Ancillary procedures

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Chapter2:Radiofrequency and microwave tumor ablation

tumor tissues between sessions. e goal of multiple treatmentsistocreatealarge,contiguoussphericalablativevolume. However, giventhegeometryoftryingtoobtainalargecompletesphericalablativezone with smaller spheres,signicant overlapofpreviouszonesisnecessaryforcompleteablation.

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Alternatively, aligningablations“endtoend”wouldresultin multipleareasofuntreatedtumor.

Combining RF with transarterial chemoembolization

ere are several potential advantages with combining RF and TACE.is includes combined two-hit cytotoxic eects



ofexposuretonon-lethal low-levelhyperthermiainperiablational tumor and combination chemotherapy.Alterationsin tumorperfusioncan potentiatethe eects of either RF abla-

Ancillary procedures

A major consideration of energy-based thermal ablation is prevention of injury to nearby, non-target structures.1 As such,several strategies havebeen devisedtoseparatecritical non-targettissuesfromtheablationzone.

Onekeytechniqueis“hydrodissection,”inwhichuidis injected through a separately introduced hollow-bore needletocreateseparationbetweenimportanttissues(e.g.,diaphragmorbowel)andtheablationzone.Fluidswithlowion content,suchas5%dextroseinwater,shouldbeusedasthey forceRFcurrentawayfrom protected tissues and decrease theincidenceofburns.Notably,0.9%salineshouldnotbe used, as this ionic solution actually increases RF current

ow.

isconcepthasalsodevelopedtoutilizeinjectionofair (e.g., “pneumodissection”),creation of articial pneumothoraxor ascites,ormechanicaldisplacementwithballooncatheters,inplaceofuid,toseparatenon-targetedtissuesfromthe ablationzone.

Otherancillaryproceduresincludetheapplicationofexternalwarmingorcoolingbagsforoverlyingskinprotection,utilizationofthermalballoonsforcontrollingsurroundingtissue temperatures,andintraluminalperfusiontoprotectnon-target structures (e.g., renal pelvicalyceal, ureteral, and bile duct protection).

Combination therapies

Withfurtherlong-termfollow-upofpatientsundergoingablationtherapy, there has been an increased incidence of detectionofprogressivelocaltumorgrowthforalltumortypesand sizesdespiteinitialindicationsofadequatetherapy,suggesting thatthereareresidualfociofviable,untreateddiseaseinasubstantial,butunknown,numberofcases.10Strategiesthatcan increasethe completenessoftumordestructionwithuniform eradicationofall malignant cells, evenforsmall tumors, are needed.Hence,investigatorshavesoughttoimproveresultsby combiningthermal ablationwith therapies such as radiation andchemotherapy.

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Combination therapies incorporate cytotoxic or chemotherapeuticagentsadministeredinconjunctionwith ablation to induce a synergistic eect.1 Potential advantages include improvedtumorcytotoxicityandreducedresiduallocaltumor atthetreatmentmargin,creationofamorecompleteareaof tumordestructionbyllinginuntreatedgapswithintheablationzone,andequivalenttumor destruction with a concomitantreductionin duration or course oftherapy(e.g., in the timetotreatalargertumor,orrequirementfor fewer repeat sessions).

tionthroughpre-ablationembolizationof tumor vasculature or TACE with postablation peripheral hyperemia increasingbloodowfor TACE.Finally,performingTACErst can improvetumorvisualization(throughintratumoraliodizedoil deposition)forRFablation.

Several studies using combination therapy have reported increases in ablation size and increased treatment ecacy withcombinationRF/TACE,particularlyastheprimarytreatmentoflarge(>5cm)unresectabletumors.Forexample,Yang et al. treated 103 patients with recurrent unresectable hepatocellular carcinoma aer hepatectomy, and reported lower intrahepaticrecurrenceandlonger3-yearsurvivalcompared to either therapy alone.65 e potentialbenetof combining RFwith TACEforsmall(< 3 cm) tumors remainsless clear, as a recent meta-analysis of randomized controlled studies reported no signicantsurvival benet for combination RF/ TACEoverRFalone.66Tailoringtreatmenttoeachindividual caseremainsimportant,aseachmodalitycanbeusedsequentiallytoeliminateanyresidualdiseaseremainingaertheinitialprimarytherapy.Notably,thequalityoflife,asdetermined by socio-family well-being and functional well-being scores, isalsosuperiorinpatientsreceivingbothchemoembolization and RF ablation,a reection of liver function, tumor recurrence,andcomplications.

