tariq n khan, md. director solid organ transplant and hepatobiliary surgery

Tariq N Khan, MD.Director Solid Organ Transplant and Hepatobiliary Surgery

Worldwide Incidence of Hepatocellular Carcinoma

High (> 30:100,000)High (> 30:100,000)

Low or data unavailable (< 3:100,000)Low or data unavailable (< 3:100,000)Intermediate (3-30:100,000)Intermediate (3-30:100,000)

Worldwide Incidence of Hepatocellular CarcinomaWorldwide Incidence of Hepatocellular Carcinoma

El-Serag HB, Gastroenterology 2004

El-Serag HB, Gastroenterology 2004

Increase In HCC Mortality Rates in the United States (1979-1998)

Age-adjusted incidence rateper 100,000


El-Serag HB, N Engl J Med 1999El-Serag HB, N Engl J Med 1999

YearYear‘79‘79 ‘81‘81 ‘83‘83 ‘85‘85 ‘87‘87 ‘89‘89 ‘91‘91 ‘93‘93 ‘95‘95

2.82.8 3 3

22

11

00‘97‘97

44

55

2.82.8 2.92.9 2.92.9 2.92.9 3.03.0 3.13.1 3.13.1 3.23.2 3.33.3 3.43.4 3.63.6 3.73.7 3.93.9 4.04.0 4.14.14.44.4 4.44.4 4.54.5 4.64.6

Racial Incidence Rates For HCCIn The United States

YearYear

76-7876-78 82-8482-84 85-8785-87 88-9088-90 91-9391-93 94-9694-96 97-9997-992000-022000-02

99

88

66

44

22

00

11

2.52.5

66

1.11.1

WhiteWhite BlackBlack Other (Asian)Other (Asian)

79-8179-81

2.52.5

55

88

2.52.5

5.25.2

1.11.1

2.62.6

6.36.3

1.31.3

2.92.9

6.66.6

1.41.4

3.43.4

7.27.2

1.71.7

3.73.7

7.27.2

1.91.9

3.93.9

8.48.4

2.32.3

4.64.6

7.97.9

El-Serag HB et al, Ann Intern Med 2003El-Serag HB et al, Ann Intern Med 2003



Temporal Trends in The Age Distribution of Hepatocellular

Carcinoma

Age (years)Age (years)

20-2420-24 30-3430-3435-3935-39

40-4440-4445-4945-49

50-5450-5455-5955-5925-2925-29

00

44

88

1212

1616

20201982 – 841991 – 932000 – 02

1982 – 841991 – 932000 – 02

60-6460-6465-6965-69

70-7470-7475-7975-79

80-8480-8485+85+

El-Serag HB, Mason A, N Engl J Med 1999El-Serag HB, Mason A, N Engl J Med 1999

Incidence rateper 100,000 PY

Incidence rateper 100,000 PY

Regional Variations in HCC-related MortalityRegional Variations in HCC-related MortalityMortality Rate / 100,000 Age-AdjustedMortality Rate / 100,000 Age-Adjusted

5.24 to 6.12 (6)4.49 to 5.24 (5)4.28 to 4.49 (5)4.09 to 4.28 (5)3.94 to 4.09 (5)3.75 to 3.94 (6)3.50 to 3.75 (5)3.19 to 3.50 (5)2.74 to 3.19 (5)2.21 to 2.74 (4)Sparse Data (0)

5.24 to 6.12 (6)4.49 to 5.24 (5)4.28 to 4.49 (5)4.09 to 4.28 (5)3.94 to 4.09 (5)3.75 to 3.94 (6)3.50 to 3.75 (5)3.19 to 3.50 (5)2.74 to 3.19 (5)2.21 to 2.74 (4)Sparse Data (0)

Regional Variations in HCC-related Mortality

El-Serag HB, Gastroenterology 2004El-Serag HB, Gastroenterology 2004

Why HCC is Rising?Why HCC is Rising?

• Rising incidence of cirrhosis• HCV (main reason)

• HBV

• Other (?NAFLD/insulin resistance)

• Improved survival of patients with cirrhosis

• Rising incidence of cirrhosis• HCV (main reason)

• HBV

• Other (?NAFLD/insulin resistance)

• Improved survival of patients with cirrhosis

Increasing prevalence of patients with cirrhosisIncreasing prevalence of patients with cirrhosis

Why HCC is Rising?

El-Serag HB, Gastroenterology 2004El-Serag HB, Gastroenterology 2004

Risk Factors for HCC Risk Factors for HCC • Cirrhosis from any cause

• HCV • HBV• Heavy alcohol consumption• Non-alcoholic fatty liver

disease• HBV• Inherited metabolic diseases

• Hemochromatosis • Alpha-1 antitrypsin deficiency • Glycogen storage disease• Porphyria cutanea tarda• Tyrosinemia • Autoimmune hepatitis

• Cirrhosis from any cause• HCV • HBV• Heavy alcohol consumption• Non-alcoholic fatty liver

disease• HBV• Inherited metabolic diseases

• Hemochromatosis • Alpha-1 antitrypsin deficiency • Glycogen storage disease• Porphyria cutanea tarda• Tyrosinemia • Autoimmune hepatitis

Risk Factors for HCC

Definitions

• Screening

Application of diagnostic test in patients at risk for HCC, but in whom there is no a priori reason to suspect that HCC is present

• Surveillance

The repeated application of screening tests.

