A Time to Kill: Ablation Techniques Deconstructed

Howard M. Richard, III, MD

Disclosures

• None

Overview

• Explain the technical aspects of how Cryoablation, radiofrequency ablation, microwave ablation, irreversible electroporation (IRE), alcohol, and focused ultrasound destroy tissue.

• Discuss the benefits of the various types of ablative technologies

• Discuss the risks and contraindications of the various ablative techniques

History

• Surgical resection is the original local ablative technique

• Percutaneous techniques allow for– Less damage to surrounding healthy tissue– Less patient pain– Improved cosmetic result– Reduced cost– Shorter hospital stay

Ablation

• Goal is to destroy abnormal tissue and a “surgical margin” of normal tissue 5 - 10 mm

• Minimal ablative margin minimizes damage to normal tissue

• Conservation of adjacent tissue vs resection– Cirrhotic liver– Renal parenchyma– Weight baring bone

Categories

• Non Thermal– Injectable– Irreversible electroporation

• Thermal– Heat– Cold

Injectable

• Ethanol• Acetic acid• Radioactive beads• Heated liquids• Heated chemotherapy• Chemotherapy• Chemotherapeutic gels

Ethanol

• First used in the 1980s• Three to six injection sessions – Twice weekly – Multi side hole needle 21 gauge

• Inexpensive• Can be used safely around bile ducts,

gallbladder and diaphragm compared to thermal techniques

Ethanol

• Two mechanisms of tissue destruction• Dehydration of the cytoplasm, protein

denaturation > coagulative necrosis• Ethanol enters microcirculation > necrosis of

the vascular endothelium, platelet aggregation, vascular thrombosis > tissue ischemic necrosis

Ethanol

• Diffuses through soft tumors such as HCC more easily than cirrhotic liver

• Is constrained by tissue planes• Concentrated inside of fibrotic capsules /

pseudo-capsules• Less likely to diffuse through fibrotic

metastatic tumors

Ethanol - Disadvantages

• Pyrexia• Pain• In liver, rise in liver enzymes• Systemic intoxication

• Randomized controlled trials demonstrate inferiority compared to RFA

Acetic acid

• Introduced 1994* for HCC• Greater diffusion coefficient than Ethanol• Does not respect tissue planes• Will cross fibrous capsules– Suitable for infiltrating tumors– Difficult to control spread

* Radiology 1994; 193:747-752

Acetic acid

• Two mechanisms of tissue destruction similar to Ethanol

• Dehydration of the cytoplasm, protein denaturation > coagulative necrosis

• Ethanol enters microcirculation > necrosis of the vascular endothelium, platelet aggregation, vascular thrombosis > tissue ischemic necrosis

Radioactive Beads

• 33 patients treated in 1996• Direct intra-lesional yttrium-90• 90 % tumor response• Frowned upon – Intra-peritoneal spillage of beads would be

catastrophic– Safety concerns for surgeons in the event of need

for emergency surgery

Hyperthermic Saline/Water

• Less irritating than Ethanol• Thermal effect...• Distilled water adds hypo-osmolarity effect• Tumor response rate* of 42%....

• Side effects mild– Pain, low grade fever, elevated liver enzymes

* J Vasc Int Radiol 1999; 22:337-341

Heated Chemotherapeutics

• Cisplatin and Laser – 75% response vs squamous cell cancer*– Cisplatin is less effective at high temperatures

• Carboplatin used in animal study**

• Experimental....

* Laser Surgery Med 1997; 21:423-431** Hepato-Gastoenterology 2001; 48: 1328-1332

Chemotherapeutics

• Cisplatin and epinephrine gel*• Phase II trial vs HCC– Response rate 52%

• Decreased systemic uptake

• Experimental

*HPB 2000; 2:273

Irreversible Electroporation

• Non thermal• Micro to milli second pulses of electrical

current• Generate electrical fields up to 3 kV/cm• Irreversible damage to cell membranes• Induces apoptosis• No heat sink effect

Irreversible Electroporation

• No heat, No heat sink problem• Large vessels have limited effect on ablation• Does not effect collagenous tissues – Vessels and ducts

• Does not effect nerves

IRE disadvantages

• Electrodes 19 gauge must be placed 1-3 cm apart.

