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Interventional Oncology vs. Liver
Tumors: What’s in the quiver?
Howard M. Richard, III, MD
Disclosures
• None
Overview
• Explain the various modalities utilized in the
treatment of liver tumors
• Discuss the nature of clinical evidence for the
various interventional oncology options for
treating liver tumors
• Discuss the rationale for choosing between
the various options based on the varied
clinical presentations of liver tumors
History
• Liver resection for cure
• Only 20% of patients are candidates for
curative resection
• Liver transplant
– Scarcity of livers > up to 30% of candidates will
have disease progression and fall off transplant
list
• Liver resection
– Lobectomy, segmentectomy...
Resection for cure
• Milan criteria for liver transplantation
– One lesion smaller than 5cm
– Three lesions smaller than 3cm
– No extra-hepatic disease
– No vascular invasion
• Partial liver resection
– Functional liver remnant
Resection for cure
• 26% functional liver reserve for patients with
normal liver function
• 40% high grade steatosis and after oxaliplatinor irinotecan-based neoadjuvant
chemotherapy
• >50% of the total liver volume for cirrhotic
Pathology
• Primary
– Hepatocellular carcinoma
• Secondary
– Colorectal liver (most common)
– Neuroendocrine
• Carcinoid
– Breast, melanoma, etc...
Modalities
• Resection
– Bridging treatment
– Prior to OLT or hepatectomy
• Resection after down-staging
– Portal vein embolization
• Palliative
– Ablation
– Embolization
– Adjuvant medications
Resection for cure
• Extended resection
• Staged resection
• Preoperative portal vein embolization to
increase future remnant liver volume
• Resection combined with tumor ablation
Portal vein embolization
• Patients with marginal or insufficient
functional liver reserve
• Ipsilateral hepatic atrophy
• Contralateral hepatic hypertrophy
• In non cirrhotic patients 40-60 % hypertrophy
of contralateral lobe
Portal vein embolization
• Ipsilateral access
into portal veins
• Limits any iatrogenic
damage to the
eventually resected
portion of the liver
Portal vein embolization
•
•
•
•
PVA
N-butyl cyanoacrylate
Fibrin glue/Lipiodol
Gelfoam and
thrombin
• Coils
• Gentamycin
• Ethanol
Portal vein embolization
• Can increase the size of the liver remnant 4060%
• More effective in enlarging the left lobe
• Using Ethanol requires balloon occlusion
Ablation
• Thermal
– RF, Laser, Microwave, HiFUS, Cryo
• Chemical
– Alcohol, acetic acid, other
• Irreversible Electroporation
Ablation
• Thermal vs Non thermal
• Thermal
– RFA is predominant
– Laser, Microwave, HiFUS, and Cryo are much less
popular
• Non thermal
– Ethanol is inexpensive
– Proven inferior to RFA
– IRE is emerging as an option
Embolization
•
•
•
•
•
Bland
Chemoinfusion
Chemoembolization
Radio embolization
Adjuvant medications
Bland embolization
• Concept of hepatic arterial embolization 1950s
• Tumors derive 90% of blood from hepatic
artery while portal vein provides majority of
flow to liver
• Goal is terminal arterial blockade
• 40 um particles optimally block tumor neovascular network
Bland embolization
• Fistulas allow systemic non-target
embolization
• Tumor ischemia > Hypoxia
• Stimulation of angiogenesis
– Up-regulate pro-angiogenic factors
– Provide mechanism for resisting apoptosis
• Associated with metastasis
– Poor outcomes
Bland embolization
• Benefits
– Inexpensive
– Repeatable
• Disadvantages
– Non target embolization of gallbladder,
pancreatitis, liver failure
– Liver abscess
Chemo infusion
• Infuse drug alone no embolization
• Infuse chemotherapeutics with first pass
hepatic metabolism