Definitions

• Lead-time bias This is the apparent improvement survival

that comes from the diagnosis being made earlier in the course of a disease than when the disease is diagnosed because of the development of symptoms.

• Length bias This is the apparent improvement in survival

that occurs because surveillance preferentially detects slow growing cancers. More rapidly growing cancers may grow too large to be treated between screening tests.

Survival TimeSurvival Time

DiagnosisConfirmedDiagnosisConfirmed

PatientExpires

DiagnosisConfirmedDiagnosisConfirmed

Screened GroupScreened Group

TimeTime

TimeTimeControl GroupControl Group

SymptomsDx. ConfirmedSymptomsDx. Confirmed

Lead TimeLead Time Survival TimeSurvival Time

Lead-time Bias

PatientExpiresPatientExpires

AggressiveAggressive

MoreIndolentMoreIndolent

TimeTime

Length-time Bias

Surveillance for HCC Improves Mortality:A Randomized Controlled Trial

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

• A study of hepatitis B carriers in China

• 18,816 randomized to surveillance with AFP + US biannual vs. no surveillance

• Adherence to surveillance was 58%

•HCC related mortality was reduced by 37% in surveillance arm.

• A study of hepatitis B carriers in China

• 18,816 randomized to surveillance with AFP + US biannual vs. no surveillance

• Adherence to surveillance was 58%

•HCC related mortality was reduced by 37% in surveillance arm.

Screening for HCC: AASLD RecommendationsScreening for HCC: AASLD Recommendations

• Lin et al . found that surveillance with AFP and ultrasound was cost effective regardless of HCC incidence.

• Patient with cirrhosis of varying etiologies , surveillance should be offered when the risk of HCC is 1.5 % / year or greater.

•Likelihood of cure is greater when HCC is diagnosed at earlier stage

Screening for HCC:AASLD RecommendationsScreening for HCC:AASLD Recommendations

Population in which screening should be done Cirrhosis (any etiology) HBV: older, family history, cirrhosis, Asian over

40

Surveillance for HCC should be performed with ultrasonography plus AFP (level II)

Screening should occur every 6 months (level II)

The surveillance interval does not need to be shortened for patients at higher risk of HCC (level III)

Population in which screening should be done Cirrhosis (any etiology) HBV: older, family history, cirrhosis, Asian over

40

Surveillance for HCC should be performed with ultrasonography plus AFP (level II)

Screening should occur every 6 months (level II)

The surveillance interval does not need to be shortened for patients at higher risk of HCC (level III)

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

Screening for HCC: AASLD RecommendationsScreening for HCC: AASLD Recommendations

Clinical Features at Presentation

Symptoms Percent of Patients

None 23%Abdominal Pain 32%Ascites 8%Jaundice 8%Anorexia/weight loss 10%Malaise 6%Bleeding 4%Encephalopathy 2%

Symptoms Percent of Patients

None 23%Abdominal Pain 32%Ascites 8%Jaundice 8%Anorexia/weight loss 10%Malaise 6%Bleeding 4%Encephalopathy 2%

Gastroenterology 2002Gastroenterology 2002

Dual Blood Supply of Liver

• The vascular supply of HCC arises from the hepatic artery through neovascularization.

• Imaging of the liver has to be performed in a triple phase manner to account for the early arterial phase followed by the portal venous phase and the delayed phases

• The vascular supply of HCC arises from the hepatic artery through neovascularization.

• Imaging of the liver has to be performed in a triple phase manner to account for the early arterial phase followed by the portal venous phase and the delayed phases

Yu JS, et al, Am J Roentgenol 1999Yu JS, et al, Am J Roentgenol 1999

Triple Phase Imaging of Hepatocellular Carcinoma

Pre-contrastPre-contrast

Portal Venous PhasePortal Venous Phase

Arterial PhaseArterial Phase

5-min Delayed5-min Delayed

Dynamic MRI Spiral CT for Diagnosis of HCC

Variables Dynamic MRI Spiral CT

Sensitivity 76% (58/76) 61% (43/70)Specificity 75 % (18/24) 66% (12/18)PPV 90% (58/64) 87% (43/49)NPV 50% (18/36) 30% (12/39)LR positive test 3.04 1.79

Variables Dynamic MRI Spiral CT

Sensitivity 76% (58/76) 61% (43/70)Specificity 75 % (18/24) 66% (12/18)PPV 90% (58/64) 87% (43/49)NPV 50% (18/36) 30% (12/39)LR positive test 3.04 1.79

Burrel M, et al, Hepatology 2003Burrel M, et al, Hepatology 2003

n= 55 cirrhotics (29 with HCC)n= 55 cirrhotics (29 with HCC)

Arterial phaseArterial phase 2-min delayed2-min delayed

5-min delayedArterial phaseArterial phase

Washout in HCCWashout in HCC

Washout in HCC

Importance of Contrast Washout of an Arterially Enhancing Mass

Variables Odds Ratio (95%CI)