• Single needle option for very small lesions• Generates dangerous electrical harmonics• Stimulates muscle contraction and dangerous

cardiac arrhythmia– General anesthesia paralysis and cardiac gating

Thermal Ablation

• Heat kills, cold kills, although slightly differently

• Heat – Radio-frequency Ablation– Laser Ablation – Microwave Ablation – High Intensity Focused Ultrasound

• Cold– Cryoablation

Thermal Ablation Therapy:Temperature Tissue Interactions

• 35 - 40 ° C Normothermia• 42 - 46 ° C Hyperthermia• 46 - 48 ° C Irreversible cellular damage 45 min• 50 - 52 ° C Coagulation necrosis, 4-6 min• 60-100 ° C Near instantaneous coag necrosis• > 110 ° C Tissue vaporization

Mechanism of Cell Death

• Hyperthermia – alters structure of the cell membrane – drives intra & extra cellular water out of tissue

resulting in coagulative necrosis

• Denature cytoskeleton and altering cellular architecture

• Impairment in DNA replication

RadioFrequency

• Similar to Electrocautery– No heat flows directly from the device

• High frequency alternating current• Ionic agitation• Frictional heating• Tissue near electrode

Angiodynamics RITA Medical Systems Generator

Procedure Overview• Power is applied

until tissue impedance (resistance to electrical current) rises

• Generator detects impedance rise and signals completion of procedure

Close-up of StarBurst XL

Close-up of StarBurst XL

Heat Generation

• Tissue death– 50 Degrees Celcius

• Three factors (in vitro)– Distance from the electrode– RF current intensity– Duration of application of RF current

Stages of RF Ablation

Conduction Over Time . . .

Stages of RF Ablation

• Frictional heating• Conductive heating

Microwave

• First percutaneous use in 1994* vs HCC• Microwave antennae placed into tumor • Electro magnetic waves induce heating• Generate temperatures over 150 degrees C

• No current induced decline in efficacy

* Cancer 1994; 74:817-825

Microwave

• Electromagnetic energy– 300 MHz to 300GHz (915 MHz or 2.45GHz)

• Heating is produced dielectric hysteresis (rotating dipoles)

• Water molecules are forced to line up– Resulting in an increase in their kinetic energy

Microwave Advantages

• Waves move readily through tissues including low conductivity such as lung, bone, dehydrated or charred tissue

• Can produce extremely high temps >150 C– More efficient than RFA– No grounding pads

Microwave Disadvantages

• Microwave energy is difficult to distribute• Coaxial cables• Wire heating is a problem– Skin injury– Cooling jackets to reduce cable heat

• Only one FDA approved system– Evident (Valleylab)

Laser• Interstitial laser photocoagulation• Percutaneous use 1989* vs mets to liver• Optical fibers are used to carry energy– MRI compatibility...

• Photon energy conduction induced heating to just over 50 Degrees C

• Tissue penetration of the laser light is only 0.4mm

* Br Med J 1989; 299:362-365

Laser Disadvantages

• No FDA approved systems• Light does not penetrate charred or

desiccated tissues• Requires multiple optical fibers• Fiber bundle must be cooled to avoid skin

injury

Focused Ultrasound

• HIFU high intensity focused ultrasound• Ultrasound beams of high energy are focused• Multiple beams from many directions focus

on a single voxel• Generates temperatures over 60 Degrees C• Requires MRI

MR guided Focused Ultrasound

• ExAblate 2000 – Focused ultrasound array system

AJR 2004; 183:1713-1719

Focused Ultrasound

• Acoustic cavitation– Expansion and contraction of gaseous nuclei in

cells through acoustic pressure– Causes collapse of mitochondria, endoplasmic

reticulum, nuclear and cell membranes

• Additional mechanical mechanism of tissue destruction

Focused Ultrasound

• Treatment of Breast and Uterine Fibroids• MRI guided• Limited by respiratory motion to targets that

do not move

Cryotherapy

• Began in the 60’ s• Popular in the 80’ s– Intra-operative US

• Argon (-187.7 0 C)– Faster cooling & thawing – Joule Thompson (J-T) effect

• Liquid Nitrogen (-195.8 0 C)– Sprays for skin tumors…

Technique

• Fast freeze, slow thaw and repeat• Direct cell injury by crystallization• Failure of microcirculation• Lethal temp required– Tissue dependent– -20 to -30 or…… -40 to -50

• Multiple cryoprobes placed and frozen simultaneously

Cellular Injury

• Formation of extracellular ice– Imbalance of solutes– Cellular dehydration

• Formation of intracellular ice crystals– Damage cellular machinery– Mechanical shear injury