Combining RF with chemotherapy

Combiningthermalablation(predominantlyusing RF-based systems)withchemotherapy(either free or contained within liposomes),whetherthrough directinjection,intravenous,or intravascular/intra-arterialadministration,increasestheoverallvolumeoftumornecrosisandintratumoraldrugaccumulation.62eseeectsoccurpreferentiallyintheperipheralzone of hyperemia surrounding the central zone of ablation, and havebeenconrmedinlargeranimaltumormodels,dierent tumorandtissuetypes,fordierentchemotherapeuticagents, andinapilotclinicalstudyinprimaryandsecondaryhepatic malignancies. inmostcasestoencompassperitumoralliver,andenabledthe destruction of the dicult-to-treat 0.5–1-cm “ablative marg i n”.68InonepilotclinicalstudybyGoldbergetal.,RFablation combined with intravenous liposomal doxorubicin resulted in more complete tumor treatment and ablative margin. Additionally, combinedRFandliposomalchemotherapycan potentiallyovercomelimitationsimposed bytumorororgan environment,suchasbloodow.

eunderlyingmechanismsofthissynergyaremultifactorial.Improvedintratumoraldrugdelivery occurs with use of aliposomalcarrier(withincreasedcirculationtime,andwith “thermosensitiveliposome”types,increaseddrugrelease)and

62,68

Inclinicalcases,thetreatmenteectextended

68,69



Section II:Principles of image-guided therapies

the well-documented vasculareects of sublethal hyperthermia (including vascular dilatationand increased endothelial permeability)intheperipheraltreatmentzone.70Additionally, thecytotoxiceectsofthechemotherapyagentcombinedwith theheat-inducedreductionincellularreparativemechanisms toincrease apoptosis.71 Finally,studiessuggestthatthereare independent heat-related cytotoxic eects of the liposome itself.71 is preliminary success with combination therapies maybeaugmentedbythedevelopmentofnewtargetingvehicles,includingseveralpolymer-basedtemperature-dependent deliverysystemscurrentlyunderinvestigation.

behindtheseandthebiophysiologyofin-vivotissueheatingis requiredtoavoidthemanypotentialpitfallsinperformingoptimalthermalablation.Wehaveprovidedabasicoverviewofthe basicprinciplesofRFandmicrowaveablation,focusedonthree main elements, including: (1) biology of heating; (2) RF and microwave technology; and (3) operator expertise and technique.Successfultumorablationisabalancebetweenobtaining completetumordestructionwhile minimizingdamagetosurroundingnormalparenchyma,andisembeddedinanappreciationandunderstandingofthesethreeinterweavingelements.

Althoughmultiplemodicationshavealreadybeendevel-

oped within the technology of RF and microwave ablation,

Combining RF ablation with radiation

Investigatorshave begun exploringcombinationRF ablation andradiationtherapy,withpromisingresults.Previousdatain theliteraturehavedemonstratedincreasedtumordestruction with external-beam radiation therapy and low-temperature hyperthermia.73 Experimental animal studies have demonstratedincreasedtumornecrosis,reducedtumorgrowth,and improvedanimalsurvivalwithcombinedtherapywhencomparedtoeithertherapyalone.

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Preliminaryclinical studies in primary lungmalignancies conrm the synergistic eects ofthese therapies.6A potentialcauseforsynergyincludesthe sensitizationof thetumortosubsequentradiationdueto the increased oxygenation resulting from hyperthermia-induced increasedbloodowtothetumor.75Anotherpossiblemechanism,whichhasbeenseeninanimaltumormodels,isaninhibitionofradiation-inducedrepairandrecoveryandincreased free-radical formation.71Immunohistochemicalstainingaer RF ablation, combined with external-beam radiation, has demonstratedanincreasein markers of oxidative and nitrosativestress.74 Futureworkis needed toidentify the optimal temperatureforablationandoptimalradiationdose,aswellas themosteective methodofadministeringradiationtherapy (external-beam radiation therapy, brachytherapy, or yttrium microspheres),onanorgan-by-organbasis.

Patient selection

Perhaps the most important variable to have the greatest impactonresultsistheinterplaybetweenoperatorandpatient selection. Given the need to achieve completeeradicationof all target tumor cells, the argument for combining several modalitiestoachievecompletetumorcelldeath–similartothe multidisciplinaryapproach,includingsurgery,radiation,and chemotherapy,thatisusedforthetreatmentofmostsolidcancers–cannotbeoverstated.Approachingeachcaseandindividualtumorwiththegoalofusingwhateveroptionsareavailable within the interventional armamentarium willlikelyprovide thehighestclinicalyield.Severalfactorsshouldbetakeninto considerationwhenplanning combinationtherapysuch that treatmentistailoredtoeachcase.eseincludetumorbiology, tumorsizeandnumber,andtumoraccessibility/visibility.