All patients (n=124)AFP > 20 ng/ml 11.7 (2.3-30.7)Washout 61 (3.8-73)

< 2 cm only (n=35) Washout 6.3 (1.8-13)

Variables Odds Ratio (95%CI)

All patients (n=124)AFP > 20 ng/ml 11.7 (2.3-30.7)Washout 61 (3.8-73)

< 2 cm only (n=35) Washout 6.3 (1.8-13)

Marrero JA, et al, Liver Transplant 2004Marrero JA, et al, Liver Transplant 2004

Performance Characteristics of Histopathology for HCC

Sensitivity Specificity

Cytology 80-75% 69-73%

Histology 61-89% 82-88%

Cytology + Histology 75-90% 100%

Sensitivity Specificity

Cytology 80-75% 69-73%

Histology 61-89% 82-88%

Cytology + Histology 75-90% 100%

Am J Gastro 1994; Acta Cytol 2000Am J Gastro 1994; Acta Cytol 2000

Guidelines for Diagnosis of HCC

< 1 cm 1-2 cm > 2 cm

Repeat US every 3-6 months

Dynamic CT, or MRI

2 tests

Typical = HCC

Atypical = biopsy

Dynamic CT, or MRI

1 test

Typical = HCC

Atypical = biopsy

Typical features of HCC = vascular nodule on arterial phase with washout in delayed phases

Typical features of HCC = vascular nodule on arterial phase with washout in delayed phases

Ultrasound findingsUltrasound findings

Bruix J, et al, Hepatology 2005Bruix J, et al, Hepatology 2005

HCC Consensus Conference Recommendations

Staging Systems forHepatocellular CarcinomaStaging Systems forHepatocellular Carcinoma

• Okuda Staging System

• Cancer of the Liver Italian Program (CLIP)

• American Joint Commission on Cancer (AJCC)/Union Internacional Contra la Cancrum (UICC) Tumor Node Metastasis (TNM)

• Japanese Staging System and Japan Integrated Staging score (JIS)

• Chinese University Prognostic Index (CUPI)

• Barcelona Clinic Liver Cancer (BCLC)

• Group d’Etude de Traitement du Carcinoma Hepatocellulaire (GRETCH)

• Okuda Staging System

• Cancer of the Liver Italian Program (CLIP)

• American Joint Commission on Cancer (AJCC)/Union Internacional Contra la Cancrum (UICC) Tumor Node Metastasis (TNM)

• Japanese Staging System and Japan Integrated Staging score (JIS)

• Chinese University Prognostic Index (CUPI)

• Barcelona Clinic Liver Cancer (BCLC)

• Group d’Etude de Traitement du Carcinoma Hepatocellulaire (GRETCH)

Staging Systems for Hepatocellular Carcinoma

Management of Hepatocellular CarcinomaManagement of Hepatocellular Carcinoma

•Most algorithms distinguish between

• Early HCC - Curative intent possible

• Intermediate-Advanced HCC - Curative intent not possible, but not terminal

• Advanced/Terminal HCC - Palliative options only

•Most algorithms distinguish between

• Early HCC - Curative intent possible

• Intermediate-Advanced HCC - Curative intent not possible, but not terminal

• Advanced/Terminal HCC - Palliative options only

Management of Hepatocellular Carcinoma

AJCC/UICC TNM Staging SystemAJCC/UICC TNM Staging System• sT1: Solitary tumor without vascular invasion• sT2: Solitary tumor with vascular invasion or multiple

tumors, none > 5 cm• sT3: Multiple tumors > 5 cm, or tumor involving a

major branch of the portal or hepatic vein(s)

• F0: Grade 0-4 fibrosis (no fibrosis to moderate fibrosis)

• F1: Grade 5-6 fibrosis (severe fibrosis or cirrhosis)

• N0: No regional lymph node metastasis• N1: Regional lymph node metastasis

• M0: No distant metastasis• M1: Distant metastasis

• sT1: Solitary tumor without vascular invasion• sT2: Solitary tumor with vascular invasion or multiple

tumors, none > 5 cm• sT3: Multiple tumors > 5 cm, or tumor involving a

major branch of the portal or hepatic vein(s)

• F0: Grade 0-4 fibrosis (no fibrosis to moderate fibrosis)

• F1: Grade 5-6 fibrosis (severe fibrosis or cirrhosis)

• N0: No regional lymph node metastasis• N1: Regional lymph node metastasis

• M0: No distant metastasis• M1: Distant metastasis

Greene FL, et al. AJCC Cancer Staging Manual (6th ed.) Springer: Chicago, 2002Greene FL, et al. AJCC Cancer Staging Manual (6th ed.) Springer: Chicago, 2002

AJCC/UICC TNM Staging System

AJCC/UICC TNM Staging SystemAJCC/UICC TNM Staging System

• Stage I sT1 N0 M0

• Stage II sT2 N0 M0

• Stage IIIAsT3 N0 M0

• Stage IIIBAny sT N1 M0

• Stage IV Any sT Any N M1

• Stage I sT1 N0 M0

• Stage II sT2 N0 M0

• Stage IIIAsT3 N0 M0

• Stage IIIBAny sT N1 M0

• Stage IV Any sT Any N M1

Greene FL, et al, AJCC Cancer Staging Manual (6th ed.) Springer: Chicago, 2002 Greene FL, et al, AJCC Cancer Staging Manual (6th ed.) Springer: Chicago, 2002

