Randomization

Pro

bab

ilit

y o

f S

urv

ival

(%

)

48 60

Chemoembolisation (n = 40)Control (n = 35)

Log-rank P < .009

Author, Journal YrPatientsLin, Gastroenterology 1988 63GETCH, NEJM 1995 96Bruix, Hepatology 1998 80Pelletier, Hepatol 1998 73Lo, Hepatology 2002 79Llovet, Lancet 2002 112Overall 503

Random Effects Model (DerSimonian & Laird)

0.01 0.1 0.51 2 10 100

z = 2.3P = .017Pts at Risk, n

OR (95% CI)


TACE: Pros and Cons

Pros

– Effective with large and hard-to-reach tumors

– May delay progression and prolong survival

– May allow downstaging of T3A tumors to T2 for transplantation candidacy

Cons

– Can produce hepatic failure (avoid in CTP class B-C or portal thrombosis)

– Rarely curative


Radioembolization: Therasphere

Glass microspheres (20-30 microns) embedded with yttrium-90, a beta emitter with half-life of 64 hrs

Embolized angiographically (like TACE)

Produce local radiation damage with path length averaging 2.5 mm

Contraindicated with large arterial portal shunts

Costs $15K per dose administered

Not widely used in the VA


Targeted Therapy: Sorafenib Multispecific, blocks tyrosine kinase receptors regulating tumor proliferation and angiogenesis

Wilhelm SM, et al. Cancer Res. 2004;64:7099-7109. Wilhelm SM, et al. Mol Cancer Ther. 2008;7:3129-3140.

RAS

Vascular cell

Angiogenesis:

VEGFF

VEGFR-2PDGFR-b

Paracrine stimulation

Mitochondria

Apoptosis

Tumor cell

PDGFVEGF

EGF / HGF

ProliferationSurvival

Mitochondria

HIF-2

Nucleus

Autocrine loop

Apoptosis

ERK

RAS

MEK

RAF

Nucleus

ERK

MEK

RAF

Differentiation

Proliferation

Migration

Tubule formation

PDGF-bEGF/HGF


Palliation of HCC: Sorafenib

Prior to 2007, no therapy was of benefit in advanced HCC

SHARP trial: CTP A patients with advanced HCC randomized to sorafenib 400 BID vs placebo

Sorafenib delayed progression and prolonged survival from 7.9 to 10.7 mos

Led to approval by the FDA in 2008 for palliation of advanced-stage HCC

It remains the only approved systemic therapy for HCC

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

SorafenibPlacebo

P < .001

Time to Radiologic Progression

Mos Since Randomization0 1 2 3 4 5 6 7 8 9 10 11 12

1.00

0.75

0.50

0.25

0

Pro

bab

ility

of

Rad

iolo

gic

P

rog

ress

ion

299 267 155 101 91 65 37 23 18 10 4 2 0303 275 142 78 62 41 21 11 10 3 1 1 0

Pts at Risk, nSorafenibPlacebo

SorafenibPlacebo

P < .001

OS

Mos Since Randomization

1.00

0.75

0.50

0.25

0Pro

bab

ility

of

Su

rviv

al

Pts at Risk. nSorafenibPlacebo

0 1 2 3 4 5 6 7 8 9 10 11 1213141516 17

299 290 270 249 234 213 200 172 140 111 89 68 48 37 24 7 1 0

303 295 272 243 217 189 174 143 108 83 69 47 31 23 14 6 3 0


Phase III SHARP Study: Sorafenib vs Placebo in Advanced HCC

Primary endpoints: OS, time to symptomatic progression

Secondary endpoint: TTP (independent review), disease control rate, safety

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

Stratified by macroscopic vascular invasion and/or extrahepatic spread;

ECOG PS; geographical region

Patients with advanced HCC, Child-Pugh A, at least

1 untreated lesion,ECOG PS ≤ 2, no previous

systemic treatment, life expectancy ≥ 12 wks

(N = 602)

Sorafenib 400 mg PO BID, continuous dosing

(n = 299)

Placebo 2 tablets PO BID, continuous dosing

(n = 303)


