Hepatocellular Carcinoma

Renown

Univ Nevada Reno

Dept of Medicine: Teaching Conf

May 2009

Disclosures: that are relevant to this presentation I have consulting and speaker arrangements with

– Bayer

– Onyx

I have research contract relationships with

– BMS

– Bayer/Onyx

I do not own stock or have any investment positions in any company relative to this presentation

HCC: Epidemiology

HCC is the most common primary liver malignancy

Worldwide incidence >600,000 cases per year

– Liver cancer is the most rapidly increasing cancer in the U.S.

– 19,160 new cases and 16,780 deaths in 2007

More common in men than women (4:1)

For resection, rate of recurrence can be as high as 50% at 2 years

– Only 12% are eligible for resection or for transplant

– 80%-90% of HCC cases occur in cirrhotic livers

International Agency for Cancer Research. Globocan 2002. Available at: http://www-dep.iarc.fr. Accessed February 19, 2008; Parkin DM et al. Int J Cancer. 2001;94;153-156; American Cancer Society. Cancer Facts & Figures 2007. Atlanta, GA; American Cancer Society, 2007. McGlynn KA et al. Int J Cancer. 2001;94:290-296; McGlynn KA et al. Cancer Epidemiol Biomarkers Prev. 2006;15:1198-1203; Jemal A et al. CA Cancer J Clin. 2006;56:106-130; El-Serag HB. Gastroenterology. 2004;127:S27-S34.

Burden of HCC in the United States

Annual prevalence, incidence, and survival with HCC estimated from SEER database

Costs distribution of costs estimated from 392 HCC patients

Annual estimated cost of HCC in the United States: $454.5 million

– Per-patient cost: $32,907

Healthcare costs accounted for 89.2% of cost

Lost productivity accounted for 10.8% of cost

Lang K, et al. J Hepatol. 2008. In press.

Goodman Z.

Goodman Z.

HCC incidenceHCC incidencetripled over the last three decadestripled over the last three decades

Altekruse, JCO 2009Altekruse, JCO 2009

White Black Hispanic Asian Other Unknown

HC

C (

%)

Kim WR, et al. AASLD 2002. Abstract 223.

25

147

51

04

0

20

40

60

80

100

Proportion of HCC by Patient Race Among Hospitalizations for HBV (1998)

Racial Differences in Survival of Patients with HCC

Racial Differences in Survival of Patients with HCC

CaucasianCaucasian

BlackBlackAsianAsian

HispanicHispanic

00

YearsYears

Su

rviv

al (

%)

Su

rviv

al (

%)

2020

4040

6060

8080

100100

00 11 22 33

Davila J, El-Serag HB. Clin Gastro Hepatol; 2006Davila J, El-Serag HB. Clin Gastro Hepatol; 2006

HCC PrognosisHCC Prognosis

Survival has been improving over last 15 yearsSurvival has been improving over last 15 years Improved survival after resectionImproved survival after resection More diagnosis at earlier stage (screening!)More diagnosis at earlier stage (screening!) More local therapy availableMore local therapy available

0%10%20%30%40%50%

'92-'93 '94-'96 '97-'99 '00-'02 '03-'05

1 Year Survival of HCC

Altekruse, JCO 2009Altekruse, JCO 2009

Overview Screening and Surveillance for HCC: who is at risk and how/when to

screen and complete follow up surveillance

Biomarkers

Imaging

Pathology

Liver Transplant

Regional Therapy for HCC

– Medical Management of Patients Undergoing Regional Therapy for Hepatocellular Carcinoma

Current Trends in the Treatment of Patients With Advanced HCC

Systemic Therapy and Supportive Care in Patients With Advanced Hepatocellular Carcinoma

Management of Hepatocellular Management of Hepatocellular Carcinoma Requires a Carcinoma Requires a

Multidisciplinary ApproachMultidisciplinary Approach

Radiation OncologyRadiation Oncology

PathologyPathology

OncologyOncology

RadiologyRadiology

Hepatobiliary Surgery

Hepatobiliary Surgery

HepatologyHepatology

13

Risk Factors for HCC in US Patients Obesity

Polesel J, et al. Ann Oncol. 2008;[Epub ahead of print]. BFRSS Database. Available at: http://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/. Accessed October 21, 2008.Polesel J, et al. Ann Oncol. 2008;[Epub ahead of print]. BFRSS Database. Available at: http://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/. Accessed October 21, 2008.

