Interventional Oncology vs. Liver Tumors: Whats in the quiver? Howard M. Richard, III, MD.

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