SHARP: Overall Survival

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

Mos Since Randomization

Pro

bab

ility

of

Su

rviv

al

0

0.25

0.50

0.75

1.00

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

SorafenibMedian: 10.7 mos(95% CI: 9.4-13.3)

PlaceboMedian: 7.9 mos(95% CI: 6.8-9.1)

HR (S/P): 0.69 (95% CI: 0.55-0.87;P < .001)


Phase III Sorafenib vs Placebo in Asian Patients With Advanced HCC

No predefined primary endpoint

Secondary endpoints: OS, TTP, TTSP (FHSI-8), disease control rate (RECIST), safety

Patients with advanced HCC, Child-Pugh A, ECOG PS 0-2, no previous systemic treatment, life expectancy ≥ 12 wks(N = 226)

Stratified by macroscopic vascular invasion and/or extrahepatic

spread, ECOG PS, geographic region

Sorafenib400 mg PO BID

(n = 150)

PlaceboPO BID(n = 76)

Randomized 2:1

Cheng AL, et al. Lancet Oncol. 2009;10:25-34.


Su

rviv

al P

rob

abili

ty

SorafenibMedian: 6.5 mos(95% CI: 5.6-7.6)

PlaceboMedian: 4.2 mos(95% CI: 3.7-5.5)

HR (S/P): 0.68 (95% CI: 0.50-0.93; P = .014)

0.25

0.50

0.75

1.00

0

Mos

150 134 103 78 53 32 21 15 13 4 1 076 62 41 26 23 15 9 5 4 1 0 0

Sorafenib

Pts at Risk, n

Placebo

0 2 4 8 10 12 14 16 20 226 18

Cheng AL, et al. Lancet Oncol. 2009;10:25-34.

Sorafenib HCC in Asia: Survival


SHARP vs Asia/Pacific Results

Eligibility criteria identical

Patient characteristics similar except for

– Substantial % with underlying HBV

– Major difference in previous therapies

Difference in outcome not readily explained

1. Llovet JM, et al. N Engl J Med. 2008;359:378-390. 2. Cheng AL, et al. Lancet Oncol. 2009;10:25-34.

OS, Mos Sorafenib Placebo

SHARP[1] 10.7 7.9

Asia/Pacific[2] 6.5 4.2


Biomarkers for Sorafenib? Not Ready for Prime Time

Tissue Biomarkers

Nuclear pERK IHC 2-4+ associated with prolonged TTP in phase 2 study of sorafenib[1]

– 33/137 (24%) had available tissue for pERK testing; 18/33 scored 2-4+

Tissue pERK staining was not associated with outcomes in SHARP[2] (N = 110/602, 18%)

Circulating Biomarkers Plasma biomarkers studied in

SHARP trial[3] (N = 491/602, ~ 81%)

– Baseline ↑ sc-Kit, ↓ HGF (SOR arm) and ↓ Ang2 and ↓ VEGF (placebo arm) associated with ↑ OS in multivariate analyses

– sVEGFR2, sVEGFR3, Ras, EGF, FGF, IGF2 were not prognostic

None predicted benefit

– Trend towards improved OS in subset with baseline ↑ sc-Kit in SOR arm over placebo

1. Abou-Alfa GK, et al. J Clin Oncol. 2006;24:4293-4300. 2. Llovet JM, et al. N Engl J Med. 2008;359:378-390. 3. Llovet JM, et al. Clin Cancer Res. 2012;18:2290-2300.


New Directions in HCC Treatment:Clinical Trials New targeted therapies

Newer locoregional therapies

– Stereotactic radiation therapy

– Radioembolization

– Proton therapy

Combinations of targeted therapies with

– Traditional chemotherapies

– Locoregional therapies (TACE, RFA)

Molecular markers to predict Rx response


Beyond Sorafenib: New Agents in HCC

Agent Molecular Targets Phase Response,

%Median OS,

MosMedian TTP,

MosMedian PFS,

MosSafety:

Grade 3-4 AEs, %

Doxorubicin ± sorafenib[1] II PR: 4.0 13.7 6.4 6.0

Fatigue (6)Hand–foot skin

reaction(6.4)

