Emerging applications

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Chapter4:High-intensity focused ultrasound

ACE

B DF

Figure 4.9 Sonication monitoring using real-time ultrasonography (US) imaging obtained in patient with hepatocellular carcinoma. (A) Before high-intensity

focused ultrasound (HIFU). (B) Hyperechoic changes were detected in the treated lesion after HIFU. Contrast-enhanced US imaging before (C) and just after HIFU (D). The blood ﬂow disappeared after HIFU. Assessment of coagulation using a computed tomography scan. (E) Before HIFU, tumor enhancement (white arrows) was detected during the arterial phase and the low-density area posterior to the tumor was a liver cyst. The arterial phase image at 1 week after HIFU treatment (F) shows the tumor enhancement has disappeared (arrows). (Reprinted with permission from Fukuda H, Ito R, Ohto M, et al. Treatment of small hepatocellular carcinomas with US-guided high intensity focused ultrasound. Ultrasound Med Biol 2011; 37: 1222–1229.90)

recorded medication data reported a reduction in opioid usage.98 e ExAblate MRgFUS system subsequently

MRgFUSsystemforpalliation ofpainfulbonemetastasesis currentlyunderway.

receivedthe EuropeanCE mark and US FDA approvalfor palliative treatment of bone metastases in 2007 and 2012, respectively.

AsubsequentstudybyHurwitzetal.demonstratedsimilarratesfor bone pain palliation withMRI-guidedHIFUas comparedtoshamintervention.99Atotalof147subjectswith painfulbonemetastaseswhohadfailed,refused,orwereineligibleforradiotherapywereenrolledandrandomly assigned 3:1 to receive MRI-guided HIFU with the ExAblate system orno treatment.Primary ecacywasassessed at 3 months via a compositeendpoint of change frombaseline in worst numericalratingscalepainscore(0–10scale)andmorphine equivalentdaily dose intake.Response rate for theprimary endpointwas 64.3% inthe MRgFUS arm and 20.0% in the placebo arm (P< .001). MRgFUS was also superior to placeboat3monthswithregardtothestudy’s secondaryendpoints,i.e.,worstscorenumerical rating scale and the Brief Pain Inventory–Quality of Life questionnaire scores (both P<0.001).99EuropeanandCanadiantestingoftheSonalleve

Emerging applications

Promising future oncologic applications of HIFU include focusedUS-mediatedtargeteddrugdeliveryandthetransient andreversibleopeningoftheBBB.eseapplicationsremain ongoing areas of research with feasibility thus far demonstratedexclusivelyinin vitroandanimalstudies.1Studiesare alsounderwaytoevaluateHIFU-mediatedhyperthermiaasa mechanismforradiationsensitization.

100,101

Targeted drug delivery

Acousticcavitationanditsassociatedmicrostreamingeectsare believed to be the mechanisms responsible for increasing cell membranepermeabilitytodrugsorplasmidsforUS-mediated drugdelivery. izeddrugdeliveryandgenetransfectionattributedtotransient permeabilizationofcellmembranesthroughUS-inducedpores inthelipidbilayer.

102

Sonoporationisassociatedwithenhancedlocal-

102

emechanismsofsonoporationarenot

Section II:Principles of image-guided therapies

A C E

B D F

Figure 4.10 Sonication monitoring using real-time ultrasound (US) imaging patient with hepatocellular carcinoma. (A) Before high-intensity focused ultrasound

(HIFU). Hyperechoic changes were detected after HIFU (B). Contrast-enhanced US imaging before (C) and just after HIFU (D). The ablated area was suﬃciently broad with a wide safety margin. Assessment of coagulation using magnetic resonance imaging (MRI). Arterial-phase MRI obtained before HIFU (E) and late-phase MRI obtained 1 week after HIFU (F). A hypointense area including the surrounding liver is visible. (Reprinted with permission from Fukuda H, Ito R, Ohto M, et al. Treatment of small hepatocellular carcinomas with US-guided high intensity focused ultrasound. Ultrasound Med Biol 2011; 37: 1222–1229.90)

fullyunderstood,butarelargelyattributedtomicrostreaming, stable and inertial cavitation. Sonoporation can be enhanced via administration of microbubble-based US contrast agents, with drug-loaded microbubbles capable of being mechanicallydestroyedby aUSbeamfocus,resultingin targeteddrug release.1 Mechanical acoustic radiation forces have also been postulated as driving mechanisms for pulsed HIFU-mediated targeteddrugdelivery.

