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Chapter8:Imaging in interventional oncology: Role of image guidance
in a recent clinical study where robotic-assisted CT-guided liver radiofrequency ablations have been shown to provide technicalanddiagnosticsuccessratessimilartothoseobtained with a manual method76 but also to decrease thenumber of needlepositionadjustments.Withintegratedsowaresystems, thecoordinatesoftargetscanbechosenandthentherobotcan deliveratooltotheprescribedlocation.is,however,requires thattheimageusedforplanningisregisteredwiththepatient andaccountsforpatientmotion.Robotshavebeenappliedto CT, MRI, uoroscopy, and even US-guided procedures.
82–84
Accuratetargeting,however,requiresthattheimageused for planningisregisteredwiththepatientandaccountsforpatient motion.ese,therefore,arethesameengineeringchallenges thatarefacedwithnavigationandfusionenhancements.
However, thefeasibilityofsuchapproacheshas beentypi­cally evaluated through experimental placements performed onphantoms,85animalmodels, or patientswithoutcompari­sontocontrolcohorts.is lackofstandardizationmaydis­torttheresultsbecauselargevariationshavebeenobservedin whatwastargeted.Moreover,theaccuracymetricsarelargely self-assessed,usingthesamesoware,withoutrespecttoxed landmarks.Itcouldbeproblematicincaseofmovingtargets.
Open access to the patient
Manyof the interventional oncology tools require physician accesstothepatientduringimaging.Physicianaccessisimpor­tantto allow real-time guidanceas the physicianadvancesa tool. Additionally, in many interventional oncology proce­dures,needlesextendoutfromthepatient’sbody.edegreeto whichthepatientisaccessiblevariesfrommodalitytomodal­ity.Forinstance,USandX-rayuoroscopyprovidethe most access. During closed-bore MR- or CT-guided procedures, accesstopatientsismorelimitedduetothegantrysurround­ingthepatient.
3–6,22,86,87
Forexample,MRor CTimagingmay notbepossibleduringthe placementofdevicessuchaslong biopsy needles, drainage catheters, and ablation applicators thatdonottinthespacebetweenthepatient’sbodysurface andthegantry.Someopen-accessMRscannersprovidelimited accessatthecostoflowereldstrength.88Manyotherimpedi­mentstoMRI-guidedinterventionhavealsobeensolved,such as the developmentof MR-compatibleinstrumentation such assemiexibleneedlesthatcanbendinaclosed-gantryenvi­ronment.89 However,higher eld magnets (1.5 T) with wide borehave been utilizedto provide higher imagequality and are facilitating interventional procedures.90 Instrument visu­alizationissues still persist,whetherduetotoo muchartifact ortoolittleconspicuity.
91,92
Noisegeneratedduringscanningis potentiallyharmfultotheinterventionalradiologist,especially with newer high-eld (3 T) systems.93 Other challenges still exist,suchaselectricalnoisefromablationdevicesinterfering withMRI.
94
Radiation exposure
Many procedures are best done utilizing CT or uoroscopy as the guidance modality. e inherent limitation of these modalitiesisthe radiationexposuretophysicianandpatient,
as observed during CT uoroscopy, because of continuous exposure at a single anatomic location. On the other hand, excessivelylowradiation doses lead to inferior image quality andresultininterferencewithinterventionalradiologyproce­dures.Inadditiontowearingleadapronsandotherprotective garb,physicianexposurecanbediminishedfurtherduringCT uoroscopy-guidedproceduresbyplacingaleadshieldonthe patientjustbelowtheimagingplanetoreducescatterradiation andbyusing“armextenders,”suchasrobots,describedabove.2
Modicationstotheimagingequipmentcanalsobeemployed to limit radiation exposure.Lowering tube currentandtube potentialbyadaptingtothepatient’ssizeandshapewiththeaim ofkeepingimagenoiseconstantthroughouttheentirestudy hasbeenprovedtolowertheradiationdosetothe minimum required.17Reducingthe timethebeamisemployedorusing navigationsowareandfusionimagingareallapproachesthat canreduceradiationexposure.
95,96
Accordingtothe aslowas reasonablyachievable(ALARA)principle,oneshouldusethe CT uoroscopic scan parameters, which provide acceptable imagequalityatthelowestpossibleradiationexposure.