Sunitinib[2]

VEGFR, PDGFR,

FLT3, KIT, RET

III CR+PR: <7 7.9 4.1 3.6Significant toxicities;

discontinued

Brivanib[3] VEGFR, FGFR II ORR: 4.3 9.8 1.8 2.0

HTN (7.3)Diarrhea (6.5)

Headache (4.3)

Linifanib (ABT-869)[4]

VEGFR, PDGFR II ORR: 6.8 9.7 3.7 NR HTN (18)

Fatigue (14)

Cabozantinib (XL184)[5]

c-MET, VEGFR2 II PR: 9.0 NR NR 4.2

Hand-foot syndrome (15)

Diarrhea(9)TP (9)

Tivantinib(ARQ197)[6] c-MET II NR MET high: 7.2 MET high: 2.9 MET high: 2.4 Neutropenic

sepsis (4.2)

1. Abou-Alfa GK, et al. JAMA. 2010;304:2154-2160. 2. Cheng A, et al. ASCO 2011. Abstract 4000. 3. Finn RS, et al. Clin Cancer Res. 2012;18:2090-2098. 4. Toh H, et al. ASCO 2010. Abstract 4038. 5. Cohn AL, et al. ASCO GI. 2012. Abstract 261. 6. Rimassa, L, et al. ASCO 2012. Abstract 4006.


Kaseb AO, et al. Oncology. 2012;82:67-74.

Phase II Trial Bevacizumab + Erlotinib in HCC (N = 58)

1.00.90.80.7

0.60.50.40.3

0.20.1

0

0 10 20 30 40Mos

OS PFS

Pro

po

rtio

n o

f P

atie

nts


Regimen Study n ResponseRate, %

Median PFS/TTP,

Mos

6-Mo PFS, % Median Survival,

Mos

Single agent Siegel[1] 46 ORR: 13 6.9 65 12.4

Malka[2] 24PR: 12.5SD: 54

NR NR NR

+ GEMOX Zhu[3] 30PR: 20SD: 27

5.3 48 9.6

+ Capecitabine and oxaliplatin

Sun[4] 30PR: 11SD: 78

5.4 40 NR

+ Capecitabine Hsu[5] 25ORR: 16DCR: 60

4.1 34 10.7

+ Erlotinib Kaseb[6] 59 ORR: 24 7.264

(at 4 mos)13.7

Bevacizumab-Based HCC Studies

1. Siegel AB, et al. J Clin Oncol. 2008;26:2992-2998. 2. Malka D, et al. ASCO 2007. Abstract 4570. 3. Zhu AX, et al. J Clin Oncol. 2006;24:1898-1903. 4. Sun W, et al. ASCO 2007. Abstract 4574. 5. Hsu C, et al. ASCO 2007. Abstract 15190. 6. Kaseb AO, et al. Oncology. 2012;82:67-74.


Cabozantinib (XL184) Target Profile

Kinase IC50 (nM)

MET 1.8

VEGFR2 0.035

RET 5.2

KIT 4.6

AXL 7.0

TIE2 14

FLT3 14

S/T Ks (47) > 200

ATP competitive, reversible

RTKCellular IC50 (nM)

Autophosphorylation

MET 8

VEGFR2 4

Yakes FM, et al. Mol Cancer Ther. 2011;10:2298-308.


HCC Cohort Effects on Measurable Lesions per Original RECIST (N = 27)*

9 of 16 pts with AFP ≥ 20 ng/mL at baseline had reductions in AFP of >50%

47% of all HCC pts were on study treatment for > 6 mos (N = 30)

0

20

40

60

- 60

- 40

- 20

- 80

% C

han

ge

Fro

m B

asel

ine

§

‡‡‡‡

Previous sorafenibNo previous sorafenib

†

*Best time point response by RECIST 1.0 in patients with ≥ 1 postbaseline tumor assessment. †0% change from baseline. ‡Confirmed PRs. §PR confirmed in randomized stage.

Cohn AL, et al. ASCO GI 2012. Abstract 261.


