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A Time to Kill: Ablation Techniques Deconstructed Howard M. Richard, III, MD.

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Presentation on theme: "A Time to Kill: Ablation Techniques Deconstructed Howard M. Richard, III, MD."— Presentation transcript:

1 A Time to Kill: Ablation Techniques Deconstructed Howard M. Richard, III, MD

2 Disclosures None

3 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

4 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

5 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

6 Categories Non Thermal – Injectable – Irreversible electroporation Thermal – Heat – Cold

7 Injectable Ethanol Acetic acid Radioactive beads Heated liquids Heated chemotherapy Chemotherapy Chemotherapeutic gels

8 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

9 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

10 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

11 Ethanol - Disadvantages Pyrexia Pain In liver, rise in liver enzymes Systemic intoxication Randomized controlled trials demonstrate inferiority compared to RFA

12 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

13 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

14 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

15 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

16 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

17 Chemotherapeutics Cisplatin and epinephrine gel* Phase II trial vs HCC – Response rate 52% Decreased systemic uptake Experimental *HPB 2000; 2:273

18 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

19 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

20 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


22 Thermal Ablation Heat kills, cold kills, although slightly differently Heat – Radio-frequency Ablation – Laser Ablation – Microwave Ablation – High Intensity Focused Ultrasound Cold – Cryoablation

23 Thermal Ablation Therapy: Temperature Tissue Interactions 35 - 40 ° CNormothermia 42 - 46 ° CHyperthermia 46 - 48 ° CIrreversible cellular damage 45 min 50 - 52 ° CCoagulation necrosis, 4-6 min 60-100 ° C Near instantaneous coag necrosis > 110 ° C Tissue vaporization

24 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

25 RadioFrequency Similar to Electrocautery – No heat flows directly from the device High frequency alternating current Ionic agitation Frictional heating Tissue near electrode

26 Angiodynamics RITA Medical Systems Generator

27 Procedure Overview Power is applied until tissue impedance (resistance to electrical current) rises Generator detects impedance rise and signals completion of procedure

28 Close-up of StarBurst XL


30 Heat Generation Tissue death – 50 Degrees Celcius Three factors (in vitro) – Distance from the electrode – RF current intensity – Duration of application of RF current

31 Stages of RF Ablation Conduction Over Time...

32 Stages of RF Ablation Frictional heating Conductive heating

33 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

34 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

35 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

36 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)

37 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

38 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

39 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

40 MR guided Focused Ultrasound ExAblate 2000 – Focused ultrasound array system AJR 2004; 183:1713-1719

41 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

42 Focused Ultrasound Treatment of Breast and Uterine Fibroids MRI guided Limited by respiratory motion to targets that do not move

43 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…

44 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

45 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

46 Cellular Injury Extracellular ice forms at -7 degrees

47 Cellular Injury At -15 degrees, ice forms in cells, causing the cell membrane to rupture

48 Cellular Injury As the temp cools further, blood vessels coagulate, cutting off oxygen and nutrients

49 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

50 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.

51 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

52 Technology Galil medical cryoprobe Argon Joules – Thompson effect

53 Technology Galil needles, 17 Gauge

54 MRI compatible Galil Medical pass through system for MRI compatibility

55 MRI compatible Galil Medical pass through system for MRI compatibility

56 Endocare console Not MRI compatible

57 Isotherms


59 Cryoablation Multiple overlapping cryoprobes can create larger iceball

60 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

61 Multi planar capability Requires MR compatible system – Galil medical can retrofit your MRI… Potential MR thermography Takes much longer… Currently investigational

62 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

63 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


65 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,

66 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

67 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

68 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

69 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

70 Discussion Risk factors for recurrence after percutaneous ablation of liver tumors – Hepatitis C – Multifocal tumor – High pretreatment alpha feto protein Greater than 4cm

71 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



74 Cryotherapy What is Cryotherapy? The use of extreme cold produced by – Liquid Nitrogen – Argon gas To destroy abnormal tissue

75 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

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