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  • 8/10/2019 CCO HepatocellularCarcinoma SlidesetModule

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    Forging Partnerships in theManagement of HepatocellularCarcinoma: Multidisciplinary Strategies

    to Provide Continuity of Care

    Jointly sponsored by Postgraduate Institute for Medicine

    and Clinical Care Options, LLC

    This program is supported by educational grants from

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    Forging Partnerships in the Management of Hepatocellular Carcinoma:

    Multidisciplinary Strategies to Provide Continuity of Care

    clinicaloptions.com/oncology

    Disclaimer

    The materials published on the Clinical Care Options Web site reflect the views of the authors, not those of

    Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The

    materials may discuss uses and dosages for therapeutic products that have not been approved by the

    United States Food and Drug Administration. A qualified healthcare professional should be consulted

    before using any therapeutic product discussed. Readers should verify all information and data before

    treating patients or using any therapies described in these materials.

    About These Slides Users are encouraged to include these slides in their own presentations, but

    we ask that content and attribution not be changed. Users are asked to honorthis intent.

    These slides may not be published or posted online or used for any othercommercial purpose without written permission from Clinical Care Options.

    We are grateful to Luigi Bolondi, MD; Adrian M. Di Bisceglie, MD, FACP;Jean-Francois Geschwind, MD; and Jorge A. Marrero, MD, MS, who aided inthe preparation of this slideset.

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    Forging Partnerships in the Management of Hepatocellular Carcinoma:

    Multidisciplinary Strategies to Provide Continuity of Care

    clinicaloptions.com/oncology

    Overview Introduction: Current Trends in the Treatment of Patients

    With Advanced HCC

    Managing Liver Dysfunction in Patients WithHepatocellular Carcinoma

    Systemic Therapy and Supportive Care in Patients WithAdvanced Hepatocellular Carcinoma

    Medical Management of Patients Undergoing RegionalTherapy for Hepatocellular Carcinoma

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    Introduction: Current Trends in theTreatment of Patients With

    Advanced HCC

    Luigi Bolondi, MDProfessor of Medicine

    ChairmanDepartment of Digestive Diseases

    and Internal Medicine

    University of Bologna

    Policlinico S. Orsola Malpighi

    Bologna, Italy

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    Forging Partnerships in the Management of Hepatocellular Carcinoma:

    Multidisciplinary Strategies to Provide Continuity of Care

    clinicaloptions.com/oncology

    Staging Strategy and Treatment for

    Patients With HCC

    Liver transplant PEI/RF

    Curative treatments

    TACE

    HCC

    Single

    Increased Associated

    diseases

    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.

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    Forging Partnerships in the Management of Hepatocellular Carcinoma:

    Multidisciplinary Strategies to Provide Continuity of Care

    clinicaloptions.com/oncology

    Surgical treatments: applicable overall to

    10% to 15% of HCC at first diagnosis and2% to 5% of recurrent HCC

    Staging Strategy and Treatment for

    Patients With HCC

    Liver transplant PEI/RF TACE

    HCC

    Single

    Increased Associated

    diseases

    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

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    Forging Partnerships in the Management of Hepatocellular Carcinoma:

    Multidisciplinary Strategies to Provide Continuity of Care

    clinicaloptions.com/oncology

    Approved Curative Treatments for

    Unresectable HCC: Percutaneous Ablation Local ablation: safe and effective therapy for patients who

    cannot undergo resection or as a bridgeto transplantation(level II)

    Alcohol injection and radiofrequency areequally effectivefor tumors< 2 cm

    However, necrotic effect of radiofrequency is more

    predictable inall tumor sizes

    In addition, efficacy is clearlysuperior to that of alcoholinjection in larger tumors(level I)

    Bruix J, et al. Hepatology. 2005;42:1208-1236.

