1. No category

Treating HCC: TACE and RFA
Janette Durham, MD
University of Colorado
May 2013
No disclosures
Learning objectives
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1. Stratify HCC by Barcelona criteria to organize
treatment options.
2. Discuss the clinical features that predict a favorable
treatment response.
3. Discuss the recent developments in the field of
percutaneous therapies for HCC.
4. Understand the role or percutaneous therapy in
relation to transplantation.
5. Understand the decision to treat with RFA vs. intraarterial therapy.
Prognostic factors in treatment of HCC
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Tumor status (number and size, portal
invasion, extrahepatic disease)
Performance status-ECOG
Liver function – CP
UNOS TNM staging
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T1
T2
1 nodule < 1.9cm
1 nodule 2.0-5.0 cm; 2-3 nodules all < 3.0 cm
T3
T4a
T4b
N1
M1
1 nodule > 5 cm; 2-3 nodules at least one > 3.0 cm
4 or more nodules
T2,T3,T4a plus vascular involvement
Regional nodes involved
Metastatic disease including extrahepatic portal or
hepatic vein involvement
Performance Status
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ECOG
 0 Fully active, able to carry on all pre-disease performance
without restriction
 1 Restricted in physically strenuous activity but ambulatory and
able to carry out work of a light or sedentary nature
 2 Ambulatory and capable of all self-care but unable to carry out
any work activities. Up and about more then 50% of waking
hours.
 3 Capable of only limited self-care, confined to bed or chair more
than 50% of waking hours
 4 Completely disabled. Cannot carry on any self-care. Totally
confined to bed or chair
 5 Dead
BCLC Classification of HCC
Stage 0
PS 0; CP A
Single < 2 cm
Early stage (A)
PS 0; CP A or B
Single < 5 cm or 3 nodules < 3 cm
Stage A-C
Intermediate stage (B)
PS 0; CP A or B
Multinodular
Stage D
PS > 2;CP C
Advanced (C)
PS 1 -2;CP A or B
Portal invasion, N1,M1
Types of percutaneous therapy
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Arterial therapy
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cTACE-conventional transarterial chemoembolization
Administration of chemotherapeutic agent mixed with
ethiodal prior to arterial obstruction with embolic beads.
Ethiodal is selectively retained within the tumor and
prolongs chemotherapy dwell time.
DEB-TACE- drug eluting beads
A bead loaded with chemotherapy that is trapped in the
capillary bead of tumors slowly releasing
chemotherapeutic agent into the tumor over days and
decreasing systemic drug toxicity
TARE-transarterial radioembolization
Radioembolization using beads loaded with yttrium that
produce internal radiation centered within the tumor
Types of percutaneous therapy
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Ablative therapy
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PEI-percutaneous ethanol injection
RFA-radiofrequency ablation
Microwave- microwave ablation
IRE – Irreversible electroporation - non thermal
ablation with electric current
Intermediate disease
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Stage B
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Multinodular (T3,T4a), PS 0, CP A and B
No macrovascular invasion
No extrahepatic disease
Survival without treatment is about 1.5 years
Therapies geared toward > 2 year survival
 cTACE, DEB, TARE
cTACE
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Chemotherapy-cytotoxic agent
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CAM
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Single agent
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Cisplatin
Doxorubicin
Mitomycin
Cisplatin
Doxorubicin
Ebirubicin
Ethiodol (Lipiodol)
Embolization
Mechanism of cTACE
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HCC exhibits intense new-angiogenic activity with
blood supply progressing from the portal vein to the
hepatic artery
Chemotherapy delivered in high concentration
enhances coagulative tumor necrosis
Arterial obstruction results in ischemic tumor necrosis
with a high rate of objective response
Perfusion to uninvolved liver is maintained by the
portal vein permitting selective targeting of tumor
Author
Patients
Lo. Hepatology 2002;35:1164
Cisplatin
80 eligible patients
TACE
40
Palliative care
40
Llovet. Lancet 2002;359:1734
Doxorubicin
112 RCT
Hepatitis C -80-90%
CP A or B;Okuda I, II
% Survival 1,2, 3Y
Hepatitis B-80%
Embolization
TACE
Palliative care
57, 31,26
32, 11,3 (p=.02)
75,50
82, 63
63, 27 (p=.009)
Systemic review of randomized trials (7)
Llovet.Hepatology 2003:37;429
TACE recommended as standard of care for Intermediate disease
Patient selection
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Careful selection required due to concomitant
ESLD
 Bilirubin < 3.0
 INR < 2.0
 Platelet count > 50,000
 Good performance status – ECOG 0 or 1
Limited embolization in ESLD
Complications
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Common
 Post embolization syndrome from arterial obstruction– fever,
abdominal pain, nausea, ileus
 Hepatic dysfunction
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Bilirubin toxicity (Grade 3 or 4) in 20% at 1 year
Progressive deterioration with multiple treatments
Severe and uncommon
 Systemic
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Bone marrow depression
Alopecia
Liver failure
Worsening encephalopathy
Death
Gastrointestinal bleeding
Hepatic abscess
Cholecystitis
Challenges
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Drug shortages
 Ethiodol/Lipiodol
 Powder Cisplatin
 Powder Doxorubicin
DEB TACE
LC Bead/DC Bead
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Drug delivery system
comprising biocompatible,
non resorable hydrogel
beads loaded with
anthracyclin derivatives
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Higher tumor
concentrations and lower
systemic concentrations of
doxorubicin compared to
cTACE
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Better tolerated permitting
repeat procedures in
shorter intervals.