Conclusion

ereisnoonerightwaytoperformRFandmicrowaveablation, yet a fundamental knowledge of the basic principles

future directions will emphasize a better understanding of tumorbiologyinordertoalterlocaltissueinteractionscoupled with ancillary procedures and combination and concurrent therapies,suchasantiangiogenetics,embolization,chemotherapeutics,andradiation.

References

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11. Dodd3rdGD,FrankMS,AribandiM,etal.Radiofrequency thermalablation:computeranalysisofthesizeofthethermal injurycreatedbyoverlappingablations.AJR Am J Roentgenol 2001;177:777–782.

Chapter2:Radiofrequency and microwave tumor ablation

12. ChenMH,YangW,YanK,etal.Largelivertumors:protocol forradiofrequencyablation,anditsclinicalapplicationin 110patients–mathematicalmodel,overlappingmode,and electrodeplacementprocess.Radiology2004;232:260–271.

13. GervaisDA,McGovernFJ,ArellanoRS,etal.Radiofrequency ablationofrenalcellcarcinoma:part1.Indications,results, androleinpatientmanagementovera6-yearperiod andablationof100tumors.AJR Am J Roentgenol2005; 185:64–71.

14. LencioniR,CrocettiL,CioniR,etal.Responseto radiofrequencyablationofpulmonarytumours:aprospective, intention-to-treat,multicentreclinicaltrial(theRAPTURE study).Lancet Oncol2008;9:621–628.

15. SchrammW,YangD,HaemmerichD.Contributionof directheating,thermalconductionandperfusionduring radiofrequencyandmicrowaveablation.Conf Proc IEEE Eng Med Biol Soc2006;1:5013–5016.

16. SeegenschmiedtM,BradyL,SauerR.Interstitial thermoradiotherapy:reviewontechnicalandclinicalaspects. Am J Clin Oncol1990;13:352–363.

17. LarsonT,BostwickD,CorciaA.Temperature-correlated histopathologicchangesfollowingmicrowavethermoablationof obstructivetissuesinpatientswithbenignprostatichyperplasia. Urology1996;47:463–469.

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19. GoldbergSN,GazelleGS,ComptonCC,etal.Treatment ofintrahepaticmalignancywithradiofrequency ablation:radiologic–pathologiccorrelation.Cancer2000; 88:2452–2463.

20. MertynaP,DewhirstMW,HalpernE,etal.Radiofrequency ablation:theeectofdistanceandbaselinetemperatureon thermaldoserequiredforcoagulation.Int J Hyperthermia2008; 24:550–559.

21. LubnerMG,BraceCL,HinshawJL,etal.Microwavetumor ablation:mechanismofaction,clinicalresultsanddevices.J Vasc Interv Radiol2010;21:192–203.

22. BraceCL.Radiofrequencyandmicrowaveablationoftheliver, lung,kidney,andbone:whatarethedierences?Curr Probl Diagn Radiol2009;38:135–143.

23. YuNC,LuDS,RamanSS,etal.Hepatocellular carcinoma:microwaveablationwithmultiplestraightandloop antennaclusters–pilotcomparisonwithpathologicndings. Radiology2006;239:269–275.

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25. GoldbergSN,HahnPF,HalpernEF,etal.Radiofrequencytissue ablation:eectofpharmacologicmodulationofbloodowon coagulationdiameter.Radiology1998;209:761–769.

26. HorkanC,AhmedM,LiuZ,etal.Radiofrequency ablation:eectofpharmacologicmodulationofhepaticand renalbloodowoncoagulationdiameterinaVX2tumor model.J Vasc Interv Radiol2004;15:269–274.

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30. GoldbergSN,AhmedM,GazelleGS,etal.Radiofrequency thermalablationwithadjuvantsalineinjection:eectof electricalconductivityontissueheatingandcoagulation. Radiology2001;219:157–165.

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32. YangD,ConverseMC,MahviDM,etal.Measurementand analysisoftissuetemperatureduringmicrowaveliverablation. IEEE Trans Biomed Eng2007;54:150–155.

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34. WolfEJ,GrandDJ,MachanJT,etal.Microwaveablationof lungmalignancies:eectiveness,CTndings,andsafetyin 50patients.Radiology2008;247:871–879.

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Section II:Principles of image-guided therapies

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68. GoldbergSN,KamelIR,KruskalJB,etal.Radiofrequency ablationofhepatictumors:increasedtumordestructionwith adjuvantliposomaldoxorubicintherapy.AJR Am J Roentgenol 2002;179:93–101.