• Vascular injury– Endothelium is damaged > thrombosis– Tumor death by ischemia

Cellular Injury

• Extracellular ice forms at -7 degrees

Cellular Injury

• At -15 degrees, ice forms in cells, causing the cell membrane to rupture

Cellular Injury

• As the temp cools further, blood vessels coagulate, cutting off oxygen and nutrients

Cellular Injury

• Thawing – Ice crystals fuse to form large crystals– Large crystals are disruptive to the cell membrane– Extracellular environment is hypotonic, water

rushes back into the shrunken cells– Cell volume increases and the cell volume

increases so the cells can rupture

Cellular injury

• Thawing augments cellular membrane lysis• Second cycle augments cellular destruction• Re-freezing increases the percent cell kill from

90 to 99 percent.

• Re-freezing can often develop a slightly larger ice ball.

Technology

• Early closed system with liquid nitrogen– 3mm probes

• New generation closed system w/ Argon– Joules – Thompson effect (ie, pressurized

gas, when allowed to expand, results in a drop in temperature)

– 1.4-mm 17 Gauge probes Galil– 2.4-mm 13-gauge probe Endocare

Technology

• Galil medical cryoprobe

• Argon • Joules –

Thompson effect

Technology

• Galil needles, 17 Gauge

MRI compatible

• Galil Medical pass through system for MRI compatibility

MRI compatible

• Galil Medical pass through system for MRI compatibility

Endocare console

• Endocare console• Not MRI compatible

Isotherms

Isotherms

Cryoablation

• Multiple overlapping cryoprobes can create larger iceball

Monitoring the freeze

• Judgment, thermocouples at periphery• Ultrasonography – Limited by posterior acoustic shadowing – See ice at 0 degrees, not cell death at -20, 30….

• CT – No shadowing, same temp limitations as US

• MRI

MRI

• Multi planar capability• Requires MR compatible system– Galil medical can retrofit your MRI…

• Potential MR thermography• Takes much longer…

• Currently investigational

Cryotherapy

• Predominate use vs renal mass– Slightly decreased risk of damaging ureter

compared to RFA

• Decreased pain compared to RFA• Can do ablation with no sedation

Cryoshock AKA

• SIR (systemic inflammatory response)• Potentially life threatening complication• Related to volume ablated• Mild cases can be managed with fluids (and

prayer)• Can lead to multi system organ failure and

death

Immunological effects

• Anecdotes of spontaneous regression of distant tumor can occur after thermoablation*

• Danger Model– Cells dying of natural causes are ignored by

immune system– Necrotic cells releasing their content into

intracellular space will trigger an immune response *Journal of Urology, 1970; 104:154–159,

RFA

• Cytokines and stress response– Interleukins and TNF are increased– Heat shock protein expression

• Cellular immunity– Increased activated T cells/ circulating NK cells

• Trials of immunomodulators are underway• Effect of existing chemotherapy are unknown

Cryo ablation

• Stimulates and suppresses immune response• Different mechanism of injury– Direct cellular damage– Vascular collapse with ischemia

• Apoptotic cells do not release cellular content and induce immunological tolerance

• Necrotic cells act as immunostimulators

Cryo ablation

• Can see elevated SIR – Cytokine release syndrome

• Cryo shock– Thrombocytopenia, disseminated intravascular

coagulation and pulmonary failure

• Antibodies to normal and ablated tissue can be seen up to ten weeks after ablation

Immunological effects

• Induced immune responses are week– Heat > sustain anti tumor activity– Cold > immunomodulatory & immunosuppressive

• Complete responses are anecdotal• Potential to be augmented

• Adjuvant and neo-adjuvant immunomodulators

Discussion

• Risk factors for recurrence after percutaneous ablation of liver tumors– Hepatitis C– Multifocal tumor– High pretreatment alpha feto protein

• Greater than 4cm

Discussion

• Most modalities will work for very small tumors ie. Less than 1.5 cm

• > 90 % clinical success in controlling < 3.5cm• RFA is superior to Ethanol / Acetic acid in RCT• Cryo ablation is more popular with Urologist• HiFUS, Laser, Microwave await trials

Cryotherapy

• What is Cryotherapy?

• The use of extreme cold produced by – Liquid Nitrogen – Argon gas

• To destroy abnormal tissue

Definition of Cryotherapy

• Invitro freezing and destruction of tissue that can be applied and controlled precisely to produce a predictable zone of tissue death that will destroy the "target lesion" (bad cells) as well as an appropriate margin of surrounding tissue

J Surg Oncology, 1966; 256-264