Emerging Risk Factor: Obesity (BMI ≥ 30)Emerging Risk Factor: Obesity (BMI ≥ 30)

No Data

< 10% 10-14% 15-19% 20-24% 25-29% ≥ 30%

Background

In the United States and Europe, the majority of HCC develops in the setting of underlying liver cirrhosis

Treatment strategies for HCC should avoid worsening liver function to such an extent that would offset their possible benefit

Staging systems for treatment allocation, therefore, must concurrently consider tumor extension and severity of the underlying liver function impairment

There is no universally accepted staging system for HCC

The BCLC staging system for HCC is the most widely used in Western countries, particularly for treatment allocation

Malignant TransformationMultistep

Potential Targets

Oxidative stress and inflammation

Viral oncogenes Carcinogens

Growth factors Telomere shortening

Cancer stem cells

Loss of cell cycle checkpoints

Antiapoptosis Angiogenesis

Normal liver

Liver cirrhosis

Hepatitis CHepatitis B

EthanolNASH

Epigenetic alterationsGenetic alterations

HCC[2]

Dysplastic nodules[1]

1. Tornillo L, et al. Lab Invest. 2002;82:547-553. 2. Verslype C, et al. AASLD 2007. Abstract 24.

•Event a 3rd line treatment such as lamivudine can decrease HCC risk

•After El Serag EASL 2007

Screening and surveillance for HCC is the standard of care

SOC

•Screening: first test

•Surveillance: all subsequent testing – typically on a regular schedule

AASLD Practice Guidelines on Screening & Surveillance for HCC AASLD recommends surveillance using AFP + US every 6-12 months for at-

risk patient groups:

– Hepatitis B carriers

– Asian males >40 years

– Asian females >50 years

– All cirrhotic hepatitis B carriers

– Family history of HCC

– Africans >20 years

– Non-cirrhotic hepatitis B carriers with high HBV DNA levels or more severe current/past levels of inflammatory activity

– Cirrhosis due to hepatitis C, alcohol, or other causes

Bruix & Sherman. AASLD Practice Guideline: Management of Hepatocellular Carcinoma, Hepatology 2005; 42(5): 1208.

HCC Screening by Ultrasound

Performance characteristics of ultrasound as a screening test

Performance Characteristic, %

Cohort 1Years 1-5

Cohort 1Years 6-8

Cohort 2Years 1-3

Sensitivity 79 87 80

Specificity 94 87 91

PPV 15 13 14

NPV 98 100 100

Collier J and Sherman M. AASLD 1995. Morris Sherman, MB BCh, PhD, FRCP(C). Data on file.

Surveillance for HCC Reduces Surveillance for HCC Reduces Mortality:Mortality:

A Randomized Controlled TrialA Randomized Controlled Trial

Zhang BH, et al. J Cancer Res Clin Oncol 2004Zhang BH, et al. J Cancer Res Clin Oncol 2004

00

Time (Years) Time (Years)

11 22 33 44 5500

.8.8

.6.6

.2.2

.4.4

ScreeningScreening

Su

rviv

al P

rob

abil

ity

(%)

Su

rviv

al P

rob

abil

ity

(%)

ControlControl

Screening/surveillance Current Strategies: US and AFP

US q 6-12 months and AFP q 6 months is the most commonly used strategy in Asia and U.S.