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70. ChenQ,KrolA,WrightA,etal.Tumormicrovascular permeabilityisakeydeterminantforantivasculareectsof doxorubicinencapsulatedinatemperaturesensitiveliposome. Int J Hyperthermia2008;24:475–482.

71. SolazzoS,AhmedM,Schor-BardachR,etal.Liposomal doxorubicinincreasesradiofrequencyablation-inducedtumor destructionbyincreasingcellularoxidativeandnitrative stressandacceleratingapoptoticpathways.Radiology2010; 255:62–74.

72. BaeY,BureshRA,WilliamsonTP,etal.Intelligentbiosynthetic nanobiomaterialsforhyperthermiccombinationchemotherapy andthermaldrugtargetingofHSP90inhibitorgeldanamycin. J Control Release2007;122:16–23.

73. AlganO,FosmireH,HynynenK,etal.Externalbeam radiotherapyandhyperthermiainthetreatmentofpatientswith locallyadvancedprostatecarcinoma.Cancer2000;89:399–403.

74. SolazzoS,MertynaP,PeddiH,etal.RFablationwithadjuvant therapy:comparisonofexternalbeamradiationandliposomal doxorubicinonablationecacyinananimaltumormodel.Int J Hyperthermia2008;24:560–567.

75. MayerR,Hamilton-FarrellMR,vanderKleijAJ,etal. Hyperbaricoxygenandradiotherapy.Strahlenther Onkol2005; 181:113–123.

Chapter

Principles of irreversible electroporation

Govindarajan Srimathveeravalli and Stephen B. Solomon

Introduction

Electroporation is a phenomenon where cells exposed to a strongexternalelectricelddevelopnano-scaleporesintheir plasmamembrane.Typically,theporesresealoncetheexternalelectriceldisremovedandthecellcontinuesfunctioning normally.However, ifthenumberorsizeofporesformedin the membraneexceeds a certainthreshold,thecell is unable torepair thepores,even aerremovaloftheexternalelectric eld.iseect has been termedirreversibleelectroporation (IRE). IRE may be considered a non-thermal ablation technique, as cell death is largely due to electroporation-related factors and is not contingent on sustained changes in temperature.However,this does notcompletelyprecludeheating ofthe treatedtissue,as Jouleheating-induceddamagetotissueduringIREhasbeenseentooccurwithina2–3-mmzone adjacentto the probes.1 e largely non-thermalmechanism ofcelllysismakesIREanattractiveoptionforthetreatmentof tumorsthatarecontraindicatedforestablishedthermalablationtechniques.AsIREablationseemsunaectedbyvariations intissueperfusionandbiologicalheat-sinkeects,ithasbeen usedtotreathypervasculartumorsandlesionsadjacenttolarge bloodvessels2(Figure3.1).Unlikethermalablationtechniques, whichcandenatureproteinsandcompletelydestroycollagenousstructureswithintheablationzone,ablationwithIREhas been observed to spare the extracellular matrix within the treatedregions.3is has allowed the safeapplication of IRE totreattumorsabuttingthebileductortherectuminpatients4 (Figure3.1).

IREpresentsanewclinicalparadigmfortheplanningand delivery of image-guided ablations. Unlike thermal ablation techniques,wheretheablationzoneiscenteredonasingleablationprobe,treatmentdeliveryusingIREis typically planned betweentwomonopolarneedleelectrodes(Figure3.2). Small variationsinthegeometryofprobeplacementcansignicantly aect the size and shape of the resulting eective ablation zone,aectingthevolumeoftissuethatundergoesdestruction (Figure 3.3). e strongelectric elds used for IRE ablation caninduceneuromuscularactivationandaect physiological functionsthataresensitivetoelectrical energy.erefore,use ofIREinpatientshasspecialanesthesiarequirements,includingtheuseofadeepparalyticagenttoreducecurrent-induced

neuromuscularstimulation.IREhastobedeliveredwithelectrocardiogram(ECG)gating toavoidventricular tachycardia, arrhythmia, and other cardiac eects.5 Finally, there is limitedinformationon best clinical practices fortheuseofIRE, withlimitedknowledgeonimagingndingsthatwouldallow treatmentfollow-upandconrmationoftherapeutic ecacy following ablation. erefore, it is crucial that the physician using IRE for tumor ablation have a rm understanding of thebiophysicalmechanismsunderlyingIREoftissue,andthe potentialimpactthateachtreatmentparametercanhaveonthe clinicaloutcomes.