Tivantinib (ARQ 197): Target MET in HCC

MET

– Only known receptor for hepatocyte growth factor

– Correlated with poor prognosis

Tivantinib

– Selective oral MET inhibitor


Tivantinib vs Placebo in Previously Treated Unresectable HCC Multicenter, randomized phase II trial

Primary endpoint: TTP

Stratification: MET status, HBV vs HCV, and duration of previous therapy

Crossover on PD

Rimassa L, et al. ASCO 2012. Abstract 4006.

Patients with unresectable HCC following failure of 1 systemic therapy,

ECOG PS < 2(N = 107)

Placebo PO BID(n = 36)

Tivantinib 360 mg PO BID(n = 38)

Tivantinib 240 mg PO BID(n = 33)


Tivantinib vs Placebo in Previously Treated Unresectable HCC: TTPMET level predictive of tivantinib benefit: TTP and OS similar with tivantinib vs placebo among patients with low MET expression

ITT

Rimassa L, et al. ASCO 2012. Abstract 4006.

MET Diagnostic High Population

Pro

po

rtio

n o

f P

atie

nts

P

rog

ress

ion

Fre

e

1.0

0.8

0.6

0.4

0

0.2

Wks to Tumor Progression0 10 20 30 40 50 60

Median TTP6.9 wks6.0 wks

TivantinibPlacebo

Patients7136

Events4630

HR: 0.64 (90% CI: 0.43-0.94;log-rank P = .04)

Pro

po

rtio

n o

f P

atie

nts

Su

rviv

ing

1.0

0.8

0.6

0.4

0

0.2

Wks From Date of Randomization0 5 10 15 20 25


TivantinibPlacebo

Patients7138

Events5630

HR: 0.90 (90% CI: 0.57-1.40;log-rank P = .63)

Pro

po

rtio

n o

f P

atie

nts

P

rog

ress

ion

Fre

e

1.0

0.8

0.6

0.4

0

0.2

Wks to Tumor Progression0 10 20 30 40


TivantinibPlacebo

Patients2215

Events1413

HR: 0.43 (95% CI: 0.19-0.97;log-rank P = .03)

Pro

po

rtio

n o

f P

atie

nts

Su

rviv

ing

1.0

0.8

0.6

0.4

0

0.2

Mos From Date of Randomization0 5 10 15 20


TivantinibPlacebo

Patients2215

Events1715

HR: 0.38 (90% CI: 0.18-0.81;log-rank P = .01)

A Multidisciplinary Approach


Multidisciplinary Approach to the Patient With HCC

Pathology Hepatology

Radiology Oncology

Primary care provider

Patient

SurgeryInterventional radiology


Key Questions for Multidisciplinary Action

Is this HCC? If uncertain, how can we best establish the diagnosis?

If HCC, is it potentially curable with surgery? RFA?

Is the patient a liver transplant candidate? If so should transplant be primary, or reserved for salvage?

If not curable, would palliative TACE be of benefit? Would systemic treatment with sorafenib be indicated?

If treated previously, was the treatment successful or is the disease progressing?

Is patient a candidate for a research protocol?


Conclusions

Early-stage HCC may be cured with

– Thermal ablation

– Resection

– Liver transplantation

Advanced-stage HCC may be palliated with

– TACE or XRT

– Sorafenib

– Experimental therapies

Local measures often fail in tumors with aggressive biology

Application of therapies may be limited by severity of cirrhosis

Choosing the optimal treatment requires collaboration of multiple specialties

Go Online for More CCO Education on HCC!

Hepatocellular Carcinoma

Authors: Ghassan K. Abou-Alfa, MD, Eileen O'Reilly, MD

clinicaloptions.com/oncology

http://www.clinicaloptions.com/inPractice/Oncology/Gastrointestinal_Cancer/ch12_GI-HCC.aspx

http://www.clinicaloptions.com/inPractice/Oncology/Gastrointestinal_Cancer/ch12_GI-HCC.aspx

http://www.clinicaloptions.com/oncology

hepatocellular carcinoma in veterans: multidisciplinary approaches to a growing clinical challenge...

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