AJCC/UICC TNM Staging System

Barcelona Clinic Liver Cancer (BCLC) Staging ClassificationBarcelona Clinic Liver Cancer (BCLC) Staging Classification

Llovet JM, et al, Lancet 2003Llovet JM, et al, Lancet 2003

Barcelona Clinic Liver Cancer (BCLC) Staging Classification

Stage Tumor Features Liver Features

Stage 0 (very early HCC) PST 0 Single < 2 cm Child-Pugh A

Stage A (early HCC) A1 PST 0 Single tumor No portal HTN, normal bilirubin A2 PST 0 Single tumor Portal HTN, normal bilirubin A1 PST 0 Single tumor Portal HTN, abnormal bilirubin A1 PST 0 3 tumors, all < 3 cm Child-Pugh A-B

Stage B (intermediate HCC) PST 0 Large multinodular Child-Pugh A-B

Stage C (advanced HCC) PST 1-2 Vascular invasion Child-Pugh A-B

or extrahepatic spread

Stage D (end-stage HCC) PST 3-4 Any Child-Pugh C

Stage Tumor Features Liver Features

Stage 0 (very early HCC) PST 0 Single < 2 cm Child-Pugh A

Stage A (early HCC) A1 PST 0 Single tumor No portal HTN, normal bilirubin A2 PST 0 Single tumor Portal HTN, normal bilirubin A1 PST 0 Single tumor Portal HTN, abnormal bilirubin A1 PST 0 3 tumors, all < 3 cm Child-Pugh A-B

Stage B (intermediate HCC) PST 0 Large multinodular Child-Pugh A-B

Stage C (advanced HCC) PST 1-2 Vascular invasion Child-Pugh A-B

or extrahepatic spread

Stage D (end-stage HCC) PST 3-4 Any Child-Pugh C

Surgical Resection: IndicationsSurgical Resection: Indications

• In patients with no cirrhosis• Tumors of any size• No macrovascular, lymph node, or extrahepatic metastases• If technically feasible

• In patients with cirrhosis• Child-Pugh A cirrhosis• No clinically significant portal hypertension• Bilirubin < 1 mg/dl

• In patients with no cirrhosis• Tumors of any size• No macrovascular, lymph node, or extrahepatic metastases• If technically feasible

• In patients with cirrhosis• Child-Pugh A cirrhosis• No clinically significant portal hypertension• Bilirubin < 1 mg/dl

Surgical Resection: Indications

Outcome of Surgical Resection for HCC in

Cirrhosis

Llovet et al, Hepatology 1999Llovet et al, Hepatology 1999

MonthsMonths00

00

Pro

babi

lity

(%)

Pro

babi

lity

(%)

1212 2424 3636 4848

2020

100100

4040

6060

8080

Patients with a single tumor <= 5 cm and Child A cirrhosisPatients with a single tumor <= 5 cm and Child A cirrhosis

Log Rank 0.00001Log Rank 0.00001

6060 7272 8484 9696

NlNl portal pressure, Bili <1 portal pressure, Bili <1

Portal pressure, Bili <1Portal pressure, Bili <1

Portal pressure, Bili Portal pressure, Bili 1 1

Liver Transplantation for Small HCC: Milan CriteriaLiver Transplantation for Small HCC: Milan Criteria

• 48 patients with cirrhosis and HCC• Single tumors ≤ 5 cm or no more than 3 nodules, ≤ 3 cm

• No vascular invasion

• No distant metastases

• 75% 4-year survival, 83% recurrence-free

• 27% exceeded criteria on path review

• 48 patients with cirrhosis and HCC• Single tumors ≤ 5 cm or no more than 3 nodules, ≤ 3 cm

• No vascular invasion

• No distant metastases

• 75% 4-year survival, 83% recurrence-free

• 27% exceeded criteria on path review

Mazzafero, et al, NEJM 1996Mazzafero, et al, NEJM 1996

Liver Transplantation for Small HCC: Milan Criteria

• 50% 4-year survival, 59% recurrence-free• 50% 4-year survival, 59% recurrence-free

UNOS Criteria for Liver Transplantation for HCCUNOS Criteria for Liver Transplantation for HCC CT or MRI of abdomen showing tumor(s)

One 2-5 cm or two or three nodules all < 3 cm CT of chest that rules out metastatic disease Bone scan One of the following:

a vascular blush in the lesion an alpha-fetoprotein level of >200 ng/ml, biopsy confirming HCC

MELD exception points 22

CT or MRI of abdomen showing tumor(s) One 2-5 cm or two or three nodules all < 3 cm

CT of chest that rules out metastatic disease Bone scan One of the following:

a vascular blush in the lesion an alpha-fetoprotein level of >200 ng/ml, biopsy confirming HCC