Pulse parameters and impactonIRE

Livingcellsusedierencesinionicconcentrationsofintra-and extracellularuidtoestablishanelectricpotentialacrosstheir plasma membrane. is transmembrane potential can vary dependingontheactivityorfunctionofthecell,andtypically rangesfrom–35to–70mV.Whencellsareexposedtoanexternalelectriceld, theirtransmembranepotentialaltersrapidly andreaches equilibriumatahigherlevelwithinafewmicrosecondsfollowingexposure.6Dependingonthetypeofcell,an increaseintransmembranepotential in the range of300mV to1Vcanaectthestructureofthebilipidlayerformingthe plasma membrane. e bilipid layer reorganizes in response tothesuddenincreaseintransmembranepotential,resulting intheformationofnano-scaleporesinthemembrane,which caneventuallyleadtoIREofthecell.7PulseparametersdrivingcellIREcanbecharacterizedbytheamplitude(voltage)of theexternalelectriceld,thelengthofexposure(pulselength), the timing between consecutive exposures (pulse repetition frequency), and groupingof exposure during delivery (pulse train).Eachoftheseparametersindependentlycontributesto theinductionofcell electroporation,andthereforehastobe carefullyselectedtoachieveIRE,whileavoidingthenon-lethal reversibleformofelectroporation.

Electric eld strength

e electric eld strength required toelevate the transmembranepotentialandinduceIREcanbedeterminedusingwhat iscommonlyknownastheSchwannequation.etransmembranepotentialinducedatanylocationinthecell membrane

Interventional Oncology, Second Edition, ed. Jean-François H.Geschwind and Michael C.Soulen. Published by Cambridge University Press. ©Cambridge University Press2016

Section II:Principles of image-guided therapies

15 mm

Figure 3.1 (A) Computed tomography (CT) image of irreversible

electroporation (IRE) probe placement to treat recurrent tumor (asterisk) adjacent to the rectum (arrowhead). (B) Magnetic resonance imaging image of tumor (asterisk) near hepatic veins and bile duct. (C) CT image showing IRE probe placement to treat the tumor (asterisk).

equationitbecomesevidentthatlargercellswillundergoIRE

–+

atlowerelectriceld strengths thansmaller cells.Also,locationsinthecellthatdirectlyfaceorfallbetweentheelectrodes will experience higher transmembrane potential than points that are perpendicular to the electrodes. is equation was developedundertheassumptionthatcellsroughlyhavesphericalshapewhensuspendedinmedia.Finiteelementmodeling andnumericalsimulationcanbeusedtoestimatetransmembranepotentialofcellsunderin-vivoconditions.Cellsintissue

20 mm

aremoretightly packed thancellsuspensions,andtheexternalelectriceldcangetdistortedbythecellsandsurrounding extracellular matrix.9 Under such conditions,the transmembranepotentialwillbehighestat the cell poles andlocations orientedatfavorableanglestotheelectrodes.To successfully induceIREinaspeciccelltype,considerationmustbegiven

Figure 3.2 Schematic showing minimum number of probes required and

resulting ablation zone. (A) Irreversible electroporation (IRE): the ablation zone is mediated between two commercially available monopolar probes. (B) Radiofrequency ablation (RFA): the ablation is centered on a single probe. MWA = microwave ablation.

duetoanexternalelectriceldisafunctionoftheradiusofthe cellandtheincludedanglebetweentheradiusandthepointat whichthemembranepotentialisbeingevaluated.8Fromthis

IRE

RFA/MWA

totheapproximatesizedistributionofcellsbeingtreatedand theexternalelectriceld strengthmustbe adjustedsuchthat minimumtransmembranepotentialofapproximately0.7–1V isachieved,eveninsmallercellsorcellsthatmaybeatanunfavorableorientationrelativetotheelectrodes.

Pulselength

Followingexposuretoanexternalelectriceldthetransmembranevoltageofacellexponentiallyincreasesbeforereachinga

Chapter3:Irreversible electroporation

(

)

( )

Figure 3.3 Computer simulation showing incomplete irreversible electroporation treatment zone (red) because: (A) improper choice of voltage for given probe

spacing results in inadequate ablation between probes (arrow); (B) unequal probe insertion resulting in ablation defect around one probe (arrow).

stablevalue.Forelectroporationtooccur,thetransmembrane potential needs to reach such an equilibrium value and be maintainedatthatpointforabriefperiodoftime(fewmicroseconds).