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    Forging Partnerships in the Management of Hepatocellular Carcinoma:

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    clinicaloptions.com/oncology

    Approved & Investigational Noncurative

    Agents for Unresectable HCC AASLD 2005 recommendations

    Chemoembolization (TACE)(with doxorubicin, cisplatin, ormitomycin) is recommendedas first-line, noncurativetherapy for nonsurgical patients with large/multifocal HCCwho do not have vascular invasion or extrahepatic spread(and are not eligible for percutaneous ablation) (level I)

    Tamoxifen, octreotide, antiandrogens, and hepatic artery

    ligation/embolization are not recommended(level I); otheroptions such as drug-eluting beads, radiolabelled yttriumglass beads, radiolabelled lipiodol, or immunotherapy cannotbe recommendedas standard therapy for advanced HCCoutside clinical trials

    Bruix J, et al. Hepatology. 2005;42:1208-1236.

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    Treatment of Advanced HCC

    (BCLC Stage C) AASLD 2005 recommendation: no standard therapy;

    patients should enroll in a randomized clinical trial[1]

    2008 recommendation: sorafenib has become thestandard of care for advanced HCC[2]

    Prolongs OS by 3 months[3]

    1-year survival: 44%[4]

    1. Bruix J, et al. Hepatology. 2005;42:1208-1236.2. Llovet JM, et al. J Hepatol. 2008;48:S20-S37.3. Llovet J, et al. ASCO 2007. Abstract LBA 1.4. Llovet J, et al. N Engl J Med. 2008;359:378-390.

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    Forging Partnerships in the Management of Hepatocellular Carcinoma:

    Multidisciplinary Strategies to Provide Continuity of Care

    clinicaloptions.com/oncology

    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

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    Sorafenib: Ongoing Studies in HCC

    Europe

    10 studies approved

    4 TACE + sorafenib (1 phase I,1 phase II, 2 phase III)

    Sorafenib + tegafur

    Sorafenib + erlotinib

    Sorafenib + temsirolimus

    Sorafenib dose escalation

    Sorafenib + gemcitabine/oxaliplatin

    Biomarkers

    Asia-Pacific

    4 studies approved

    Sorafenib + tegafur

    Sorafenib + capecitabine/oxaliplatin

    Sorafenib + bevacizumab

    Sorafenib + gemcitabine

    United States

    4 studies (nonactivated)

    2 TACE + sorafenib

    Sorafenib + erlotinib

    Sorafenib + lapatinib

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    Managing Liver Dysfunction inPatients With Hepatocellular

    Carcinoma

    Jorge A. Marrero, MD, MScAssociate Professor of Medicine

    Director, Multidisciplinary LiverTumor Program

    University of Michigan Health System

    Ann Arbor, Michigan

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    Forging Partnerships in the Management of Hepatocellular Carcinoma:

    Multidisciplinary Strategies to Provide Continuity of Care

    clinicaloptions.com/oncology

    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 C

    Hepatitis B

    Ethanol

    NASH

    Epigenetic alterations

    Genetic 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.

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    Child-Pugh Score

    Measure 1 Point

    Each

    2 Points

    Each

    3 Points

    Each

    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) 1.0-3.0 4.0-6.0 > 6.0

    Ascites None Slight Moderate

    Encephalopathy (grade) None I-II III-IV

    Grade Total Points Surgical Risk

    A 5-6 Good

    B 7-9 Moderate

    C 10-15 Poor

    Pugh RN, et al. Br J Surg.1973;60:646-649.

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    MELD Score Predicts Severity of Liver

    Disease and Cirrhosis-Related MortalityMELD score: (0.957 x Ln[creatinine] + 0.378 x Ln[bilirubin] +1.12 x Ln[INR] + 0.643) x 10

    Mortality by MELD score

    < 9: 2.9% (n = 12)

    10-19: 7.7% (n = 180)

    20-29: 23.5% (n = 1038)

    30-39: 60.0% (n = 295)

    > 40: 81.0% (n = 126)

    Wiesner RH, et al. Gastroenterology. 2003;124:91-96.

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    Forging Partnerships in the Management of Hepatocellular Carcinoma:

    Multidisciplinary Strategies to Provide Continuity of Care

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    Survival of Cirrhotic Patients

    Markedly longer survival in patients with compensatedcirrhosis vs those with decompensated cirrhosis

    Median survival

    Compensated cirrhosis: > 12 years

    Decompensated cirrhosis: ~ 2 years

    DAmico G, et al. J Hepatology. 2006;44:217-231.