MELD exception points 22

UNOS Criteria for Liver Transplantation for HCC

Ablation TherapyAblation Therapy

•Chemically-mediated ablation

• Ethanol injection

• Acetic acid injection

•Energy-mediated ablation

• Cryoablation

• Microwave ablation

• Radiofrequency ablation

•Chemically-mediated ablation

• Ethanol injection

• Acetic acid injection

•Energy-mediated ablation

• Cryoablation

• Microwave ablation

• Radiofrequency ablation

Ablation Therapy

Local Ablation Therapy for Transplant CandidatesLocal Ablation Therapy for Transplant Candidates

•Can serve as “bridge” to transplant•Minimally invasive•Avoids upper abdominal scar

•Provides effective control of the tumor up to 1-2 year from the treatment

•Additional benefit from tumor reduction prior to transplantation

•Can serve as “bridge” to transplant•Minimally invasive•Avoids upper abdominal scar

•Provides effective control of the tumor up to 1-2 year from the treatment

•Additional benefit from tumor reduction prior to transplantation

Local Ablation Therapy for Transplant Candidates

Prospective Study of RFA in Early HCCProspective Study of RFA in Early HCC

Livraghi T, et al. Hepatology. 2008; 47:429Livraghi T, et al. Hepatology. 2008; 47:429

Kaplan-Meier survival estimates, by operabilityKaplan-Meier survival estimates, by operability

97% complete response upon a median F/U time of 31 mo97% complete response upon a median F/U time of 31 mo

1.01.0

.75.75

.5.5

.25.25

00

00 66 1212

2424

3636

4848

6060

7272

InoperableInoperable

00 66 1212

2424

3636

4848

6060

7272

OperableOperable

95% CISurvivor function95% CISurvivor function

Prospective Study of RFA in Early HCC Prospective Study of RFA in Early HCC

Randomized Trials RFA vs PEIRandomized Trials RFA vs PEI

Author N size PEI RFA PEI RFADifference

Livraghi 80 <3 cm 80 90 4.8 1.2 No

Lencioni 102 Milan 82 91 5.4 1.1 Yes Recur-free

Lin 157 <4 cm 88 96 6.5 1.6 Yes

Shiina 232 Milan NA NA 6.4 2.1 Yes

Livraghi 80 <3 cm 80 90 4.8 1.2 No

Lencioni 102 Milan 82 91 5.4 1.1 Yes Recur-free

Lin 157 <4 cm 88 96 6.5 1.6 Yes

Shiina 232 Milan NA NA 6.4 2.1 Yes

Livraghi T, et al. Radiology 1999; 210:655Lencioni R, et al. Radiology 2003; 228:235Lin SM, et al. Gastroenterology 2004; 217:1714Shiina S, et al. Gastroenterology 2005; 129:122

Livraghi T, et al. Radiology 1999; 210:655Lencioni R, et al. Radiology 2003; 228:235Lin SM, et al. Gastroenterology 2004; 217:1714Shiina S, et al. Gastroenterology 2005; 129:122

PEI = percutaneous ethanol injectionRFA=radiofrequency ablationPEI = percutaneous ethanol injectionRFA=radiofrequency ablation

Tumor CR(%) SessionsSurvival

Randomized Trials RFA vs PEI

Radiofrequency Ablation

Radiofrequency Ablation for Hepatocellular Carcinoma

Probe insertionProbe insertion Deployment of tines and treatmentof tumor and surrounding regionDeployment of tines and treatmentof tumor and surrounding region

Percutaneous Ethanol Injection vs Radiofrequency AblationPercutaneous Ethanol Injection vs Radiofrequency Ablation

RF produces complete tumor necrosis in a single session RF allows clearer definition of treatment margin RF shows higher rates of needle track seeding in some

studies, particularly for liver surface tumors Large vessels act as heat sink, leading to incomplete

treatment RF probe is larger; surface tumors have higher risk of

bleeding Laparoscopic RF reduces risk, expands indications

RF produces complete tumor necrosis in a single session RF allows clearer definition of treatment margin RF shows higher rates of needle track seeding in some

studies, particularly for liver surface tumors Large vessels act as heat sink, leading to incomplete

treatment RF probe is larger; surface tumors have higher risk of

bleeding Laparoscopic RF reduces risk, expands indications

Percutaneous Ethanol Injection (PEI) Percutaneous Ethanol Injection (PEI)

Advantages•Well established therapeutic effect•Simple, inexpensive•Small needle size

Disadvantages•Unequal distribution of the ethanol•Requires repeat treatments•Small risk of tumor seeding

Advantages•Well established therapeutic effect•Simple, inexpensive•Small needle size

Disadvantages•Unequal distribution of the ethanol•Requires repeat treatments•Small risk of tumor seeding

Percutaneous Ethanol Injection (PEI)

Trans-arterial Chemoembolization for Hepatocellular CancerTrans-arterial Chemoembolization for Hepatocellular Cancer

• Chemotherapy ( adriamycin, cisplatin or mitomycin ) is suspended in lipiodol agent.

• Lipiodol is selectively retained in tumor.

• Contraindicated in PVT.

• Not indicated for BCLC stage C or D.

