tariq n khan, md. director solid organ transplant and hepatobiliary surgery
TRANSCRIPT
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
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
Age-adjusted incidence rateper 100,000
Age-adjusted incidence rateper 100,000
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
NexavarMedian: 5.5 months(95% CI, 18.0-30.0)
NexavarMedian: 5.5 months(95% CI, 18.0-30.0)
PlaceboMedian: 2.8 months(95% CI, 11.7-17.1)
PlaceboMedian: 2.8 months(95% CI, 11.7-17.1)
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
GT MR, week of consult
Non Contrast MR (T1, fat sat) Post Contrast MR, Arterial Phase
GT MR, week of consult
Non Contrast MR (T1, fat sat) Post Contrast MR, Arterial Phase
GT MR, week of consult
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
GT MR, week of consult
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