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    Survival of Cirrhotic Patients

    Child-Pugh classification also important

    Child-Pugh class A disease had better 1- and 2-yearsurvival

    Median 1- and 2-year survival by Child-Pugh class

    Class A: 95% and 90%, respectively

    Class B: 80% and 70%, respectively

    Class C: 45% and 38%, respectively

    DAmico G, et al. J Hepatology. 2006;44:217-231.

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    Portal Hypertension

    Portal hypertension

    Cirrhosis

    Increased intrahepaticvascular resistance

    Decreased nitric oxide

    Portal hypertension

    Hyperdynamic circulation

    Increased splanchnic bloodflow

    Increased total blood volume

    Increased cardiac output

    Systemic vasodilation(decreased systemic vascular

    resistance)

    Increased renin-angiotensin,vasopressin, sympatheticsystems

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    Forging Partnerships in the Management of Hepatocellular Carcinoma:

    Multidisciplinary Strategies to Provide Continuity of Care

    clinicaloptions.com/oncology

    Diagnosis

    The gold standard is biopsy because it is the only way toascertain the degree of fibrosis

    Noninvasive diagnosis

    Physical exam indicating stigmata of liver disease

    Evidence of splenomegaly

    Thrombocytopenia

    Cirrhotic-appearing liver on ultrasound or CT

    Presence of chronic liver disease

    Evidence of portal hypertension (ie, presence of varices, caput)

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    Forging Partnerships in the Management of Hepatocellular Carcinoma:

    Multidisciplinary Strategies to Provide Continuity of Care

    clinicaloptions.com/oncology

    Treatment of Liver Disease

    Hepatitis C: IFN + RBV

    Hepatitis B: IFN, lamivudine, adefovir, entecavir

    Alcohol: Abstinence

    Primary biliary cirrhosis: Ursodeoxycholic acid

    Hemochromatosis: Phlebotomy

    Alpha-1 ATD: None

    Nonalcoholic fatty liver: Diet and exercise

    Wilsons disease: Zinc, trientene

    Sclerosing cholangitis: Ursodeoxycholic acid, biliary stents

    Autoimmune hepatitis: Immunosuppression

    f C

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    Forging Partnerships in the Management of Hepatocellular Carcinoma:

    Multidisciplinary Strategies to Provide Continuity of Care

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    Complications of Cirrhosis

    Cirrhosis

    Variceal bleeding

    Ascites/hepatorenalsyndrome

    Hepatic encephalopathy

    HCC

    F i P t hi i th M t f H t ll l C i

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    Gastroesophageal Varices

    Present in approximately 50% of cirrhotics

    Correlates with hepatic function

    Child-Pugh class A: 40% prevalence

    Child-Pugh class C: 85% prevalence

    Hemorrhage rate: 10% to 30% per year

    Threshold portal pressure: 12 mm Hg

    Mortality: 30% to 50%

    Garcia-Tsao G. Gastroenterology. 2001;120:726-748.

    F i P t hi i th M t f H t ll l C i

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    Forging Partnerships in the Management of Hepatocellular Carcinoma:

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    Variceal Hemorrhage

    Courtesy of Jorge A. Marrero, MD.

    F i P t hi i th M t f H t ll l C i

    http://www.gastrointestinalatlas.com/Varixstds6.mpghttp://www.gastrointestinalatlas.com/Varixstds10.mpghttp://www.gastrointestinalatlas.com/Varixstds.mpg
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    Forging Partnerships in the Management of Hepatocellular Carcinoma:

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    clinicaloptions.com/oncology

    Treatment of Variceal Bleeding

    Resuscitative measures

    Hematocrit replaced to 25% to 30%

    Prophylactic antibiotics because of development ofinfections

    First Line Second Line Third Line

    Endoscopy + TIPS/shunt surgery Balloonsomatostatin tamponade

    Garcia-Tsao G. Gastroenterology. 2001;120:726-748.