• Post TACE syndrome is seen in 50% of patients, consist of fever, RUQ pain, and ileus.

• No difference in TAE or TACE

• Chemotherapy ( adriamycin, cisplatin or mitomycin ) is suspended in lipiodol agent.

• Lipiodol is selectively retained in tumor.

• Contraindicated in PVT.

• Not indicated for BCLC stage C or D.

• Post TACE syndrome is seen in 50% of patients, consist of fever, RUQ pain, and ileus.

• No difference in TAE or TACE

Trans-arterial Chemoembolization for Hepatocellular Cancer

• Objective response rate ( tumor necrosis ) is 16% to 60 %.

• Improvement in survival ranges from 20% to 60%.

• Can result in down sizing of tumor for MELD exemption points

Trans-arterial Chemoembolizationfor Hepatocellular Cancer

Resection vs. OLT vs. AblationRecent citations 1995-2001Resection vs. OLT vs. AblationRecent citations 1995-2001

Survival 1 yr 5 yr

• Resection 74-96% 25-72%

• OLT 84-90% 69-75%

• Ablation 87-98% 29-54%

Survival 1 yr 5 yr

• Resection 74-96% 25-72%

• OLT 84-90% 69-75%

• Ablation 87-98% 29-54%

Bruix and Llovet, Hepatology 2002Bruix and Llovet, Hepatology 2002

Sur

viva

l(K

apla

n M

eier

Est

imat

e)S

urvi

val

(Kap

lan

Mei

er E

stim

ate)

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: Observational Population-based study

El-Serag HB, et al, J Hepatology 2006El-Serag HB, et al, J Hepatology 2006

Other Locoregional Therapies for Hepatocellular CancerOther Locoregional Therapies for Hepatocellular Cancer

• Radioactive Yttrium90-impregnated glass microspheres (TheraSphere®)

• Conformal conventional gamma radiation therapy and proton-beam therapy

• Microwave coagulation therapy

• Laser beam therapy

• Cryotherapy

• Cisplatinum gel injection

• Radioactive Yttrium90-impregnated glass microspheres (TheraSphere®)

• Conformal conventional gamma radiation therapy and proton-beam therapy

• Microwave coagulation therapy

• Laser beam therapy

• Cryotherapy

• Cisplatinum gel injection

Systemic Therapies for Hepatocellular CancerSystemic Therapies for Hepatocellular Cancer

• No safe and effective systemic chemotherapy regimens to date - doxorubicin/adriamycin the FDA standard (10-15% response rates)

• Tamoxifen ineffective

• Antiandrogens ineffective

• Somatostatin and analogs ineffective

• No clear benefit from interferon alone; combinations with other agents have high toxicity

• No safe and effective systemic chemotherapy regimens to date - doxorubicin/adriamycin the FDA standard (10-15% response rates)

• Tamoxifen ineffective

• Antiandrogens ineffective

• Somatostatin and analogs ineffective

• No clear benefit from interferon alone; combinations with other agents have high toxicity

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

*O’Brien-Fleming threshold for statistical significance was P = 0.0077CI=confidence interval; Nex/Pbo = Nexavar/placebo. Llovet JM et al. NEJM. 2008; 359(4):378

*O’Brien-Fleming threshold for statistical significance was P = 0.0077CI=confidence interval; Nex/Pbo = Nexavar/placebo. Llovet JM et al. NEJM. 2008; 359(4):378

Patients at risk Nexavar:

Patients at risk Nexavar:Placebo:Placebo:

Survival ProbabilitySurvival Probability

274274 241241 205205 161161 108108 6767 3838 1212 00276276 224224 179179 126126 7878 4747 2525 77 22

299299303303

Time (months)Time (months)

Hazard ratio (Nex/Pbo): 0.69(95% CI, 0.55-0.87) P = 0.00058*

Hazard ratio (Nex/Pbo): 0.69(95% CI, 0.55-0.87) P = 0.00058*

1.001.00

00

0.750.75

0.500.50

0.250.25

00 22 66 1010 1414 1818

NexavarMedian: 10.7 months(95% CI, 40.9-57.9)

NexavarMedian: 10.7 months(95% CI, 40.9-57.9)PlaceboMedian: 7.9 months(95% CI, 29.4-39.4)

PlaceboMedian: 7.9 months(95% CI, 29.4-39.4)

Phase III SHARP Trial: Overall Survival

Phase III SHARP Trial: Time to Tumor Progression (Independent

Review)

Llovet JM et al. NEJM. 2008;359(4):378Llovet JM et al. NEJM. 2008;359(4):378

Progression-Free Probability

Progression-Free Probability

Patients at risk Nexavar:

Patients at risk Nexavar:Placebo:Placebo:

Hazard ratio (Nex/Pbo): 0.58(95% CI, 0.45-0.74) P = 0.000007

Hazard ratio (Nex/Pbo): 0.58(95% CI, 0.45-0.74) P = 0.000007

33 66 99 121200

196196 126126 8080 5050 2828 1414 88 22192192 101101 5757 3131 1212 88 22 11

299299303303

Time (months)Time (months)

1.001.00

00

0.750.75

0.500.50

0.250.25





Nexavar Placebon = 297 (%) n = 302 (%)

Nexavar Placebon = 297 (%) n = 302 (%)

*Grade 5 events — 2 (<1%) in the Nexavar treatment arm.