Rationale for 6-month screening/surveillance interval

– Doubling time: median = 6 mo (range, 1-19 mo)

– Growth from 1 to 3 cm: 4 mo for most aggressive, 18 mo for moderately aggressive, 5 yr for indolent HCC

Median detectable subclinical period for HCC = 3.2 yr

Making the diagnosis of HCC

Biopsy is very rarely indicated

– Risk of tracking tumor cells

– High false negative rate

Diagnosis is by imaging criteria

DIAGNOSTIC CRITERIA FOR HCC

EASL CONFERENCES ON HCC, BARCELONA 2005AASLD PRACTICE GUIDELINE, HEPATOLOGY 2005

• Cyto-histological criteria

• Non-invasive criteria (cirrhotic patients)

1. One imaging technique * Focal lesion > 2 cm with arterial hypervascularizationand venous wash-out

2. Two coincident imaging techniques * Focal lesion 1-2 cm with arterial hypervascularizationand venous wash-out

* Three techniques considered: contrast US, CT, and dynamic MRI

AP

PVP

Arterial Phase hypervascular necrotic

Portal Venous Phase“washout” to less than liver

HCC

How do we use AFP ?

AFP is a useful biomarker of a patients increased RISK for HCC in the future

AFP is not a screening or surveillance tool for HCC

Performance Characteristics ofAFP to diagnose HCC Based on Cutoff Level

Colli A, et al. Am J Gastro 2005

Cutoff 10-11 17-21 50 > 100Studies 4 7 4 5(#)

%

Sensitivity/Specificity of DCP and AFP as a Function of Disease Stage Effect of tumor size on the diagnosis of HCC by DCP, AFP

Nakamura S, et al. Am J Gastroenterol. 2006;101:2038-2043.

DCP

Tumor Size Tumor Size

AFP

1-Specificity

Sen

siti

vity

0

0.2

0.4

0.6

0.8

1.0

0 0.2 0.4 0.6 0.8 1.0

3 cm3-5 cm5 cm

1-Specificity

Sen

siti

vity

0

0.2

0.4

0.6

0.8

1.0

0 0.2 0.4 0.6 0.8 1.0

3 cm3-5 cm5 cm

AMERICAN JOURNAL OF GASTROENTEROLOGY by Nakamura S, et al. Copyright 2006 by Blackwell Publishing - Journals. Reproduced with permission of Blackwell Publishing - Journals in the format Copy via Copyright Clearance Center.

Months

AF

P: n

g/m

L

AF

P-L

3%

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

AFP L3% rises before AFP in typical course of HCC occurrence case

21 months

HCC diagnosisTumor size:

3-5 cm

Before HCC diagnosis

Tumor size: ≤ 2 cm

Sterling, Am J Gastro

Current Biomarkers and Risk of Portal Vein Invasion AFP-L3 ≥ 15%

– RR: 2.459 (95% CI: 1.005-6.017; P = .0487)

DCP ≥ 100 mAU/mL

– RR: 3.019 (95% CI: 1.077-8.464; P = .0357)

Number of HCC tumors ≥ 2

– RR: 4.912 (95% CI: 1.619-14.905; P = .0049)

Hagiwara S, et al. J Gastroenterol. 2006;41:1214-1219.

Current Biomarkers and Risk of Microvascular Invasion Independent predictors of microvascular invasion

– Tumor size (< 2, 2-4, > 4 cm)

– Odds ratio: 3.4 (95% CI: 1.5-4.1)

– Preoperative DCP levels (< 100, 100-500, > 500 mAU/mL)

– Odds ratio: 2.2 (95% CI: 1.1-2.4)

– Tumor grade (3-grade system)

– Odds ratio: 2.2 (95% CI: 1.1-3.7)

Shirabe K, et al. J Surg Oncol. 2007;95:235-240.