    Forging Partnerships in the Management of Hepatocell lar Carcinoma

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    Ascites

    The second most frequent complication of cirrhosis

    5-year cumulative rate: 30%

    Once ascites develops, the 1-year survival is ~ 50%

    Treatment will improve quality of life and preventspontaneous bacterial peritonitis and hepatorenalsyndrome

    Gines P, et al. Semin Liver Dis. 2008;28:43-58.

    Forging Partnerships in the Management of Hepatocellular Carcinoma:

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    Diagnostic Paracentesis

    Tests to be ordered (20-50 mL samples)

    Cell count + differential

    Albumin

    Total protein

    Culture in blood culture bottle

    Glucose, LDH, amylase Serum-ascites albumin gradient

    > 1.1: portal hypertension

    < 1.1: infection, cancer, renal

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    Multidisciplinary Strategies to Provide Continuity of Care

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    Management of Ascites

    2 g sodium diet

    Promote natriuresis with a combination of K-sparing andloop diuretics

    Large volume paracentesis (> 5 L) is safe

    Albumin infusion concomitantly prevents circulatorydysfunction

    TIPS

    Importantly, patients who develop hepatorenal syndromehave a poor prognosis

    Garcia-Tsao G. Gastroenterology. 2001;120:726-748.

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    Hepatic Encephalopathy

    Type A is related to acute liver failure

    Type B occurs in the setting of normal liver histology andthe presence of a hepatic vascular bypass

    Type C, due to cirrhosis, involves the majority of cases

    Incidence in cirrhotics: ~ 10%

    Forging Partnerships in the Management of Hepatocellular Carcinoma:

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    Management of Hepatic

    Encephalopathy First line

    Lactulose, a nonabsorbable disaccharide, should be initiatedand titrated to approximately 4 bowel movements per day

    Second line

    Enteric flora modification with antibiotics, such asmetronidazole or neomycin

    Third line

    L-ornithine-L-aspartate administration

    Marrero J, et al. Am J Respir Crit Care Med. 2003;168:1421-1426.

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    Conclusions

    The incidence of chronic liver disease is rising

    The improved survival of patients with cirrhosis will likelyincrease the number of patients with HCC

    Because most patients with HCC have underlying cirrhosisof the liver, attention in managing these complications isimportant

    HCC is best managed in a multidisciplinary setting

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    Systemic Therapy and SupportiveCare in Patients With Advanced

    Hepatocellular CarcinomaAdrian M. Di Bisceglie, MD, FACPProfessor of Internal Medicine

    Acting Chairman

    Department of Internal Medicine

    Saint Louis University School of Medicine

    Chief, Hepatology

    Division of Gastroenterology and

    Hepatology

    Saint Louis University Hospital

    St Louis, Missouri

    Forging Partnerships in the Management of Hepatocellular Carcinoma:

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    Management of HCC

    Liver transplantation

    Resection

    Tumor ablation Radiofrequency thermal ablation

    Alcohol injection

    Chemoembolization

    Targeted molecular therapy

    Chemotherapy

    Regional/systemic

    Potentially

    curative

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    Evidence of Benefit in Treatment

    of HCCTreatment Benefit Evidence

    Surgical treatments

    Resection Increased survival Case series

    Adjuvant therapies Uncertain Randomized trial,

    meta-analysis, nonblinded

    Liver transplantation Increased survival Case series

    Neoadjuvant therapies Treatment response Nonrandomized trials

    Locoregional treatment

    Percutaneous treatment Increased survival Case series

    RFA vs PEI Better local control Randomized trial,meta-analysis, nonblinded

    Chemoembolization Increased survivalRandomized trial,

    meta-analysis, nonblinded

    Arterial chemotherapy Treatment response Case series

    Internal radiation Treatment response Case series

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

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    Evidence of Benefit in Treatment

    of HCC (contd)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 benefit Randomized trial, meta-analysis, nonblinded

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

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    Staging Strategy and Treatment for

    Patients With HCC

    Liver transplant PEI/RF

    Curative treatments

    TACE

    HCC

    Single

    Increased Associated

    diseases

    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.