NCI-CTC v3.0=National Cancer Institute–Common Toxicity Criteria version 3.0.Data on file. Bayer HealthCare.

*Grade 5 events — 2 (<1%) in the Nexavar treatment arm.

NCI-CTC v3.0=National Cancer Institute–Common Toxicity Criteria version 3.0.Data on file. Bayer HealthCare.

SHARP: All-Grade Treatment-Emergent SHARP: All-Grade Treatment-Emergent Adverse Events Reported in ≥10% of PatientsAdverse Events Reported in ≥10% of PatientsSHARP: All-Grade Treatment-Emergent SHARP: All-Grade Treatment-Emergent Adverse Events Reported in ≥10% of PatientsAdverse Events Reported in ≥10% of Patients

Adverse Event All Grade Grade AllGrade GradeNCI-CTC v3.0 Grades 3 4 Grades 3

4

Any adverse event 98 39 6 96 24

8Diarrhea 55 10 <1 25 2

0Fatigue 45 9 1 45 12

2Pain (abdomen) 31 9 0 26 6

1Weight loss 30 2 0 10 1

0Nausea 24 1 0 20 3

0Hand-foot skin reaction 21 8 0 3 <1

0Rash / desquamation 19 1 0 14 0

0Hemorrhage / bleeding 18 3 2 20 5

4Vomiting 15 2 0 11 2

0

Adverse Event All Grade Grade AllGrade GradeNCI-CTC v3.0 Grades 3 4 Grades 3

4

Any adverse event 98 39 6 96 24

8Diarrhea 55 10 <1 25 2

0Fatigue 45 9 1 45 12

2Pain (abdomen) 31 9 0 26 6

1Weight loss 30 2 0 10 1

0Nausea 24 1 0 20 3

0Hand-foot skin reaction 21 8 0 3 <1

0Rash / desquamation 19 1 0 14 0

0Hemorrhage / bleeding 18 3 2 20 5

4Vomiting 15 2 0 11 2

0

SHARP: All-Grade Treatment-Emergent Adverse Events Reported in ≥10% of PatientsSHARP: All-Grade Treatment-Emergent Adverse Events Reported in ≥10% of Patients

Hand-Foot Skin Reaction (HFSR)Hand-Foot Skin Reaction (HFSR) HFSR is a group of symptoms affecting the hands and/or feet1,2

Varying degrees of severity that tends to decrease during the course of therapy

Side effects of anti-angiogenic therapies usually occur during the first few weeks of treatment3

Patients may require2,3

Topical treatments Temporary suspension of treatment or dose reduction until the episode resolves Permanent dose reduction (in Grade 2 or 3)

HFSR is a group of symptoms affecting the hands and/or feet1,2

Varying degrees of severity that tends to decrease during the course of therapy

Side effects of anti-angiogenic therapies usually occur during the first few weeks of treatment3

Patients may require2,3

Topical treatments Temporary suspension of treatment or dose reduction until the episode resolves Permanent dose reduction (in Grade 2 or 3)

*Incidence reported from the SHARP trial; data on file, BayerHealthCare.1. Moldawer N, Wood LS. Kidney Cancer Journal. 2006;4:2-8.2. Wood LS. Commun Oncol. 2006;3:558-562.3. Alexandrescu DT, et al. Clin Exp Dermatol. 2007;32:71-74.Photos courtesy of Elizabeth Manchen, RN, MS, OCN.

*Incidence reported from the SHARP trial; data on file, BayerHealthCare.1. Moldawer N, Wood LS. Kidney Cancer Journal. 2006;4:2-8.2. Wood LS. Commun Oncol. 2006;3:558-562.3. Alexandrescu DT, et al. Clin Exp Dermatol. 2007;32:71-74.Photos courtesy of Elizabeth Manchen, RN, MS, OCN.

Grade 1Incidence: 8%*Grade 1Incidence: 8%*

Grade 2 Incidence: 6%* Grade 2 Incidence: 6%*

Grade 3 Incidence: 8%*Grade 3 Incidence: 8%*

Hand-Foot Skin Reaction (HFSR)Hand-Foot Skin Reaction (HFSR)

The Barcelona Approach to HCCThe Barcelona Approach to HCC

Llovet JM, et al, Lancet 2003Llovet JM, et al, Lancet 2003

Stage 0PST 0, Child-Pugh A, Okuda 1

Stage 0PST 0, Child-Pugh A, Okuda 1

Surgical ResectionSurgical

ResectionLiver Transplantation

(OLT/LDLT)Liver Transplantation

(OLT/LDLT)

Terminalstage D

Terminalstage D

Stage DOkuda 3, PST>2, Child-Pugh C

Stage DOkuda 3, PST>2, Child-Pugh C

Transplant Candidate?Transplant Candidate?