8,10

 For an external electric eld of xed strength, largercells will develophighertransmembranepotentialbut take more time to achieve stable values when compared to smallercellstreatedwithsimilarpulseparameters.Ifthelength ofexposuretotheelectriceld(pulse length)issmallerthan thechargingtimeofthecell,thenthetransmembranepotential may notreach a threshold sucient for electroporation. Alternately,ifthepulselengthismuchlongerthanthechargingtimerequiredforachievingastabletransmembranepotential,theexcessenergy is dissipatedthroughJouleor resistive heating.erefore,thepulselengthhastobeadjustedtoallow transmembranepotentialtoreachcriticalthresholdinthecells beingtreated,butatthesametimehastobekeptsmallenough toavoidheating eects. Based on these considerations,pulse length between 50 and100 μs has been reported to be optimalforinducingIREinhumancancercellswithoutsignicant Jouleheatingeects.

Numerical simulations

e treatment eects of IRE under in-vivo conditions are largelycontingentonthedistributionandintensityoftheelectriceldarisingfromapplicationofavoltagebetweenneedle electrodes. e electric eld distribution can be mathematicallyevaluatedatdierentlocationsinthetissuebysolvingthe Laplaceequationfortheappliedelectriceld

−∇ ∇

Fromthisequation,itbecomesevidentthatthemagnitudeof electriceld(ϕ)strengthdevelopedinvivoisafunctionofthe appliedexternalvoltage(ϕ=V0atthepositiveelectrode)and the electrical conductivity(σ)of the tissue underconsideration.Tumorsandtheirsurroundingenvironmentcanbe heterogeneousatamacroscopiclevel,consistingofdierenttissue types likeblood vessels, nerves, adipose tissue, bile duct, or urinarycollectingsystem.Dierenttissuesinturnexhibitlarge variationsin the electrical conductivity,andthereforeimpact orinuencetheelectriceldstrengthdevelopedwithinthem. Forexample,simulationsfromNealandDavalos15suggestthat, despiteusingoptimalprobeplacementandtreatmentparameters,thedierenceinelectricalconductivitybetweentumor

σφ

and surrounding normal tissue mayultimatelyinuence the

Number ofpulses

Electroporationisacumulativeprocess,whererepeatedexposuretotheexternalelectriceldcontributestothetotalnumberandsizeofporesformedonthecellmembrane.eoretical modelsimplyalogarithmicrelationbetweenamplitudeofthe electric eld and the number of pulses required to achieve electroporation.Othermodelssuggestthatcelldeaththrough IREmay be considered a statisticalprocess,whereincreased exposureandappliedvoltagein combinationaectcellsina targetregioninanexponentialprocess.11Whilesomeofthese theoretical models havebeen veried through in-vitrostudies,suchmodelsremainlargelyunveriedunderin-vivoconditions.However,it is widely acceptedthatapproximately10 pulsesaresucienttoinducereversibleorIRE intissuecontingenton the appliedeldstrength.Typically50–100pulses mustbeappliedtoensurecellsinatargetvolumeoftissuehave undergoneIRE.

successofablation(Figure3.4). Ben-Davidet al.suggestthat locoregionalvariationsinelectricalconductivity,suchaswhat isobservedneartherenalcollectingsystem,16canalsoimpact thesizeandshapeofIREtreatmentzone when comparedto ablationsperformed awayfrom such locations. Metallic elementssuchas stents,markerseeds,and ablationprobeswith exposedtipsnotbeingusedfortreatmentmayalsopotentially altertheablativeelectriceld.

DevelopingnumericalsimulationasareliabletoolforplanningIREtreatmentshasbeenaresearchchallenge.etypeof tissuebeingtreated,thenumericalmodelemployed,andcorrelationwithpathology or imaging17all impact theaccuracy andreliabilitywithwhich treatmentzones can be estimated. Also,limitationsin nite element modeling necessitategross representationoftissuetypesandproperties,andthereforeat the current stage it is challenging to determine electric eld distributionatsubmillimeterthresholds.Hence,theutilityof

13,14



Section II:Principles of image-guided therapies

asingleablationprobe.20However,mostofthesestudieshave beencarriedoutin apreclinicalsettingtodemonstratefeasibility,andrequiresignicantecacyandsafetystudiesbefore theycanbetranslatedforpatientuse.

Clinical considerations

Asanimage-guidedablationtechnique,thereisalackoftissue samplesthatcanbeusedforperformingpathologyanalysisto conrmtreatmentecacyfollowingIREoftumors.erefore, itis crucial to identify imaging parametersand other physiologicalchangesthatwillserveassurrogateindicatorsoftreatment completion following IRE. A dramatic change in the electricalconductivityofthetreatedtissueisalwaysobserved duringandimmediatelyaerelectroporation.Inthe absence ofotherindicators,thischangeinelectricalconductivityofthe treatedtissuehasbeen consideredas a means for measuring therelativeeectivenessofelectroporation.