103

Analternativeapproachistoemploy thermo-sensitive liposomes, in which case the HIFU beam servesasanexternalsourceofhyperthermia,enablinglocalized, controlleddrug release.

104,105

 ese mechanisms areassociated withelevateddrug concentrationsattheUS beam focus, with thepotentialforenhancedlocalizedtherapythatcould obviate thesystemicrisksassociatedwithhighsystemicdosesofchemotherapeutic agents.1 As noted by Jenneet al., however,there remaincriticalquestionsthatmustbeaddressedpriortoclinical implementationofthesetechniques.1eseincludemethodsto ensurelongerlocaldrug exposures than currently achieved in preclinicalstudiesforasustainedanticancereect.Additional as yet unanswered questions include the pharmacodynamic and long-term clinical eects of systemically administered drug-loadedUScontrastagentsandthermosensitiveliposomes.

Blood–brain barrier disruption

Chemotherapyforthetreatmentofbraintumorsisconstrained by the inability of chemotherapeutic agents to penetrate an intactBBB. deliverytothebrain. ofpreformedmicrobubbleshavebeenshowntocausereversible openingoftheBBBinrabbits,asevidencedbythedetectionof MRcontrastatthetargetedlocations. theBBBappearstoremainpermeableupto24hoursaerUS exposurewithoptimalbrainuptakeoccurringwithin6hours. SafeBBBdisruption,intheabsenceofbraintissueinjury,has beenobserved to be consistentlyproducedwith concomitant administrationofmicrobubbles,whichreduce the US intensitythatneedstobeadministered. changesinendothelialcell morphology resulting in theBBB openinginrabbitssuggestthatseveralmechanismsoftranscapillarypassagearepossible. thelialcellcytoplasmicopeningsviafenestrationandchannel formation,openingofapartoftightjunctionsandfreepassagethroughtheinjuredendothelium,thelatterobservedwith

higher-powersonications.

106

LocalBBBopeningcanfacilitatetargeted drug

107

HIFUexposuresappliedinthepresence

108

MRIhasrevealedthat

108

AnalysesofUS-induced

107

eseincludetranscytosis,endo-

107

US-mediatedBBBdisruptionhas

Chapter4:High-intensity focused ultrasound

beenconrmedin additionalanimalmodels,includingmice andnon-humanprimates.

102,106–110

InconjunctionwithHIFU, delivery of dopamine receptor antibodies and DNAforgene therapyhasbeen observed, aswellasenhanced brain tumor responsetodoxorubicinandtrastuzamab.

102,106,109,111–114

Conclusion

Since the rstpotential clinical application for focusedUS was proposed in the 1940s, HIFU has been viewed as a promising image-guidedtherapeuticmodality.Withtheadventofmodern meansof real-timeimagingandtreatmentmonitoring,US-and MRI-guidedHIFUhavebeeneectivelyutilizedinthetreatment ofawiderangeofbenignandmalignantneoplasms.Clinicaloncologicecacybaseduponlarge-scale,prospective,randomizedtrialsremainslargelyunprovenforabroadspectrumofapplications of US- and MRI-guided HIFU-mediated thermoablation. is remainsa stimulatingarea forongoingclinicalandtranslational investigation.Additionalthermalandnon-thermal HIFU bioeffectswithpotentialoncologicapplicationsarealsoofclinicaland scientic interest, including hyperthermia-mediated radiation sensitization,targeteddrugdeliveryforthepurposesofdrugand genedelivery,anddisruptionoftheblood–brainbarrier.Current clinicalandscienticresearchmomentumbehindtherapeuticUS isexpected toexpand,rene,andfurthermatureHIFU clinical applications.IncreasingvalidationwilldriveacceptanceandintegrationofHIFUintomultimodalitycancercareinthefuture.

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91. SibilleA,PratF,ChapelonJY,etal.Extracorporealablationof livertissuebyhigh-intensityfocusedultrasound.Oncology1993; 50:375–379.