YesYes NoNo

Portal invasion, N1, M1Portal invasion, N1, M1

Curative TreatmentsCurative Treatments

HCCHCC

Symptomatic treatment

Symptomatic treatmentRandomized controlled trialsRandomized controlled trials

PEI/RFPEI/RF

SingleSingle

NormalNormal

Stage A-CPST 1-2, Child-Pugh A-B, Okuda 1-2

Stage A-CPST 1-2, Child-Pugh A-B, Okuda 1-2

Very early stage (0)Single < 2 cm

Carcinoma in situ

Very early stage (0)Single < 2 cm

Carcinoma in situ

ChemoembolizationChemoembolization NewAgentsNew

Agents

IncreasedIncreased

Early stage (A)Single or

3 nodules ≤ 3 cm

Early stage (A)Single or

3 nodules ≤ 3 cm

Portal pressure/BilirubinPortal pressure/Bilirubin

3 nodules ≤3 cm3 nodules ≤3 cm

Intermediate stage (B)Multinodular, PS 0

Intermediate stage (B)Multinodular, PS 0

Advanced stage (C)Portal invasion, N1, M1, PS 1-2

Advanced stage (C)Portal invasion, N1, M1, PS 1-2

NoNo YesYes

Management Algorithm for HCCManagement Algorithm for HCC

No CirrhosisNo Cirrhosis

No extrahepatic spread No involvement of major

portal structures Tumor may be large

No extrahepatic spread No involvement of major

portal structures Tumor may be large

Surgical ResectionSurgical Resection

Extrahepatic spread Involvement of major

portal structures Multilobar disease

Extrahepatic spread Involvement of major

portal structures Multilobar disease

SorafenibSorafenib

Management Algorithm for HCCManagement Algorithm for HCC

Management of Hepatocellular Carcinoma Requires a Multidisciplinary

Approach

Liver Transplant ProgramLiver Transplant Program

PathologyPathology

OncologyOncology

RadiologyRadiology

Hepatobiliary SurgeryHepatobiliary Surgery

HepatologyHepatology

Hepatic TACE(TransArterial ChemoEmbolization)• Joshua Plorde, MD

• Interventional Radiologist

Patient GT

• 50 male, referred for elevated LFTs

• Hepatitis C

• Alcoholic cirrhosis– Esophageal varices, UGI bleed, banded– Splenomegaly– Abstinent for 1 month

• AFP 27

CT Arterial Phase CT Venous Phase

GT post consult Day 1GT post consult Day 1

CT Arterial Phase

Coronal Reconstruction

7cm mass

Hepatic Angiogram

GT post consult Day 40GT post consult Day 40

Sub-selective Right lobe Hepatic Angiogram

Coronal CT Reformation during Angiography

Post ChemoEmbolization (TACE)

CT Coronal Reformation Post Chemo-Embolization

Post TACE x2

Outcome: Mass decreased to 4.5cm, AFP 3, listed for Tx

Received orthotopic liver Tx 9months post initial consultation

Patient BB

• 65 male, referred for elevated LFTs

• No Hx of cirrhosis, no strong risk factors

• Negative hepatitis profile

• AFP <6

Outside Inst. Non Contrast CT & Bx

12cm mass HCC

GT MR, week of consult

Non Contrast MR (T1, fat sat) Post Contrast Coronal MR


Non Contrast MR (T1, fat sat) Post Contrast MR, Arterial Phase


Post Contrast MR,

Portal Venous Phase

Post Contrast MR,

Washout Phase

GT post consult Day 14Hepatic Angiogram

Hepatic Angiogram

Early enhancing mass Tumor vascularity

ChemoEmbolization (TACE)

Post ChemoEmbolization Tumor staining, Pruned vasculature

Post TACE #1

Middle and Left Hepatic Artery Supply Remain

CT Post TACE #1, medial component treated with TACE #2

GT 6 month follow up

Post TACE x3Initial diagnosis

GT 6 month follow up

CT Arterial Phase, limited enhancement CT Venous Phase, mass 5.5cm

Plan: Follow-up at 9 months, assess tumor size Treatment options: Transplant, local resection vs. conservative Rx

Patient BA

• 47 Sudanese female, presenting with fevers, chills, abdominal pain

• Hx Hepatitis B, cirrhosis– Esophageal varices, UGI bleed, banded– Portal hypertensive gastropathy,

splenomegaly

• AFP 105

Presenting (Conventional) CT with Contrast

4cm right lobe mass Little/no contrast enhancement

Presenting (Conventional) CT with Contrast

Coronal Reformation


Non Contrast MR (T1, fat sat) T2, STIR

MR and CT BxNon Contrast T1Post Contrast

Venous Phase

Post Contrast Equilibrium Phase CT Bx, post consult day 5

GT post consult Day 21

Early enhancing mass Contrast “puddling”

Hepatic Angiogram

Sub-selective Right Lobe Hepatic Angiogram

Tumor Vascularity Delayed “staining”

ChemoEmbolization

Tumor staining Pruned vasculature

CT 1 day post TACECT 3 months post TACE,

Arterial Phase

CT 3 months post TACE, Venous PhaseOutcome: Tumor size 3cm, AFP 3

Listed for Tx 3 months post consult Tx 6 month later

tariq n khan, md. director solid organ transplant and hepatobiliary surgery

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