21,22

Undernormal

conditions,biologicaltissueexhibitsanon-linearincreasein

Figure 3.4 Computer simulation of irreversible electroporation ablation of

tumor (circle; arrowhead) and ablation margin (arrow) when: (A) tumor has higher electrical conductivity than surrounding tissue; (B) tumor has lower electrical conductivity than surrounding tissue.

simulations for IRE treatment is restricted to gross estimationofexpectedelectricelddistributionandcannotberelied uponforpredictionsofecacyatthecellularlevel.

Equipment and ablationprobes

IRE treatment requires the availability of a high-voltage square-wave generator and suitable electrodes for delivering direct current (DC) electric pulses into the target tissue. e onlygeneratorcleared by the Food and DrugAdministration (FDA)forso-tissueablationistheNanoknifelow-energyDC electroporation device (Angiodynamics, Latham, NY). e generatoriscapableofdeliveringamaximumof100pulsesata time,withanamplitudeintherangeof500–3,000Vandofpulse lengthintherangeof70–100μs. e generatordeliversthese pulsesin groups of ten, with eachpulseseparatedby250 ms andthepulsetrainsseparatedby3.5seconds.egeneratoris capableofsupportingup to six ablation probesatatimeand thepulsesaredeliveredusingECGsynchronization.esystem comeswith19G(1mmdiameter)ablationprobesthatareavailablein15-cmlength.WhiletherearenootherFDA-approved generatorsordevicesforpatientuse,systemssuchastheECM 830square-wavegenerator(BTX,HarvardApparatus)arecapableofenergyoutputequivalenttotheNanoknifeandareoen usedinpreclinicalanimalmodelstudies.

Anumberofpreclinicalstudiesreport noveldevices that extendtheuseofIREtoapplicationsotherthanpercutaneous so-tissueablationusingneedleelectrodes.Maoretal.report acatheterfortheIREofvascularsmoothmuscleinbloodvessels,18 Srimathveeravalli et al. report the development of an endorectalprobeforfocal-transmuraltreatmentoftherectal wall,19andNealet al. have reported a bipolar electrode congurationthatwouldallowso-tissueablationusingIREwith

electrical conductivityinresponsetoincreasingfrequencyat which electrical current is applied. e maximum electrical conductivityofthetissueisseenintheMHzfrequencyrange orhigher.isispartlyduetothecomplexelectricalbehavior ofcells,whichbehavesimilartoaresistor-capacitor(RC)circuitfunctioninginparalleltotheelectricallyconductivepath providedbytheextracellularuid.Successfulelectroporation ofthesecellscausestwoeects:thereleaseofintracellularuid into the extracellular regions and the short-circuiting of the normalRC circuit behavior of thecells.ese two eects in combinationhave been observed to cause large increases in tissue conductivity even at lower electrical frequencies. is changeintheelectricalconductivityofthetreatedtissuecanbe observedbothduringtheapplicationofeachpulseandinsum totaloverthedurationoftreatmentdelivery.Nealetal.23have investigatedthis eect foruseasasurrogatemarker forsuccessfulIREoftissueandhavereportedsomecorrelationwith pathologyexaminationfollowingIREtreatmentofprostatein 2patients.Whileapromisingandusefultechnique,thecaveat isthat,whilethemagnitudeofconductivitychangesisindicativeofIRE,itdoesnotquantifythetypeorvolumeoftissuethat hasundergoneelectroporation.istechnique requiresmore researchbeforeitcanbeconsideredforuseasastand-alone indicatoroftheadequacyofIREablationinpatients.

Atthemoment,contrast-enhancedcomputedtomography (CECT)andultrasound(US)aretheprimarytoolsforguiding IREtreatment,andfortheconrmationofablationoutcomes inpatients.On immediateposttreatmentCECT imaging, tissuetreatedwithIREappearsasahypodenseregionwithaconcentriczoneofenhancementoutsidetheablationborder.e centralzonecorrelatestothenecroticcoreofthetreatedarea andtheenhancingperipheryislikelytreatedtissuethatexperiencedreversibleelectroporationandhasdevelopedleakyblood vessels(Figure3.5).esendingsaresimilartoobservations commonly found during immediate posttreatment imaging ndings, seen sometimes following radiofrequency ablation ormicrowaveablation.However, incontrastto thermalablationtechniques,treatmentoftumorsintheliverusingIREis

Chapter3:Irreversible electroporation

believedtoresultinlesserdegreeofbrosisandscarformation. As a consequence, posttreatmentfollow-up imaging of IRE-treatedtissueseemstoappearandevolvedierentlywhen comparedtotumorstreatedwithradiofrequency ablationor microwaveablation.We have observed that follow-up imagingofsuccessfullocalcontrolinpatientswhounderwentIRE ablationof livermetastasisshowedinvolutionoftheablation defect,withapproximately22%reductionatthe1-monthtime pointandupto35%reductioninsizeat3months.isearly evidenceneedsvericationinalargecontrolled studybefore theevolutionoftheablationzonefollowingIREcanbeusedto prognosticatetreatmentresponseatanearlystage.