Incidence of Portal Venous Invasion of HCCin relation to the Serum DCP level 　 at diagnosis

DCP(-): 183 patients with DCP < 100 mAU/mL

Koike Y, et al. Cancer 2001 Feb 1;91(3):561-9

DCP(+): 37 patients with DCP > 100 mAU/mL

DCP predicts clinical course

HCC: overall survival

HCC is treatable

HCC is curable !–In selected patients–Justifying screening and surveillance

Management of HCC

Liver transplantation

Resection

Tumor ablation

– Radiofrequency thermal ablation

– Alcohol injection

– Chemoembolization

Targeted molecular therapy

Chemotherapy

– Regional/systemic

Potentially curative

Staging Strategy and Treatment for Patients With HCC

Liver transplant PEI/RF

Curative treatments

TACE

HCC

Single

Increased Associateddiseases

Normal No Yes No Yes

Terminalstage

PST 0-2, Child-Pugh A-B

Multinodular, PST 0

Portal invasion, N1, M1

Sorafenib

Portal pressure/bilirubin

3 nodules ≤ 3 cm

Intermediate stage

PST > 2, Child-Pugh C

Very early stageSingle < 2 cm

Early stageSingle or 3 nodules

≤ 3 cm, PST 0

Advanced stagePortal invasion,

N1, M1, PST 1-2

PST 0, Child-Pugh A

Resection

Symptomatic (unless LT)

Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.Bruix J, et al. Hepatology. 2005;42:1208-1236.

Treatment for HCC Often Suboptimal

Proportion of patients receiving potentially curative therapy

– 34.0% of patients with single lesions

– 34.0% of patients with lesions < 3 cm

– 19.3% of patients with lesions > 10 cm

– 4.9% of patients with metastatic disease

11.5% of patients ideal for transplantation received it

14.3% of patients ideal for surgical resection received it

El-Serag HB, et al. J Hepatol. 2006;44:158-166.

0.0040.0040.0040.0041.46-7.191.46-7.191.46-7.191.46-7.193.243.243.243.24 AtlantaAtlanta AtlantaAtlanta

0.0100.0100.0100.0101.29-6.291.29-6.291.29-6.291.29-6.292.852.852.852.85 New MexicoNew Mexico New MexicoNew Mexico0.0070.0070.0070.0071.28-4.741.28-4.741.28-4.741.28-4.742.472.472.472.47 Los AngelesLos Angeles Los AngelesLos Angeles0.0470.0470.0470.0471.01-4.551.01-4.551.01-4.551.01-4.552.152.152.152.15 IowaIowa IowaIowa

0.2870.2870.2870.2870.73-3.000.73-3.000.73-3.000.73-3.001.471.471.471.47 San FranciscoSan Francisco San FranciscoSan Francisco

0.5650.5650.5650.5650.60-2.590.60-2.590.60-2.590.60-2.591.241.241.241.24 SeattleSeattle SeattleSeattle

0.0720.0720.0720.0720.94-4.360.94-4.360.94-4.360.94-4.362.022.022.022.02 HawaiiHawaii HawaiiHawaii0.1190.1190.1190.1190.86-3.610.86-3.610.86-3.610.86-3.611.771.771.771.77 DetroitDetroit DetroitDetroit0.0240.0240.0240.0241.12-5.181.12-5.181.12-5.181.12-5.182.412.412.412.41 ConnecticutConnecticut ConnecticutConnecticut0.0080.0080.0080.0081.41-9.421.41-9.421.41-9.421.41-9.423.653.653.653.65 UtahUtah UtahUtahReferenceReferenceReferenceReference----1.00 1.00 1.00 1.00 San JoseSan Jose San JoseSan Jose

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

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

Influence of Cirrhosis on Operative Mortality for HCC

StudyMortality of

Non-cirrhoticsMortality of Cirrhotics

Shanghai 2nd Mil Col, 1960-1977

2% 12%

Keio Univ, 1973-1988 3% 13%Chang Gung Mem Hosp,

1977-19872% 7%

Med Hochschule Hannover, 1974-1988

7% 23%

Shimane Univ, 1980-1990 6% 12%

Hopital Paul Brousse, 1980-1991

3% 10%

MSKCC, 1970-1992 1% 14%

Surgical Resection: only for patients without portal hypertension

Hepatic resection

Percentage of HCCs deemed resectable at diagnosis

1

2

30% resectable

70% unresectable

Colombo, Antiviral Research, 2003

Treatment of HCC in US non-Federal Hospitals in 2000

Surgical Resection: 4.9%

Liver Transplant: 1.8%

Local Ablation: 3.5%

Embolization: 5.5%

Chemotherapy: 11%

Kim WR et al. Gastroenterology 2005

Su

rviv

alS

urv

ival

00 0.50.5 11 1.51.5 22 2.52.5 33 3.53.5 44 4.54.5 55

Follow up Duration (Years) Follow up Duration (Years)