– Maximize tumor exposure to drug
– Minimize systemic toxicity
Chemo infusion
• First premise > liver can clear the drug at first
pass even at high dose
• Second premise > increased drug
concentration in liver leads to increased
response
• Third premise > regional drug delivery leads to
decreased systemic exposure to drug
Chemo infusion
• Colorectal cancer
– Floxuridine FUDR
• Increase response rate when compared to
systemic chemo
• Usual referral is for patients who progress on
traditional chemo
• HCC no improvement in survival when
compared to systemic chemo
Chemo embolization
• Drugs and Gelfoam embolization introduced
in the 1970s by Yamada
• Currently defined as
– Infusion of a mixture of chemotherapeutics with
or without iodized oil followed by particle
embolization
• Purpose
– Prevent washout of drug
– Induce tumor ischemia
Chemo embolization
• Higher local drug concentrations
• Lower systemic drug exposure
– Compared to systemic treatment
• Lipiodol is believed to increase intra-tumoral
retention of the chemotherapeutics
• Worldwide > single agent Doxyrubicin
• US > Doxyrubicin, Cisplatin and Mitomycin C
Chemo embolization
• 2002 Lo and Llovet reported RCT vs HCC
– Survival benefit for TX of HCC
– When compared to standard supportive
treatment
• 2006 Geschwind reported RCT vs CRC
– Survival benefit for TX of CRC
• Effective in generating tumor response
– Neuroendocrine, breast, cholangiocarcinoma...
Chemo embolization
• 2009 Vogl retrospective TACE with
– Mitomycin C vs Mitomycin C and Gemcitabine for
neuroendocrine liver mets
• Combination therapy
• Improved local control
• Improved five year survival
Chemo embolization
• Breast cancer mets to liver
– Local control can be established
• Sarcoma mets to liver
– Significant tumor necrosis
– Improved survival
Drug eluting Beads
• Chemoembolization with special beads
• Load PVA based beads with various types of
chemo and deliver to hepatic artery
• Once on location, beads release drug
• Sustained and controlled release
• Improve local delivery and minimize systemic
exposure
Drug eluting beads
•
•
•
•
DC beads Biocompatibles
100-300 Yellow
300-500 Blue
500-700 Red
Drug eluting beads
• Quadraspheres
Biosphere/Meritt
• Beads swell upon
exposure to ionic fluids
– Conforms to vessels
• Studies as a bland
agent
• Can absorb
Doxyrubicin
Drug eluting beads
• Doxyrubicin-capable or DC beads
– Load with doxyrubicin 25mg/ml by immersion in
drug solution for 1-120 minutes.
– Requires drug compounding in the pharmacy
• DC beads have been loaded with Irinotecan
for use against colorectal liver mets
• Quadraspheres can be loaded with
Doxyrubicin
Drug eluting beads
• Tumor response rates for DC beads vs HCC
– 10-20% total response
– 40-60% partial response rates
• Irinotecan vs CRC mets
– 19 month overall survival in patients who had
progressed on systemic chemo
• Safe and effective
• Expensive
Radio embolization
Yttrium-90 microsphere
• Glass sphere
• Yttrium-89 is
converted to
Yttrium-90
• Beta decay to
Zirconium-90
100 Gy HCC study
Objectives:
• Define activity of Yttrium-90 microspheres
in previously untreated patients with HCC
• Evaluate treatment response and survival
of patients treated with Yttrium-90
microspheres
• Survival benefit
Dancey, JE, Shepherd, FA, Paul, K, Sniderman, KW, Houle, S, Gabrys,
J, Hendler, AL, & Goin, JE. Treatment of Nonresectable
Hepatocellular Carcinoma with Intrahepatic 90 Y-Microspheres
J Nucl Med 2000; 41: 1673-1681
100 Gy HCC study
1.0
Survival of Patients Receiving TheraSphere
By Liver Dose
0.9
0.8
> 104 Gy (N = 10)
Median Survival = 635 days
0.7
0.6
0.5
0.4
0.3
0.2
< 104Gy (N = 10)
Median Survival = 323 days
0.1
0.0
0
100
200