    RCTs (50%)

    Median survival: 11-20 mos

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    o g g a e s ps e a age e o epa oce u a Ca c o a

    Multidisciplinary Strategies to Provide Continuity of Care

    clinicaloptions.com/oncology

    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.

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    g g p g p

    Multidisciplinary Strategies to Provide Continuity of Care

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    Sorafenib in Advanced HCC:

    The SHARP Trial Entry criteria

    Advanced HCC

    Not eligible for or failed surgical or locoregional therapies

    Child-Pugh class A disease

    At least 1 untreated target lesion

    Exclusions

    Previous chemotherapy

    Previous molecularly targeted therapy

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

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    Multidisciplinary Strategies to Provide Continuity of Care

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    226 discontinued sorafenib

    86 had an adverse event61 had radiologic and

    systematic progression28 withdrew consent

    1 had ECOG score of 4

    3 died

    47 had other reason

    297 received sorafenib

    (safety population)

    71 included in the ongoing study

    1 had an adverse event1 had a protocol violation

    299 were assigned to receive sorafenib(intent-to-treat population)

    602 underwent randomization

    902 patients were screened

    300 were excluded

    244 had protocol exclusioncriteria

    24 withdrew consent15 had an adverse event

    11 died

    6 were lost to follow-up

    303 were assigned to receive placebo(intent-to-treat population)

    1 had a protocol violation

    302 received placebo

    (safety population)

    242 discontinued placebo

    90 had an adverse event62 had radiologic and

    systematic progression25 withdrew consent

    7 had ECOG score of 4

    6 died

    52 had other reason

    60 included in the ongoing study

    Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med.

    2008;359:378-390. 2008, Massachusetts Medical Society. All rights reserved.

    Sorafenib in Advanced HCC:

    The SHARP Trial

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    SHARP Trial: Baseline Characteristics

    Characteristic Sorafenib(n = 299)

    Placebo

    (n = 303)

    Median age, yrs 64.9 66.3

    Male, % 87 87BCLC stage, %

    B (intermediate) 18 17

    C (advanced) 82 83

    Vascular invasion, % 70 70

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

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    Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med.

    2008;359:378-390. 2008, Massachusetts Medical Society. All rights reserved.

    Median OS

    Sorafenib: 10.7 mos

    Placebo: 7.9 mos

    Median TTSP

    Sorafenib: 4.1 mos

    Placebo: 4.9 mos

    Median TTRP

    Sorafenib: 5.5 mos

    Placebo: 2.8 mos

    The SHARP Trial: OS and Time to

    Progression

    Months Since Randomization

    Pr

    obabilityof

    Survival

    0.000.25

    0.50

    0.75

    1.00

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

    P < .001

    A OS

    Months Since Randomization

    Prob

    abilityofNo

    Sy

    mptomatic

    Progression

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

    P - 0.77

    B Time to Symptomatic Progression

    180.00

    0.25

    0.50

    0.75

    1.00

    Months Since Randomization

    Probabilityof

    Radiologic

    Progression

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

    Placebo

    SorafenibP < 0.001

    C Time to Radiologic Progression

    0.00

    0.25

    0.50

    0.75

    1.00

    12

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    Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med.

    2008;359:378-390. 2008, Massachusetts Medical Society. All rights reserved.

    The SHARP Trial: OS and Baseline

    Prognostic Factors

    0.0 0.5 1.0 1.5

    Sorafenib

    Better

    Placebo

    Better

    Subgroup

    ECOG score

    0

    1-2

    Extrahepatic spread

    No

    Yes

    Macroscopic vascular invasion

    No

    Yes

    Macroscopic vascular invasion,

    extrahepatic spread, or both

    NoYes

    Hazard Ratio (95% CI)

    0

    0.68 (0.50-0.95)

    0.71 (0.52-0.96)

    0.55 (0.39-0.77)

    0.85 (0.64-1.14)

    0.74 (0.54-1.00)

    0.68 (0.49-0.93)

    0.52 (0.32-0.85)0.77 (0.60-0.99)

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    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) PValue

    AnyGrade

    Grade 3 Grade 4 AnyGrade

    Grade 3 Grade4

    AnyGrade

    Grade 3or 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 skinreaction 21 8 0 3 < 1 0 < .001 < .001