IRE treatment can alter the echogenic properties of the treated tissue and US imaging has been evaluated for the real-time observation of ablationprogressand forimmediate posttreatmentconrmationoftheablatedregion.

24,25

However, resultsreportedintheliteraturewereobtainedfollowingIREof normalporcineliveranduseof USimagingisyet toundergo extensive evaluation for guiding and conrming ablation of malignant tissue. e presence of the tumor may confound or impact the resolution of US imaging ndings, and thereforereducetheacuitywithwhichitcanidentifychangesinthe ablatedregion.IREofcellscauseslargereleaseofintracellular uidintotheextracellularspace,andhasbeenobservedtodisrupt vascular ow within treated regions. ese eects have beenusedtomapnormalbrain,26prostate(Figure3.6),kidney,27 andlivertumors28thatweretreatedusingIRE.Magneticresonanceimaging(MRI)hasprovenusefulfordelineatingregions ablatedwithIREfromsurroundingregionsthatweretransiently electroporated.esendingsarefrompreclinicalstudies,and, asclinicalIREisnotMR-compatible,thelogisticsofusingMRI forfollow-uponIREablationsperformedinpatientsmayprove challenging.Inuorodeoxyglucose-avidlesions,positronemission tomography (PET)-CT guidance may prove useful for guidingandfollowinguponIREablations.29UnlikeCTorMRI, PETimagesthefunctionalstateofcellswithinthetreatedtissue andthereforemayprovideaclearerpicturewithoutbeingconfoundedbymorphologicalchangesthatarenormallyobserved followingIRE.Earlytrialsinpatients(Figure3.7)demonstrate PET-CTtobeapromisingnewtechniqueforconrmingtreatmentadequacyintheimmediateposttreatmentsetting.

Clinical experience

ere is relatively limited clinical experience with IRE and

Figure 3.5 Contrast-enhanced computed tomography image taken

immediately following irreversible electroporation ablation of colorectal metastasis (asterisk) in the liver. An enhancing rim is seen around the treatment region (arrowhead).

most evidence of ecacy or safety is based upon reports of small numbers of patients. A review article from Scheer etal.30reports16publishedstudies,withatotalof221patients and325tumorstreatedacrossallofthem.emajorportions ofIREtreatmentswereperformedontumorsintheliver(129)

Figure 3.6 (A) Intraoperative ultrasound image with prostate and irreversible electroporation probes outlined. (B) Hypointense region corresponding to the

treatment zone seen on 3-month follow-up magnetic resonance imaging. (Courtesy of Dr. Jonathan Coleman.)

Section II:Principles of image-guided therapies

Figure 3.7 Positron emission tomography (PET)

imaging performed using split-dose technique. (A) Tumor (arrowhead) on pretreatment image. (B) Tumor (arrowhead) shows lack of enhancement following ablation on immediate posttreatment split-dose PET image.

andpancreas(69).Accordingtotheirreport,ecacyoftreatments in the liver ranged from 55% to 95% at the 6-month follow-up time point, with limited complication prole. ClinicalreportsfromCannonetal.,31Kinghametal.,2andSilk etal.4clearlyindicatesafetyofapplicationofIREclosetobile ductsandlargebloodvesselsfortreatmentoftumorsincentral liver.Pneumothoraxandmildbileduct occlusionseemtobe occasionalcomplicationsfollowingIRE oflesionsintheliver. IREtreatmentofpancreatictumorsseemstobestowsurvival benettopatientsaccordingtoreportsfromMartinetal.32and Narayananetal.33Bileductleakageandportalveinthrombosis representsignicantcomplicationsthatmaymanifestfollowingIREablationinthepancreas.Afewcasesofmildpancreatitishavealsobeenreported.

Conclusion

IREisapromisingnewclinicaltool thatissafetouse forthe local management of tumors that are suitable for treatment with established thermal ablation techniques. ere is some evidenceofsafetyofapplyingIRE adjacentto sensitivestructuressuchasthebileduct.However,asanewtechnique,there is limited knowledge for correctly directing IRE treatment and assessing ablation ecacy with existing imaging tools. erefore,physiciansusingIRE must educate themselves on the biophysics of this treatment modality so that they may choose appropriatetreatmentparametersthatwill maximize benettopatientswhileminimizingtheriskprole.

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