92. FischerK,GedroycW,JoleszFA.Focusedultrasoundasalocal therapyforlivercancer.Cancer J2010;16:118–124.

93. QuessonB,MerleM,KöhlerMO,etal.AmethodforMRI guidanceofintercostalhighintensityfocusedultrasound ablationintheliver.Med Phys2010;37:2533–2540.

94. JungSE,ChoSH,JangJH,HanJY.High-intensity focusedultrasoundablationinhepaticandpancreatic cancer:complications.Abdom Imaging2011;36:185–195.

95. NgKK,PoonRT,ChanSC,etal.High-intensityfocused ultrasoundforhepatocellularcarcinoma:asingle-center experience.Ann Surg2011;253:981–987.

96. WuF,WangZB,ChenWZ,etal.Advancedhepatocellular carcinoma:treatmentwithhigh-intensityfocusedultrasound ablationcombinedwithtranscatheterarterialembolization. Radiology2005;235:659–667.

97. ChenW,ZhuH,ZhangL,etal.Primarybone malignancy:eectivetreatmentwithhigh-intensityfocused ultrasoundablation.Radiology2010;255:967–978.

98. LibermanB,GianfeliceD,InbarY,etal.Painpalliationin patientswithbonemetastasesusingMR-guidedfocused ultrasoundsurgery:amulticenterstudy.Ann Surg Oncol2009; 16:140–146.

Section II:Principles of image-guided therapies

99. HurwitzMD,GhanouniP,KanaevSV,etal.Magnetic resonance-guidedfocusedultrasoundforpatientswithpainful bonemetastases:phaseIIItrialresults.J Natl Cancer Inst2014; 106:1–9.

100. BorasiG,MelzerA,RussoG,etal.Cancertherapycombining high-intensityfocusedultrasoundandmegavoltageradiation. Int J Radiat Oncol Biol Phys2014;89:926–927.

101. SalgaonkarVA,PrakashP,RiekeV,etal.Modelbased feasibilityassessmentandevaluationofprostatehyperthermia withacommercialMR-guidedendorectalHIFUablationarray. Med Phys2014;41:033301.

102. PhenixCP,TogtemaM,PichardoS,ZehbeI,CurielL.High intensityfocusedultrasoundtechnology,itsscopeand applicationsintherapyanddrugdelivery.J Pharm Sci2014; 17:136–153.

103. HancockHA,SmithLH,CuestaJ,etal.Investigations intopulsedhigh-intensityfocusedultrasound-enhanced delivery:preliminaryevidenceforanovelmechanism. Ultrasound Med Biol.2009;35:1722–1736.

104. RanjanA,JacobsGC,WoodsDL,etal.Image-guideddrug deliverywithmagneticresonanceguidedhighintensity focusedultrasoundandtemperaturesensitiveliposomes inarabbitVx2tumormodel.J Control Release2012; 158:487–494.

105. GasselhuberA,DreherMR,PartanenA,etal.Targeteddrug deliverybyhighintensityfocusedultrasoundmediated hyperthermiacombinedwithtemperature-sensitive liposomes:computationalmodellingandpreliminaryinvivo validation.Int J Hyperthermia2012;28:337–348.

106. TreatLH,McDannoldN,VykhodtsevaN,ZhangY,TamK, HynynenK.Targeteddeliveryofdoxorubicintotheratbrainat therapeuticlevelsusingMRI-guidedfocusedultrasound.Int J Cancer2007;121:901–907.

107. SheikovN,McDannoldN,VykhodtsevaN,JoleszF,Hynynen K.Cellularmechanismsoftheblood–brainbarrieropening inducedbyultrasoundinpresenceofmicrobubbles. Ultrasound Med Biol2004;30:979–989.

108. HynynenK,McDannoldN,VykhodtsevaN,JoleszFA. NoninvasiveMRimaging-guidedfocalopeningofthe blood–brainbarrierinrabbits.Radiology2001;220:640–646.

109. KinoshitaM,McDannoldN,JoleszFA,HynynenK.Targeted deliveryofantibodiesthroughtheblood–brainbarrier byMRI-guidedfocusedultrasound.Biochem Biophys Res Commun2006;340:1085–1090.