    Pruritus 8 0 0 7 < 1 0 .65 1.00

    Rash ordesquamation

    16 1 0 11 0 0 .12 .12

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

    The SHARP Trial: Drug-Related AEs

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    The SHARP Trial: Drug-Related AEs

    (Contd)AEs, % Sorafenib (N = 297) Placebo (N = 302) PValue

    AnyGrade

    Grade 3 Grade 4 AnyGrade

    Grade 3 Grade4

    AnyGrade

    Grade 3or 4

    Gastrointestinal events

    Anorexia 14 < 1 0 3 1 0 < .001 1.0

    Diarrhea 39 8 0 11 2 0 < .001 < .001

    Nausea 11 < 1 0 8 1 0 .16 .62

    Vomiting 5 1 0 3 1 0 .14 .68

    Voice changes 6 0 0 1 0 0 < .001 NA

    Hypertension 5 2 0 2 1 0 .05 .28

    Liver dysfunction < 1 < 1 0 0 0 0 .50 .50

    Abdominal pain nototherwise specified

    8 2 0 3 1 0 .007 .17

    Bleeding 7 1 0 4 1 < 1 .07 1.00

    Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med.

    2008;359:378-390. 2008, Massachusetts Medical Society. All rights reserved.

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    Multidisciplinary Strategies to Provide Continuity of Care

    clinicaloptions.com/oncologyScheithauer W, et al. Oncology (Williston Park) 2004; 18:1161.

    Hand-Foot Syndrome

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    Grading of Hand-Foot Syndrome

    Grade Symptom

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

    2Skin changes (eg, peeling, blisters, bleeding, edema) or pain,

    not interfering with function3 Skin changes with pain, interfering with function

    Common Terminology Criteria for Adverse Events, Version 3.0. Available

    at: http://ctep.cancer.gov. Accessed October 13, 2008.

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    M ltidi i li St t i t P id C ti it f C

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    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

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    Erlotinib in HCC: EGFR Inhibitor

    Phase II study in patients with unresectable HCC (N = 40)

    Oral erlotinib 150 mg/day, 28-day cycles

    No CRs or PRs

    PFS rate at 16 weeks: 43%

    Drug-related adverse events: diarrhea, folliculitis, fatigue,pruritus, dry skin, xerostomia, epistaxis

    Thomas MB, et al. Cancer. 2007;110:1059-1067.

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    Possible Future Studies in HCC

    New targeted molecular agents

    Small molecules in combination

    With each other

    With local ablation

    With conventional chemotherapy

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    Ongoing HCC Trials in the US

    117 studies registered at ClinicalTrials.gov

    Radiation: 21

    Targeted molecular therapies: 18

    Chemotherapy: 26

    Local ablative therapy: 8

    Other

    ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov.

    Accessed October 13, 2008.

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    Targeted Molecular Therapies:

    Mechanisms of Action VEGF antagonists

    Cediranib

    ABT-869

    NF-B antagonists

    Perifosine

    Proteasome inhibitors Bortezomib

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    Targeted Molecular Therapies:

    Mechanisms of Action (contd) EGFR tyrosine kinase inhibitors

    Lapatinib

    Sunitinib

    Erlotinib

    TRAIL receptor antibodies

    Mapatumumab BCR-ABL inhibitors

    Dasatinib

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    Targeted Molecular Therapies

    Mechanisms of Action (contd) Multiple pathways

    Sorafenib

    RAF/MEK/ERK signaling

    VEGFR-2

    PDGF-

    Brivanib

    VEGFR-2

    FGFR-1 kinase

    Pazopanib

    VEGFR-1, -2, -3

    PDGF-, -

    c-KIT

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    Dasatinib: CML

    Bevacizumab: breast cancer, NSCLC, CRC

    Erlotinib: NSCLC, pancreatic cancer

    Sunitinib: RCC, GIST

    Lapatinib: breast cancer

    Bortezomib: myeloma, mantle cell lymphoma

    Sorafenib: RCC, HCC

    Temsirolimus: RCC

    Approved Targeted Molecular Therapies

    With Possible Efficacy in HCC

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    Endpoints in Clinical Trials of HCC