PRECISION V
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212 patients with intermediate stage HCC not
suitable for curative treatments and naive to
chemotherapy or radiotherapy
Randomized to cTACE or DEB
Primary end point was MRI tumor response
(EASL) at 6 months
Lammer.Cardiovasc Intervent Radiol 2010;33:41
Technique
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cTACE
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Selective injection of 50-75 mg/m2 doxorubicin –
lipiodol emulsion
Embolization to stasis with gelatin sponge
DC Bead
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Selective injection of 2 vials of DC Beads loaded
with 150 mg Doxorubicin.
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1 vial of 300-500 um beads
1 vial of 500-700 um beads
Embolization to stasis
Treatment at 2 month intervals for up to 3
sessions with follow up at 3 months
Lammer.Cardiovasc Intervent Radiol 2010;33:41
6 Month response
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% CR
% Objective response
% Disease control
DC Bead
cTACE
27
52
63
22
44
52
Superiority was not found
Significant advantage in OR in advanced liver
disease (CP B, ECOG 1, bilobar disease,
recurrent disease patients).
Significant reduction in liver toxicity and lower rate
of doxorubicin related side effects
Lammer.Cardiovasc Intervent Radiol 2010;33:41
TARE
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Yttrium 90 is a β particle emitter as it decays to
stable zirconium-90
Maximum penetration < 10mm (mean < 2.5
mm)
Half life of 64 hrs, mean life of 3.85 days
94% of radiation delivered in 11 days
Tumor to non-tumor uptake may triple the
absorbed dose in tumor
Radiation hepatitis
30 Gy
35 Gy
43 Gy
TARE
70-90 Gy
Focused XRT
150 Gy
Curative Doses:
Adenocarcinoma
Whole liver XRT
Radiation pneumonitis
Andrews. J Nucl Med 1994;35:1637-1644
Herba. Semin Oncol 2002;29:152-159
Yittrium 90 Microspheres - Products
TheraSphere ® (MDS
Nordion-Ottawa ON,
Canada)
•20-30 µm glass
spheres
•3-8 million spheres
per dose
• 2500 Bq per sphere
•2000 FDA approval
(HDE) for HCC
SIR-Spheres ® (Sirtex
Medical Limited-Sydney,
Australia
•20-30 µm resin spheres
•30-60 million spheres
per dose
•50 Bq per sphere
•2002 FDA approval for
colorectal liver
metastases
Response
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Imaging more difficult to interpret
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Less embolization effect so enhancement not
eliminated
Looking for changes in lesion size
Treatment response slow (6m)
Changes in liver morphology common
Y90 Results
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Retrospective review of 245 B/C patients
treated with cTACE vs 123 treated with y90
at a single institution
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Abdominal pain and increased transaminase more
frequent after cTACE
RR 49 vs 36% favored y90 (NS)
TTP 13.3 vs 8.4m favored y90 (p = .046)
Median survival 20.5 vs 17.4m (NS)
Intermediate disease survival 17.5 vs 17.2 (NS)
Salem. Gastroenterolgoy 2012;140:497
Cost
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cTACE: < $1000
DEB: $1,500 per vial
Y90: $15-20,000 per vial
Sorafenib $5,400 /month
Advanced disease
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Stage C
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Portal invasion, N1,M1,PS 1-2, CP A and B
Survival without treatment .5 y
Therapies geared toward > 3 month survival
benefit
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Sorafenib advanced disease - increased survival from
7.9 - 10.7m
N Engl J MED 2008;359:378
cTACE, DEB TACE
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cTACE
 Retrospective review of 172 patients treated with cTACE –CAM
 Median survival Stage A/B/C: 40.0/17.4/6.6m
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DEB-TACE
 Consecutive treatment of 121 patients with Stage C disease with DEBTACE
 Median survival 13.5m ( 17.8 m CP A)
 Survival worse with T4b disease – 18.8 vs 4.4m in CP A patients
Lewandowski.Radiology 2010;255:955
Prajapati.J Vasc Interv Radiol 2013;24:307
Comparison to medical therapy
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Retrospective evaluation of 97 Stage C patients with
TACE (34) at a single institution or Sorafenib (63) at
multiple institutions.