110. MarquetF,TungYS,TeichertT,FerreraVP,KonofagouEE. Noninvasive,transientandselectiveblood–brainbarrier openinginnon-humanprimatesinvivo.PLoS ONE2011; 6:e22598.

111. AryalM,VykhodtsevaN,ZhangYZ,ParkJ,McDannold N.Multipletreatmentswithliposomaldoxorubicinand ultrasound-induceddisruptionofblood–tumorand blood–brainbarriersimproveoutcomesinaratgliomamodel. J Control Release2013;169:103–111.

112. AlonsoA,ReinzE,LeuchsB,etal.Focaldeliveryof AAV2/1-transgenesintotheratbrainbylocalized ultrasound-inducedBBBopening.Mol er Nucleic Acids2013; 2:e73.

113. ParkEJ,ZhangYZ,VykhodtsevaN,McDannoldN. Ultrasound-mediatedblood–brain/blood–tumorbarrier disruptionimprovesoutcomeswithtrastuzamabinabreast cancerbrainmetastasismodel.J Control Release2012; 163:277–284.

114. KinoshitaM,McDannoldN,JoleszFA,HynynenK. NoninvasivelocalizeddeliveryofHerceptintothemouse brainbyMRI-guidedfocusedultrasound-induced blood–brainbarrierdisruption.Proc Natl Acad Sci USA2006; 103:11719–11723.

Chapter

Principles of tumor embolotherapy and chemoembolization

Tumor embolotherapy

General indications

epercutaneousangiographictechniquewasoriginallyintroduced by Seldinger,1 and modern embolotherapy was rst attemptedbyRöschetal.2tocontrolduodenalbleedingin1972. etermembolizationreferstotheinductionofvascularocclusionbyintroducingan embolic agent intoavesselthrougha selectivelyplacedcatheterfortherapeuticpurposes.

bleedingcontrol,tumordevascularization,arteriovenousstulas andmalformations,aneurysms,organortissueablation,varicoceles,blood ow redistribution, and perigraleakage.Tumors that are indicated for devascularization by embolotherapy includerenalcellcarcinoma,3angiomyolipoma,4hepatictumors,5 boneandso-tissuetumors,6anduterinebroids.7Transcatheter arterialembolization(TAE)oflivertumorswasrstreportedby Doyonetal.,8whilechemoembolizationusingGelfoamandanticancerdrugswasoriginallyreportedbyYamadaetal.

microcatheter systems have been developed, making possible thepreciseandsafedeliveryofembolicmaterialstoanylocation in the body through blood vessels. e embolization process involves the precise localization of a target lesion, the selection of idealembolic materials, thecompleteembolizationof thetargetlesion,andthepreservationofnon-targetedregions. Foreectiveembolization,theselectiveandsuperselectivetechniques are importantin inducing completeembolizationand preservingnormalparenchymaandtargetorganfunction.

Embolic materials

Various embolic materials are now commercially available. Embolicmaterialsmustbechosenwiththefollowingcharacteristicsinmind:embolizationlevel(proximalordistal),regularsizeandshape(constantorchanging),durationofocclusion (permanentortemporary),easeofinjectionthroughacatheter (solid, elastic, or liquid) and potential risk of complication. Manyembolic materialshavebeenintroducedforTAE,such asgelatinspongeparticles,9microspheres,10autologousblood clots,11 polyvinyl alcohol(PVA) particles,12 n-butyl cyanoacrylate(NBCA,glue),13andabsoluteethanol.