    Primary and secondaryendpoints

    Survival (phase III)

    Time to recurrence(phase II/III)

    Time to progression(phase II)

    Time to local recurrence(locoregional treatment)

    Tertiary endpoints

    Cancer-specific death

    Time to symptomaticprogression

    DFS

    PFS

    Response rate

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

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    Summary and Conclusion

    The demonstration that sorafenib improves survival inHCC is a major milestone

    Other agents are available or being developed that target

    known molecular pathways in HCC

    AASLD has outlined endpoints for study of new agents

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    Transcatheter Intra-arterialTherapies for Hepatocellular

    Carcinoma

    Jean-Francois Geschwind, MDProfessor, Radiology, Surgery, and

    Oncology

    Director, Vascular and Interventional

    Radiology

    Johns Hopkins University School of

    Medicine

    Baltimore, Maryland

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    Intra-arterial Locoregional Therapy

    Established

    TACE

    Radioembolization: yttrium-90 radioactive microspheres

    Undergoing clinical trials

    Drug-eluting beads

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    Primary Treatment Modality Used in

    Korea

    TACE48.2%

    RFA

    1.5%

    Surgery11.2%

    Chemotherapy

    7.5%

    Radiotherapy

    2.1%

    Conservativetreatment

    29.5%

    N = 1078

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

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    Chemoembolization: Randomized

    Trials (Nearly Identical Techniques)

    TechniqueSurvival, %

    Year 1 Year 2 Year 3

    TACE 57 31 26

    Supportive care 32 11 3

    Technique Survival, %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.

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    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.

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    p y g y

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    Largest Prospective Study of TACE for

    Unresectable HCC to Date N = 8510 patients

    Primary endpoint: OS

    Multivariate analysis conducted of factors affecting survival

    OS

    Year 1: 82%; Year 3: 47%; Year 5: 26%; Year 7: 16%

    OS better with lesser degree of liver damage

    Factors affecting survival

    Child-Pugh stage

    TNM stage (OS better with stage I, increasingly worse progressing toward stage IV)

    Alpha-fetoprotein level

    Takayasu K, et al. Gastroenterology. 2006;131:461-469.

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    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.

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    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 ofhepatic 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.

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    Can TACE Be Used as a Determinant

    of Tumor Biology?

    96 consecutivepatients treatedwith TACE

    62 exceeded Milancriteria

    34 meeting Milan criterialisted immediately

    50 patients

    transplanted

    27 exceeded Milancriteria

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

    Functional

    Decompensation (n = 1)

    Patients with HCC;

    age 65 years without

    contraindication against LT

    (n = 96)

    Milan criteria fulfilled

    (n = 34)

    Listing

    TACE

    Milan criteria exceeded

    (n = 62)

    6 weeks

    6 weeks

    6 weeks

    TACE

    Listing (n = 34)

    WL (n = 4) WL (n = 1)

    Progress (n = 6)

    Functional

    decompensation (n = 5)

    Functional

    decompensation (n = 1)

    Extrahepatic

    disease (n = 5)

    Stable 18

    Progress* 927 LT

    Stable 21

    Progress 223 LT

    TACE

    Regress Stable or progress (n = 23)

    Restaging

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    clinicaloptions.com/oncologyOtto G, et al. Liver Transpl. 2006;12:1260-1267.

    Transplanted

    All

    patients

    TACE

    nonresponders

    Overall 5-year survival:51.9%

    Highly significant difference in

    5-year survival betweendownstaged (transplanted)patients and patients notresponding to TACE(P< .0001)

    Survival calculated from the

    beginning of TACE treatment

    Surv

    iva

    l

    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

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    TACE nonresponders

    TACE responders

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

    Response to TACE as a Biological

    Selection Criterion for LT in HCC

    0

    Free

    dom

    From

    Rec

    urrence

    0

    0.2

    0.4

    0.6

    0.8

    1.0

    365 730 1095 1460 1825

    Days

    35.4%

    94.5%

    P= .0017

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    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

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    32 patients with HCC and PVT

    Median OS: 10 months

    Child-Pugh score: best prognostic factor (ie, most stronglyrelated to survival)

    30-day mortality: 0%

    No evidence of TACE-related hepatic infarction or acute

    liver failure

    Safety & Efficacy of TACE in Patients

    With Unresectable HCC & PVT

    Georgiades CS, et al. J Vasc Interv Radiol. 2005;16:1653-1659.