TransplantTransplant

ResectionResection

AblationAblationTACETACE

11

0.80.8

0.60.6

0.40.4

0.20.2

00

Outcomes of HCC Treatment in the Elderly

El-Serag HB et al J Hepatology 2006

Ablation

RFA or TACE is/are the current standard(s)

PEI is for developing countries with limited resources

Microwave is faster to full tumor ablation but resources are expensive

Cryosurgery is no longer used due to length of time of procedure and complications of “ice ball”

-Survival Rates of Patients with small HCC treated with RFA

Trial Year Type of study

# of Pts

Survival Rate %

1 yr 3 yr 5 y

Recurrence Rate %

1y 3 y 5 y

Lencioni

et al

1997 Prospective 206 97 71 48 18 55 83

Lencioni

et al

2000 RCT 102 100 98

Rossi et al 2000 Prospective 41 87 50 19 47

Guglielmi et al

2000 Prospective 53 87 45

Siperstein 2000 Prospective 548 77 38

Cervantes 2003 Prospective 34 94 61 0 20

Treatment: Chemoembolization

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

Tumor receives most of its blood supply from the hepatic artery

Injection into the hepatic artery spares most of the normal liver

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

Tumor

Liver

Portal vein

Hepaticartery

Catheter placement forchemoembolization

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

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%)

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

Lee HS, et al. J Clin Oncol. 2002;20:4459-4465.

Chemoembolization: Efficacy Before Transplantation Major issue: dropout rate (~ 20%)

– Lower in US since adoption of MELD criteria

Role of TACE

– Control tumor and prevent progression

– Should be considered if waiting time > 6 months

Complications from TACE: rare (no increased rate of hepatic artery complications)

Richard HM 3rd, et al. Radiology. 2000;214:775-779.Graziadei IW, et al. Liver Transpl. 2003;9:557-563.Alba E, et al. Am J Roentgenol. 2008;190:1341-1348.

Primary Treatment Modality Used in Korea

TACE 48.2%

RFA1.5%

Surgery 11.2%

Chemotherapy7.5%

Radiotherapy2.1%

Conservative treatment 29.5%

N = 1078

Joong-Won Park, MD, National Cancer Center. Adapted with permission.

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)

1. Lo CM, et al. Hepatology. 2002;35:1164-1171.2. Llovet JM, et al. Lancet. 2002;359:1734-1739.

New Therapies Under New Therapies Under InvestigationInvestigation

Targeted and Targeted and ChemotherapyChemotherapy

Sorafenib* (Nexavar)Sorafenib* (Nexavar) Erlotinib (Tarceva)Erlotinib (Tarceva) Sirolimus (Rapamune)Sirolimus (Rapamune) Capecitabine (Xeloda)Capecitabine (Xeloda) Floxuridine (FUDR)Floxuridine (FUDR) Bevacizumab Bevacizumab

(Avastin)(Avastin) Sargramostim Sargramostim

(Leukine)(Leukine) Oxaliplatin (Eloxatin)Oxaliplatin (Eloxatin) Imatinib (Gleevac)Imatinib (Gleevac)

Local TherapyLocal Therapy Radiation TherapyRadiation Therapy

9090Yttrium microspheres Yttrium microspheres (Therasphere/SIRsphere)(Therasphere/SIRsphere)

Stereotactic RadioSurgery Stereotactic RadioSurgery (Cyberknife)(Cyberknife)

Doxorubicin Doxorubicin Eluting Beads (DC Eluting Beads (DC Bead)Bead)

Photoactive Photoactive chemicals (Litx)chemicals (Litx)