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Results
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TTP similar
Median survival 9.2 vs 7.4m favoring TACE (NS)
Pinter.Radiology 2012;263:590
Y90 Results
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Phase 2 – prospective study of 52 patients with Intermediate (17)
and Advanced disease (35) all with PVT looking at safety and
efficacy with a mean fup of 36 m
Results:
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TTP
TR
11m ( 7 vs 13 m if PVT present (NS))
CR 10%
OR 40%
DC 79%
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OS
15m (13 vs 18m if PVT present (NS))
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Safety
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Various grades of liver decompensation in 35% at 6 m (TACE 20%)
Mortality 3.8% at 90 d
Mazzaferro.Hepatology 2013:57:1826
Y90 emerging role
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PVT
Advanced disease with well preserved liver
function
Intermediate disease
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Large lesions
Multiple bi-lobar nodules
Early stage disease (A)
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Stage A
 Single tumors < 5 cm, 3 nodules < 3 cm
CP A-B, PS 0-2
 Therapies geared toward minimum median survival of
5 years
 Resection
 Transplantation
 Ablation
Role of percutaneous therapy is brideging and
downstaging for transplant.
Ablation therapy
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Recurrence rates with RFA appear lower
than PEI at the expense of higher
complications and cost
Complete response in 80% of tumors less
than 3 cm and 50% if 3-5 cm
Best results – 5 year survival of 40-70%
Predictors of best results– Child-Pugh A,
single tumors, less than 2 cm, initial response
Gervais. J Vasc Inaterv Radiol 2009;20.
RFA Complications
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Morbidity 7%; Mortality , 1%
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Bleeding requiring transfusion 1%
Abscess 1% - highest when biliary enteric
anastomosis
Tract seeding < 1% with tract coagulation-
Gervais. J Vasc Inaterv Radiol 2009;20.
Current Role of RFA
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Indications
 Primary treatment instead of partial hepetectomy for lesions < 3
cm
 Unresectable small HCC
 Recurrent small HCC
 Bridging therapy before liver transplantation
 Increasing role in 3-5 cm lesions
 Chen: solitary HCC < 5 cm
 4 year survival 68% (46% DF) vs. 64% (51%DF)
 Lu: solitary HCC < 5 cm or < 3 nodules < 3 cm
 3 year survival: 87% (51% DF) vs.86% (82% DF)
Lau.Ann Surg 2009;249:20
Chen Ann Surg 2006;243:321
Lu Zhonghua Yi Xuwe Za Zhi 2006;86:801
Microwave
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Electromagnetic radiation
 More efficient energy deposition
 Desiccation and charring not limiting
Changes in design decrease skin burns or pain
Faster heating, higher temperatures, larger ablation volumes,
shorter ablation zones
Less susceptibility to heat sink
Maybe safer around bile ducts
Easier to use – no grounding pads, easier to run machine
Role for microwave in larger lesions
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80 patients with HCC 3- 8cm (mFUP 32m)
 CP A and B
 < UNOS T4
 23 with recurrent disease
 Lesion size
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52 - 3-5 cm
28 - 5-8 cm
Results
 Complete ablation – 87.5%
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22% local recurrence
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15% vs 41% depending on size
Location near bile duct
54% distant recurrence
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94% cw 75% depending on size
More frequent in recurrent HCC
Complications – 7.5% without mortality
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1 tract seeding
Liu 2012 Clin Radiol 2012: 68;21
Survival
1
81%
2
68%
3
56%
5 years
34%
Liu 2012 Clin Radiol 2012: 68;21
Conclusions
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Strong evidence:
 cTACE for Stage B patients suggesting disease
control and benefit over medical therapy
 Equivalency of DC Bead cw cTACE in Stage B
patients with lower toxicity ( and y90 is also equivalent
with further reduction in toxicity)
 DEB-TACE and y90 may provide better results in
selected Stage C patients than Sorafenib
 Similar survival outcomes with ablation cw resection
for small Stage 0- A tumors
 RFA best results in Stage A disease but microwave is
increasing the success in Stage B disease