Intraprocedural monitoring

An important challenge in most interventional oncologic therapiesisknowingwhenenoughtherapyhasbeendelivered. Ideally,therewouldbesomeclearendpointfortherapycom­pletion.Imaging is one potentialsolutionforanon-invasive measure of completeness. e goal of monitoring is to not onlydetermineifthetreatmentiscomplete,butalsotodisplay thesurroundingcriticalstructuresthatshouldnotbeaected morethan is necessary to completethetreatmenteectively andsafely.Severalimagingmodalitieshavebeenusedtoassess completenessoftherapy.eseprimarilyrevolvearoundmeas­uresofbloodow.Angiographyaer(chemo-)embolizationof hypervascular tumorscanshowhemostasis and a completely embolized tumor bed. Lipiodol or contrast-laden embolic materialuptakemaybeusedtovisualizeprogressduringchem­oembolization and bland embolization procedures, respec­tively.ismaybe especiallywellvisualizedon3Drotational at-panelCT.Inarecentstudy97ithasbeendemonstratedthat patternofretainedcontrastonimmediatepostprocedureCT) aerparticleembolizationofhepatictumorspredictedmodi­edResponseEvaluationCriteriaInSolidTumors(mRECIST) response.RecentlycombinedMR–X-raysystemshaveallowed intraproceduraltranscatheterintra-arterial perfusionMRIto be performed during hepatic artery embolization to permit intraproceduralperfusionchangesandmonitoring.
WithUS,Dopplerowandcontrastagentshavebeenused toassessbloodowanddeterminewhenatumornolongerhas aviablebloodsupplyaeranablation.
30,37
USmayalsobeused without contrast to monitorthe eects of an ablation based on changes in echogenicity.During radiofrequency ablation, increased echogenicity can show in the ablation zonewhich diametercorrelateswiththediameterofnecrosis.99However, thesolitarydiameteroftheechogenicresponsemaybegreater thanthesmallestdiameterandlessthanthelargestdiameterof theareaoftissue necrosis. erefore,theechogenicresponse
98
69
Section II:Principles of image-guided therapies
18-uorodeoxyglucose (18FDG) or15O-H2O.Benets of PET CThavebeen provedin oncology byallowingadequatestag­ingofdisease ticresponse.
106–112
aswellasearlyevaluationofthetherapeu-
113–115
Moreover,FDGPETCThasbeenproposed recently for the guidance of biopsies or to monitorthermal ablations.
55–58
Preliminaryresultsshowedpromisingresultsfor those lesions that were hypermetabolicon a baseline exami­nation,
116
 in particular by using the split-dose technique
56,117
 (Figure 8.4). is technique permits both target localization andevaluation of treatment eectiveness by injecting a total of4mCi(148MBq)ofFDGbeforetheprocedureforlocaliza­tionandimagingguidanceandanadditional8mCi(296MBq) FDGatcompletionoftheablation.eshort,2-minutehalf-life of15Omakesitpossibleto performrepeatedPETimagingat 20-minuteintervals at multiple time points beforeand aer
Figure 8.5 Computed tomography-guided renal cryoablation. Imaging
used for intraprocedural monitoring. Visualization of the low-density ice ball (arrowheads) around the cryoprobe during percutaneous cryotherapy allows the user to be certain that the tumor is well contained within the ice ball.
image-guidedtherapyandpermitsvisualizationoftheablated tumorregionwherenouptakeisobserved.
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Imaging for therapy assessment

Patientswho receiveimage-guidedtherapyarefollowedwith periodic diagnostic-qualityimagingstudies.Interpretationof theseimagescanbeextremelydicultgiventhatdistinguish­ing expected changesaer the therapyfrom changes associ­atedwithtumorgrowthcanbeverychallenging.Itistherefore
associatedwithradiofrequencyablationshouldbeviewedonly asaroughapproximationoftheareaofinducedtissuenecro­sis;thenalassessmentoftheadequacyofablationshouldbe deferredto an alternative imaging technique.99 Furthermore, this increased echogenicitymay obscure imaging during the procedureandhinderprobereplacement.Duringcryotherapy, anechogenicmass-likestructurewithdistalacousticshadow­ingrepresentingtheiceballformationmaybenoted.
100
CTandMRalsousecontrastimagingtoassessvascularityof thetreatmentzoneandprovideintraproceduralimagingfeed­backduringatherapy.ContrastagentsmaybeusedinCTand MRItoassessvascularityofthetreatmentzone.UnlikeUS,the cryotherapyiceballcanbeviewedinitsentiretyusingbothCT andMRI
101
(Figure 8.5). Duringethanol ablationprocedures, low-attenuation CT associated with percutaneous ethanol injectioncanguideproceduretermination.
