Post on 26-Mar-2015
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 oxaliplatin- or 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 40-60%
• 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 neo-
vascular 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
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> 104 Gy (N = 10)Median Survival = 635 days
< 104 Gy (N = 10)Median Survival = 323 days
Survival of Patients Receiving TheraSphere By Liver Dose
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 μm• 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
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TARGETED DELIVERY 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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PET Before TheraSphere®PET After
TheraSphere®
MAA
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