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

    Yttrium-90 microspheres

    Average diameter: 20-30 m

    100% pure beta emitter (0.9367 MeV)

    Physical half-life: 64.2 hours

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

    Intra-arterial Radioembolization With

    Yttrium-90: Rationale and History

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

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    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.

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

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

    Median dose: 134 Gy

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

    Adverse event rate highest in patients with main PVT andcirrhosis

    Median survival, main PVT: 260 days

    Branch PVT: 370 days

    No PVT: 460 days

    Yttrium-90 Radiotherapy for HCC

    Patients With and Without PVT

    Kulik LM, et al. Hepatology. 2008;47:5-7.

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    Lessons Learned

    Patient selection

    Good performance status (ECOG PS < 2)

    Total bilirubin < 2.0 mg/dL (possibly < 1.4 mg/dL) Tumor burden < 50%

    90Y or TACE: Which is best forfirst-line treatment of HCC?

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    27 patients with Child-Pugh A stage disease

    Response rate (assessed

    by CT) at 6 months: 75%

    1- and 2-year survivalrates: 92% and 89%

    Median follow-up:28 months

    Varela M, et al. J Hepatol. 2007;46:474-481.

    Doxorub

    icina

    t

    Serum

    (ng

    /mL)

    Do

    xoru

    bicina

    t

    Se

    rum

    (ng

    /mL)

    DEB-TACE

    Conventional TACE

    Time Postprocedure

    Time Postprocedure

    0

    200

    400

    600

    800

    1000

    0

    200

    400600

    800

    1000

    TACE With Doxorubicin-Eluting Beads:

    Efficacy and Pharmacokinetics

    Forging Partnerships in the Management of Hepatocellular Carcinoma:

    Multidisciplinary Strategies to Provide Continuity of Care

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    clinicaloptions.com/oncologyCourtesy Jean-Francois Geschwind, MD.

    65-Year-Old Woman, Child-Pugh B Disease,

    and Large HCC: First Treatment

    Forging Partnerships in the Management of Hepatocellular Carcinoma:

    Multidisciplinary Strategies to Provide Continuity of Care

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    clinicaloptions.com/oncology

    Posttreatment 1: Residual Viable Tumor

    Pretreatment

    Pretreatment and Posttreatment 1

    Courtesy Jean-Francois Geschwind, MD.

    Forging Partnerships in the Management of Hepatocellular Carcinoma:

    Multidisciplinary Strategies to Provide Continuity of Care

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    Second Treatment

    Courtesy Jean-Francois Geschwind, MD.

    Forging Partnerships in the Management of Hepatocellular Carcinoma:

    Multidisciplinary Strategies to Provide Continuity of Care

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    clinicaloptions.com/oncology

    Underwent successful resection Tumor free 16 months after initial treatment

    MRI Posttreatment 2

    Courtesy Jean-Francois Geschwind, MD.

    Forging Partnerships in the Management of Hepatocellular Carcinoma:

    Multidisciplinary Strategies to Provide Continuity of Care

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    clinicaloptions.com/oncology

    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, pendingoutcome of clinical trials

    Conclusions

    Forging Partnerships in the Management of Hepatocellular Carcinoma:

    Multidisciplinary Strategies to Provide Continuity of Care

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    M H t l /O l

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    Medical Meeting Coverage: key data plus Expert Analysispaneldiscussions exploring clinical implications

    Treatment Updates:comprehensive programscovering the most important new concepts

    Interactive Cases:test your ability tomanage patients

    clinicaloptions.com/oncology

    More Hematology/Oncology

    Available Online

    http://www.clinicaloptions.com/oncologyhttp://www.clinicaloptions.com/oncology