Hwan Jun Jae, Jae Hyung Park, and Jin WookChung

ere are various indications of embolization, including

Recently, catheters with hydrophilic coatings and coaxial

Gelfoam

Gelatin sponge (Gelfoam) is a porous,pliable product that ispreparedfrompuriedporkskinandappliedtobleeding surfacesasahemostatic.Gelfoamisthemostfrequentlyused embolicmaterialforthedevascularizationoftumors,andfor vascularocclusionforbleeding control.Gelatinsponge particlesof500–1,000 μm donotcauseserioushepaticdamage inexperimentalanimalsorhumanswithgoodhepaticfunctionalreserve.14Gelfoammaybecuttotherequiredsize,but isusuallyusedin1–3-mm cubes (Figure 5.1).Aerpassage through a microcatheter, Gelfoam may be broken up into smaller particles, whichrangefrom 10 to 700 μm in diameter (mainly 10–50 μm). A large pieceof Gelfoam can also beinjectedwithatuberculinsyringeindilutecontrastmaterialasa“Gelfoamtorpedo,”inordertoobtainproximal-vessel occlusion.However,theuseofGelfoampowderisconsidered dangerousas it increases the risk of ischemic complications suchasischemicbowelinfarctionorbiliarydamagebyperipheralandcapillaryocclusion.Gelfoamisausefulembolicagent forthecontroloftraumatic,gastrointestinal,andsolid-organ bleeding, and may cause eective tumor devascularization in various organs. It is usually absorbed 4–6 weeks aer embolization.

Polyvinyl alcoholfoam

PVAfoamistheproductofthereactionbetweenfoamedPVA andformaldehyde.Itis an insolublerigidmaterialwhen dry butisresilientwhenwet.However,itmaycauseaforeign-body reactioninlivingtissue.Particlesizesvaryfrom50to1000μm (Figure5.2A). It is recommendedthat PVAparticles be preparedas awell-suspendedpowderinacontrastmedium,and itisimportanttopreparethismediumsothatithasthesame specicgravityasthePVAparticles(Figure5.2B).istypeof suspensionis commonlyusedfortheembolizationofhepatic tumors,15 renal cell carcinomas, uterine broids,7 metastatic bonetumors,arteriovenousmalformations,andgastrointestinalhemorrhages.

Coils

Coilsarepermanentembolicmaterialsandthelevelofocclusiondependsoncoilsize. Coilsare made ofstainlesssteelor platinum and may have Dacron bers attached along their

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

entire length to induce thrombosis. Coils are available in a rangeofsizesfrom0.010to0.035–0.038inches.Microcoilsare

0.018inchesorlessin size,anddesigned forusewithcoaxial

microcatheters(Figure5.3),whereaslargercoilsaredelivered throughstandard4–5Fcatheters.Microcoilsareusefulforthe superselective embolization of specic branches to control gastrointestinal,renal,and hepatic bleeding, andto preserve adjacentnormalparenchyma.Intermsoftumorembolization, coilsandmicrocoilsareusedtomodifybloodow,toredirect bloodowsoasto improvetheeectivenessofintra-arterial chemotherapyorchemoembolization,andtooccludeanartery ofanon-targetedorgantoavoidcomplications(Figure5.4).16 Detachable coils are also useful when precise placement or optimalsizingis critical, in spiteoftheirrelativelyhighcost.

Controlledreleasefromthedeploymentwirecanbeachieved by mechanical release using interlocking system or electrochemicaldissolutionofanattachmentjoint.

Absolute ethanol

Absoluteethanolisapotentembolicagentforvascularocclusionandtissueablation.Onceinfusedintoavessel,itcauses the denaturation of proteinaceous blood elements, which resultsinclotformationandendothelialdamage,andthuspermanentlyoccludesvessels.Becauseitisaradiolucentmaterial, absoluteethanolmaybeused aer it is mixed with Lipiodol

Figure 5.1 Gelfoam particles. (A) A gelatin sponge sheet is easily cut into

smaller-size particles. (B) These particles, 2 × 2 × 2 mm cubes, can be sterilized with ethylene oxide gas in a 10-cc syringe.

ornon-ioniccontrastmedia to allow for the visualizationof anagentunderuoroscopy.17Ethanolhasbeen used totreat renalcellcarcinoma,3renalangiomyolipoma,18hepatocellular carcinoma,19 esophageal varices, and arteriovenous malformations. During such procedures, great care must be taken

Figure 5.2 Polyvinyl alcohol (PVA)

particles. (A) PVA particles (Contour) are available commercially in diﬀerent sizes (150–1,000 μm). (B) Dilution of contrast media. Particles are suspended in contrast media (left) and precipitated in saline (middle) and then freely dispersed in the bottle of speciﬁc gravity-matched contrast media (right).

Chapter5:Tumor embolotherapy and chemoembolization

toavoidthereuxoftheembolicmaterial,asretrogradeow maycausetheinadvertentembolizationofanon-targetorgan. Targetvesselidenticationisalsoimportant,becauseethanol isaparticularlydangerousagentwhichcancausethenecrosis ofneighboringtissues,includingnerveandskin,withitsdiusioncapacityintosurroundingtissues.