* Sorafenib approved November * Sorafenib approved November 20072007

Absolute contraindications

– Child-Pugh class C disease

– Poor performance status (ECOG PS > 2)

Relative contraindication

– Extrahepatic disease (benefit unclear)

Former contraindication

– PVT

– Minimize embolization and be more selective

Chemoembolization: Ineligibility Criteria

Chemoembolization: Predictors of Survival Lo et al[1]

– Absence of presenting symptoms (ECOG PS < 2)

– Absence of portal vein obstruction

– Tumor size (≤ vs > 5 cm)

– Okuda stage (I vs II)

Llovet et al[2]

– Absence of constitutional syndrome (ECOG PS < 2)

– Low serum bilirubin

– Treatment response (modified WHO criteria, > 6 months)

1. Lo CM, et al. Hepatology. 2002;35:1164-1171.2. Llovet JM, et al. Lancet. 2002;359:1734-1739.

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

Yttrium-90 microspheres

– Average diameter: 20-30 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)

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

Murthy R, et al. Biomed Imaging Interv J. 2006;3:e43.

Clinical Response to Yttrium-90 MicrospheresOutcome Dancey

et al[1]

(N = 20)

Carr et al[2]

(N = 65)Geschwind

et al[3]

(N = 80)

Salem et al[4]

(N = 43)

Response rate, % 39 47

Median survival 378 days(> 104 Gy)

Okuda stage I 649 days 628 days 24.4 mos

Okuda stage II 302 days 384 days 12.5 mos

1. Dancey JE, et al. J Nucl Med. 2000;41:1673-1681.2. Carr BI. Liver Transpl. 2004;10(2 suppl 1):S107-S110.3. Geschwind JF, et al. Gastroenterology. 2004;127(5 suppl 1):S194-S205.4. Salem R, et al. J Vasc Interv Radiol. 2005;16:1627-1639.

Drug Eluting Beads

LC Bead is a Drug Delivery Embolisation System capable of loading and the controlled release of high doses of chemotherapeutic agents

– Doses per ml and per treatment:

– Doxorubicin maximum dose of 37.5mg/ml and 150mg/treatment with 4ml

Novel N-fil technology sulphonate modified hydrogel polymer

Blue tinted to aid visualisation

Delivered as vials containing 2ml Beads in 6ml saline

LC Bead is available in 3 sizes.

– 100-300um

– 300-500um

– 500-700um

Mechanism of Loading the LC Bead with Doxorubicin

The LC Bead has a negative charge where as doxorubicin has a positive charge…

The doxorubicin is loaded and eluted by an ‘reversible ionic exchange mechanism’.

Hydrated Beads

Hydration shell associated with PVA and ionic groups

Bulk (non-bound) waterInteraction of doxorubicin with SO3 groups displaces water from the hydration shells

Loaded Beads

Reducing Systemic Exposure

This is the relative drug distribution for standard arterial chemotherapy vs. conventional TACE vs. precision TACE

Relative Drug Distributions

Conventional TACE vs DCBs-TACEOverall 6-Month Tumour Response Rates

p = 0.11

Disease Control = Objective Response + Stable Disease Objective Response = Complete Response + Partial Response

Lammer et al, CIRSE 2008

ComplicationsSAE Comparison : Conventional TACE vs PRECISION TACE

75% Reduction in SAE’s at the same institution

90Yttrium vs. TACE

90Yttrium does not occlude the vessels at the arteriolar level

– Option for repeat embolic treatment

– Less ischemic damage

Response rates seem to be similar (no head-to-head comparisons)

Equivalent side effect profile

90Yttrium can be used in portal vein thrombosis and in more extensive disease

TACE accepted as treatment of choice for unresectable (nonablatable?) HCC

Prolonged survival established through randomized trials and prospective studies

Best vs good performance status, Child-Pugh class A-B

Role for yttrium-90 microspheres

Growing role for doxorubicin-loaded beads, pending outcome of clinical trials

Conclusions

Surgical treatments: applicable overall to 10% to 15% of HCC at first diagnosis and