300
400
500
600
700
DAYS
800
900
1000
1100
1200
1300
TheraSphere
®
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SIR-Spheres
• Initially developed
in 1990
• 35 micron spheres
• Impregnated with
yttrium-90
• Particles emit beta
radiation
SIR Sphere Characteristics
• 35  m
• 100% ß emitter
0.9367 MeV
• Half-life of 64.2 h
• 2.5 mm av (max 11)
• Glass/Ceramic matrix
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SIR-Spheres
• Selective Internal
Radiation
• Particles lodge in
capillaries of
tumor
• Size and number
of tumors does
not matter
SIR-Spheres
• 90Y-microspheres do not undergo any
biologic degradation
• Activity decays to infinity at a mean life of
3.86 d
• Beta particle decay
– average range in tissue is 2.5 mm
– with a maximum range of < 11mm
Trans-Arterial Hepatic LDR Brachytherapy
TARGETED DELIVERY
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LETHALITY
Radioembolization
• Response rate 90% *
– Falling tumor markers and serial 3-monthly CT
scans
• HCC can be down-staged to OLT, resection or
ablation
• Increased survival, tumor response time and
time to progression when compared to 5-FU
vs CRC
* Hepatogastroenterology. 2001 Mar-Apr;48(38):333-7.
Dose Distribution and Effect
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MAA
PET Before
TheraSphere®
PET After
TheraSphere®
Adjuvant chemotherapy
• Sorafenib (Nexavar, Bayer)
– MultiKinase inhibitor (anti VEGF)
– Can be used to decrease intratumoral
arteriovenous fistulas and enable SIR
• Bevacizumab (Avastin, Genentech)
– Monoclonal antibody to vascular endothelial
growth factor
– Augments efficacy of TACE vs HCC
Discussion
• Radioembolization vs HCC
– Treatment can down stage patients to become
eligible for transplant, resection or ablation
• Radioembolization vs CRC
– Compared to hepatic artery chemotherapy
• Decreased time to progression
• Increased survival
• Radioembolization vs neuroendocrine
– Increased survival compared to systemic treatment
Discussion
• Lo and llovet RCT for HCC
– Chemoembolization is superior to best supportive
care
• DEB vs embolization
– DEB is superior to bland embolization
– Longer time to progression
Discussion
• DEB vs chemoembolization
– DEB higher rate of response
– DEB fewer adverse events
– DEB has yet to show a survival benefit
• Radioembolization vs Chemoembolization
– SIR better at downstaging HCC
– SIR less toxicity
– SIR has yet to show survival benefit
Discussion
• Surgery compared to embolization and
ablation for HCC up to 7cm
– Five year survival 56 to 54%
• Chemoembolization vs CE and ablation for
HCC 3-5cm
– CE & RFA is more effective
• Radio embolization & 5-FU vs 5-FU for CRC
– SIR & 5-FU is well tolerated, improved time to
progression
Conclusions
• Ablation with RFA is choice for small tumors
when surgery or transplantation is not
feasible
• IRE is a choice when ablation target is
adjacent to large vessels (Heat Sink) or central
bile ducts
• Ethanol or cryoablation can be used if target is
in sensitive location ie. Near the dome of the
diaphragm or heart
Conclusions
• Chemoembolization is standard for
intermediate/ advanced unresectable HCC
• CE can help select patients for OLT (bridge)
• Combination of CE and Ablation is effective
with limited toxicity
• Drug eluting bead will replace oil based
chemoembolization
Conclusions
• Y-90 is safe and effective as outpatient TX
• Y-90 for HCC
– Downstaging / bridging to transplantation or
resection
– Portal vein thrombosis
– Advanced disease
Decisions decisions
• Milan criteria for resection
– If close consider portal vein embolization, CE, SIR
• Few lesions
– Ablation
• Moderate disease
– CE
• Extensive disease
– SIR