Microspheres

Severaldierenttypesofmicrospheresareusedforembolization. Embospheres (Biosphere Medical, Rockland, MA) are madeoftrisacrylgelatinmicrospheres.eyarecompressible andhavehydrophilicsurfaces,andthusarelesspronetoaggregate.SeveraldierenttypesofmicrospheresmadeofPVAare alsoavailable,includingBead Block(Biocompatibles,Farhan, UK)andContourSE(BostonScientic,Natick,MA).Because

oftheiruniformsizeandinabilitytoaggregate,microspheres areeasiertodeliverthroughmicrocathetersthannon-spherical PVA. Also,thereis moreprecisecorrelationbetweenthesize ofmicrospheresandthediameterofoccludedvessels,making accuratetargetedembolizationpossible.20

Embolization:Technical considerations

Pre-embolization evaluation

Forecient embolization by superselective catheterization, a pre-procedural computed tomographic (CT) evaluation is essential. Recent technical advances in CT angiography makeitpossibletovisualizemajorbranchesoftheaortaand majorarterialvariationsbeforeprocedures.Evaluationofthe relationshipbetween arterialanatomyandatargetlesionis mandatory before embolization. A number of arterial anatomicalvariationsarepossibleforeachorgan.Knowledgeof individual anatomyis important to achieving the complete embolizationofatargetlesion,while avoidingunnecessary complicationsand preservingnormal parenchymaas much aspossible.

Roadmap and superselective arteriography

Foraccurate superselective catheterization,a roadmap function is helpful during uoroscopy for embolization. A ne feedingbranchlocatedasdistallyaspossibleshouldbeselected foreectivesuperselectiveembolization.Magniedviewsand obliqueprojectionsatdierentanglesareusefulandrepeated angiographiesare also periodically necessary to conrm the superselectivepositionofacatheter.However,itisnecessaryto weighthebenetsofrepeatedangiographyagainsttheradiationhazards.

especialshapingofamicroguidewireis recommended for selective catheterization of target vessels with dicult anatomy–acutebranchingangle,tortuosity,smallbranchvesselarisingfrommuchlargerparentartery.Forexample,ashepherd’shooktechniquehas beendescribedfortheselectionof

Figure 5.3 Microcoils. Several diﬀerent types of microcoils are currently

available, i.e., spiral (A) or tornado (B) types, with thrombogenic Dacron ﬁbers.

anarterybranchinginacuteanglefromthemuchlargerparent artery,alongwiththeuseofamicrocatheterandamicroguidewire.21Operatorsshouldbefamiliarwithnemodicationsof

Figure 5.4 Redirecting blood ﬂow by

microcoil embolization for tumor treatment. (A) Selective left hepatic arteriograph revealing a prominent accessory left gastric artery (arrows) from the left hepatic artery supplying gastric fundus in a patient with multiple nodular-type hepatocellular carcinomas. (B) After microcoil embolization (arrow), ﬂow to the accessory left gastric artery from the left hepatic artery ceased. Chemoembolization was performed safely to control multinodular lesions via the left hepatic artery during follow-up.

Section II:Principles of image-guided therapies

monthsaerTACE,thetissueconcentrationsofchemotherapeuticagentswithintumorsare40timeshigherthaninsurroundingnormalliverparenchyma.

26,27

Chemotherapeutic agents used for chemoembolization

A large variety of chemotherapeutic agents have been used for TACE, and still controversypersists regarding the selectionofthemostpotentofthesedrugs.e mostwidelyused

Figure 5.5 Various forms of pre-shaped microguidewires. Special shaping

of a microguidewire can be made according to the target vessel anatomy for superselective catheterization.

theexibledistaltipofmicroguidewiresduringsuperselective catheterization(Figure5.5).