2% to 5% of recurrent HCC

Staging Strategy and Treatment for Patients With HCC

Liver transplant PEI/RF TACE

HCC

Single

Increased Associateddiseases

Normal No Yes No Yes

Terminalstage

PST 0-2, Child-Pugh A-B

Multinodular, PST 0

Portal invasion, N1, M1

Sorafenib

Portal pressure/bilirubin

3 nodules ≤ 3 cm

Intermediate stage

PST > 2, Child-Pugh C

Very early stageSingle < 2 cm

Early stageSingle or 3 nodules

≤ 3 cm, PST 0

Advanced stagePortal invasion,

N1, M1, PST 1-2

PST 0, Child-Pugh A

Resection

Symptomatic (unless LT)Nonsurgical treatments: applicable

overall to 65% to 75% of HCC at first diagnosis and 50% to 70% of

recurrent HCC

Liver Transplantation

The only treatment with a major chance of cure for HCC

Su

rviv

alS

urv

ival

00 0.50.5 11 1.51.5 22 2.52.5 33 3.53.5 44 4.54.5 55

Follow up Duration (Years) Follow up Duration (Years)

TransplantTransplant

ResectionResection

AblationAblationTACETACE

11

0.80.8

0.60.6

0.40.4

0.20.2

00

Outcomes of HCC Treatment in the Elderly

El-Serag HB et al J Hepatology 2006

Liver Transplant for HCC in cirrhosisMilan Criteria (Stage I+II)

++Absence of Macroscopic Vascular Invasion

Absence of Extrahepatic Spread

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

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

0.2

0.4

0.6

1

0 12 24 36 48 60Time (months)

Su

rviv

al

Transplant N=239

Other Treatment N=917

Survival Curves for Transplant vs. Other Treatment for Hepatocellular Carcinoma

0.8

Automatic MELD Upgrades for patients with unresectable HCC

Surgery with resection is the current standard of care for patient without cirrhosis

22 points at diagnosis

25 points 3 months

28 - 6 months

29 - 9 months

31 – 12 months

Liver Transplantation For HCC in patients with cirrhosis

Four -Year Survival

0

10

20

30

40

50

60

70

80

Unselected 1991 Milan Criteria Other Dx

40%

75% 76%

%Surviving

Mazzaferro N Engl J Med 1996

Intermediate/Advanced HCC: Future Directions 499 trials registered at clinicaltrials.gov for HCC as of

August 21, 2008, including

– Improving efficacy of RF and TACE (drug-eluting beads)

– Exploring alternative treatments for intermediate HCC (yttrium-90)

– Molecularly targeted agents in combination regimens (advanced HCC)

– Molecularly targeted agents in combination with current modalities (early/intermediate HCC)

– Improving tumor targeting of chemotherapeutic agents

– New molecular targets and new molecularly targeted agents

Surgical treatments: applicable overall to 10% to 15% of HCC at first diagnosis and

2% to 5% of recurrent HCC

Staging Strategy and Treatment for Patients With HCC

Liver transplant PEI/RF TACE

HCC

Single

Increased Associateddiseases

Normal No Yes No Yes

Terminalstage

PST 0-2, Child-Pugh A-B

Multinodular, PST 0

Portal invasion, N1, M1

Sorafenib

Portal pressure/bilirubin

3 nodules ≤ 3 cm

Intermediate stage

PST > 2, Child-Pugh C

Very early stageSingle < 2 cm

Early stageSingle or 3 nodules

≤ 3 cm, PST 0

Advanced stagePortal invasion,

N1, M1, PST 1-2

PST 0, Child-Pugh A

Resection

Symptomatic (unless LT)Nonsurgical treatments: applicable

overall to 65% to 75% of HCC at first diagnosis and 50% to 70% of

recurrent HCC

Evidence of Benefit in Treatment of HCC (cont’d)Treatment Benefit Evidence

Systemic therapies

Sorafenib Increased survivalRandomized trial, meta-analysis, double blinded

Tamoxifen No benefitRandomized trial, meta-analysis, double blinded

Chemotherapy No benefitRandomized trial, meta-

analysis, nonblinded

IFN No benefitRandomized trial, meta-

analysis, nonblinded

Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.