Chemoembolization

Basic principle

A normal liver receives a dual supply of blood from the hepaticarteryandthe portalvein.Approximatelyone-third of normal hepatic blood ow originates from the hepatic artery,whiletheothertwo-thirdsoriginatefromtheportal vein.Aboutone-halfoftheoxygenrequirementoftheliver is supplied by the portal vein. Conversely, both primary andsecondary liver tumorsderive90% of their bloodsupplyfromthehepaticartery,withasmaller(10%) contributioncomingfromthe portalvein.22erefore,intra-arterial agentshavebeenrecommendedforthetargetedtreatmentof hepatocellularcarcinoma(HCC).Inan experimentalstudy, intratumoral concentrations of chemotherapeutic agents increasedtenfoldwhen chemoembolic materialwasadministeredviathehepaticarteryasopposedtotheportalvein.23 Transarterialchemoembolization(TACE)involvestheselectiveintra-arterialdeliveryofchemotherapeuticagentintothe tumor,followedbytheembolizationofthetumorvascularity withthe goal of inducing tumor necrosis. e rationale for chemoembolizationisthatischemiacausedbytheembolizationofarterialfeederssupplyingthetumorhasasynergistic eectwithcytotoxicdrugs.eischemicnecrosisofatumor due to embolization may cause failure of transmembrane pumpsintumorcells,whichcanresultinthegreaterabsorption of chemotherapeutic agents by tumor cells.24 In a cell cultureexperiment,anincreaseduptakeof3H-daunomycin (ananalogofdoxorubicin)byhepatomacells was foundto occur under hypoxic conditions.25 is suggests thatselectivehepaticarterialocclusionmayfacilitateincreasedchemotherapeutic agent uptake into liver tumors. In addition, the reduction of arterial ow aer embolization may cause chemotherapeuticagentstoremainwithintumortissuefor prolongedperiodsoftime.Ithasbeenreportedthat,several

singlechemotherapeuticagentisdoxorubicin,whilethemost commoncombinationdrugregimeninvolvescisplatin,doxorubicin, and mitomycin C.28 However, there is currently no evidence of the superiority of any single chemotherapeutic agentoverotherdrugsorofmonotherapyversuscombination chemotherapy.

Lipiodol chemoembolization

In the early 1980s, iodized oil (Lipiodol; Andre Guerbet, Aulnay-sous-Bois, France), a lymphangiographic dye, was found to remain selectively in the neovasculature and the extravascular spaces of liver tumors when injected into the hepatic artery.30 Since then, TACEbased on Lipiodol mixed withdierentanticanceragentsor,moreoen,withanemulsion of Lipiodol and anticanceragents followed by Gelfoam embolization, has been widely used for the management of unresectablehepatocellularcarcinoma.

When injected into the hepatic artery, Lipiodol persists selectivelyinatumorforafewweeksormonths, because of hemodynamic dierences between hypervascular hepatic tumorsandliverparenchyma,andpresumablybecauseofthe absenceofKupercellsintumors.22Nakajoetal.havereported thatiodine-131 Lipiodolaccumulatedinvasculartumorsata ratethat was 7.5–21 times higher thanthat in adjacent normal parenchyma.31 In contrast,in normal liver parenchyma, Lipiodolinjectedintothehepaticarteryusuallydoesnotcause completeocclusionof the hepaticartery,andaccumulatesin theperipheralportalveinthroughmultiplearterioportalcommunications.Itthensubsequentlypassesthroughthesinusoids andintothesystemiccirculation.

InLipiodolchemoembolization,Lipiodolisusednotonly asanembolicmaterialbutalsoasacarrierofchemotherapeuticagents.33Inastudyonthe biodistributionofdoxorubicin aerchemoembolization,amixtureofLipiodolanddoxorubicin was found to lowerthe peak concentrationofdoxorubicin in plasma, and to increase intratumoral concentration andprolonghalf-life.Moreover,acombinationofdoxorubicin, Lipiodol,andGelfoamwasfoundtoproducethehighestintratumoralconcentrations.

WhenpreparingamixtureofLipiodolandchemotherapeuticagents,thechemotherapeuticdrugsareusuallypre-dissolved in a water-soluble contrast agent and then emulsied in the Lipiodolbyusingapumpingmethod(Figure5.6).Tomakeasta- blewater-in-oiltypeofemulsion,anexcessvolumeofLipiodol overthecontrastmediumisrequiredandtheadjustmentofthe mixing volume of Lipiodol and doxorubicin to a 2–4:1 ratio (Lipiodol/doxorubicinsolution)isrecommended.34estability

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