Key Pathways in Hepatocarcinogenesis: Possible Targets for Novel Therapies Growth factor-stimulated receptor tyrosine kinase signaling

Wnt/beta-catenin pathway

p13Kinase/AKT/mTOR

JAK/STAT signaling

Angiogenic signaling pathways

p53 and cell cycle regulatory pathways

Ubiquitin-proteasome pathway

Epigenetic promoter methylation and histone acetylation pathways

Ras-Raf-MEK-MAPK pathway

Roberts LR, et al. Semin Liver Dis. 2005;25:212-225.

OS in the SHARP and Asia-Pacific Trials

Months from Randomization

Su

rviv

al P

rob

abil

ity

Sorafenib (n=299)Median: 10.7 months95% CI: 9.4-13.3

Placebo (n=303)Median: 7.9 months95% CI: 6.8-9.1

HR (S/P): 0.6995% CI: 0.55-0.87P=0.00058

0.25

0.50

0.75

1.00

00

4 8 12 16 20

SHARP1

Sorafenib (n=150)Median: 6.5 months 95% CI: 5.6-7.6

Placebo (n=76)Median: 4.2 months 95% CI: 3.7-5.5

HR (S/P): 0.68 95% CI: 0.50-0.93P=0.014

0.25

0.50

0.75

1.00

00

4 8 12 16 20

Asia-Pacific2

Months from Randomization

Su

rviv

al P

rob

abil

ity

1. Llovet JM, et al. N Engl J Med. 2008;359(4):378-390.2. Cheng AL, et al. Lancet Oncol. 2009;10:25-34.

Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. © 2008, Massachusetts Medical Society. All rights reserved.

AEs, % Sorafenib (N = 297) Placebo (N = 302) P Value

Any Grade

Grade 3 Grade 4 Any Grade

Grade 3 Grade 4

Any Grade

Grade 3 or 4

Overall incidence 80 52

Constitutional symptoms

Fatigue 22 3 1 16 3 < 1 .07 1.00

Weight Loss 9 2 0 1 0 0 < .001 .03

Dermatologic events

Alopecia 14 0 0 2 0 0 < .001 NA

Dry skin 8 0 0 4 0 0 .04 NA

Hand-foot skin reaction

21 8 0 3 < 1 0 < .001 < .001

Pruritus 8 0 0 7 < 1 0 .65 1.00

Rash or desquamation

16 1 0 11 0 0 .12 .12

Other 5 1 0 1 0 0 < .001 .12

The SHARP Trial: Drug-Related AEs

Scheithauer W, et al. Oncology (Williston Park) 2004; 18:1161.

Hand-Foot Syndrome

Strategies for Managing AEs

Hand-foot syndrome

– Creams and lotions

– Avoid tight footwear

– May require dose reduction

Diarrhea

– Antidiarrheal agents if severe

Fatigue

– Consider modafinil or methylphenidate if severe

Hypertension

– Start or adjust antihypertensives

Possible Future Studies in HCC

New targeted molecular agents

Small molecules in combination

– With each other

– With local ablation

– With conventional chemotherapy

Summary

Hepatocellular Carcinoma

– Prevention is possible by vaccine

– Risk driven by cirrhosis

– Viral load in HBV

– Treatment of underlying disease decreases risk

– Surveillance for HCC is SOC in selected patients

– HCC is curable in some patients

– Team approach is current standard to manage HCC

Management of Hepatocellular Management of Hepatocellular Carcinoma Requires a Carcinoma Requires a

Multidisciplinary ApproachMultidisciplinary Approach

Radiation OncologyRadiation Oncology

PathologyPathology

OncologyOncology

RadiologyRadiology

Hepatobiliary Surgery

Hepatobiliary Surgery

HepatologyHepatology