102,103
Recently,imag­ingmeasurementsoftemperaturehavebeenusedtodetermine completenessofthermalablationmainlywithMR,
104
whichcan providea quantitativenon-invasivemethodof evaluating the completenessof a thermal ablation. Understanding the ther­maldosedeliveredmayevenfacilitatesomeselectivityoftissue destructionsincedierenttissueshavedierentthresholdsfor
105
death.
Several MR thermometry techniques exist, basedon
the relaxationtime (T1), the diusion coecient (D),orpro­tonresonancefrequency oftissuewater.
105
Usingprotonreso­nancefrequencychangesthatareassociatedwithtemperature change,onecanmeasuretissuetemperaturechangesintheMR towithin1°C.41LimitationsofMRthermometrystillexistdue tomotion,magnetic-eldinhomogeneitiescreatedbyablation toolsorfattyenvironments,andthoseduetothelimitedtempo­ralresolutionofthetechnique.
Conceivably, nuclear medicine agents may be use-
ful to measure tumor viability during a procedure such as
critical to obtain a baseline imaging study shortly aer the image-guided therapy. Whichever is the choice of imaging study,itisprobablybesttocontinuetousethesamemodality infollow-uptoallowfordirectcomparison.
In most cases, follow-up studies are contrast-enhanced CTorcontrast-enhancedMR.PETCTstudiesmay be par­ticularly helpful with FDG-avid tumors but have not been rigorously proven superior.
119
 Subtraction imaging can be particularlyusefulindetectingsubtlerecurrence.Subtraction maybeespeciallyhelpfulwhenusingcontrast-enhancedMR techniques.
30
In2000andrevisedin2009,theRECISTcriteriamadeuse of unidimensional measurements and addressed several pit­fallsandlimitationsoftheoriginalWorldHealthOrganization criteria.
120
 However, treatment strategies have changed over thepastdecade,andthelimitationsofusingtumorsizealone inpatientsundergoingablative therapy(includingarbitrarily determined cuto values to categorize tumor response and progression,lackofinformationaboutchangesintumorCT attenuationorsignal,inabilitytohelpdistinguishviabletumor fromnon-viablecomponents,andinconsistencyofsizemeas­urements) necessitated revision of these criteria and several criteriaarenowproposed,includingthe enhancementorthe activityofthelesionobserved.Forexample,apanelofexperts onhepatocellularcarcinomahaveproposedthatestimationof viable tumor with contrast-enhanced imaging should be the optimalmethodforassessing treatmentresponse,referred to as mRECIST.
121
 Although these criteria have been useful in the systemic chemotherapy setting, they may not be useful when assessing image-guided interventions. Aer successful image-guidedtherapy,thetreatedlesionsmayin fact appear larger, not smaller,than the pretreated lesions. e increase in anatomic size on CT or MR is likely due to associated
70
Chapter8:Imaging in interventional oncology: Role of image guidance
AB
hemorrhage,edema, andinammation,as wellasintentional destruction of surrounding tissue for a safety margin
122,123
(Figure 8.6). Unidimensional tumor measurements would suggestgrowthofthetumorratherthansuccessfultreatment, whichisnotthecase.Hence,intheeldofimage-guidedther­apy,theRECISTcriteriafailandnewermethodsofposttherapy assessmentaremandatory.
Newer imaging techniques may provide an opportunity forimprovedassessmentoftheposttherapytumorbed.ese techniques include MR diusion, MR spectroscopy,CT/MR perfusionimaging,andPETimaging.
MR diusion imaging assesses water molecule diusion inthetissue.Viabletumorcellshavemembranesthatrestrict watermovement,whereasnecroticcellswithdisruptedmem­braneshaveincreasedwatermovement.eapparentdiusion coecient may thereforebe higher in areas of necrosis than inareasofviabletumor.istechniquehasbeenparticularly appliedinchemoembolizationcases.
124
etechniqueislim­itedinareaswith respiratorymotionorinareasof magnetic susceptibility,suchaswithairinthelungs.
Assessing choline levels with proton-MR spectros­copyis another method of assessing tumor viability aeran image-guidedtherapy.Cholineisanessentialcomponentofcell membranebiosynthesis.Elevatedcholinelevelsareassociated withincreasedcellproliferationinseveraltumors.Posttherapy necroticareasarebelievedtohavelowcholinelevelscompared withareasofviablerecurrenttumor.
125
AnumberofCTandMRenhancementandperfusiontech­niqueshavebeenappliedtotumorimagingtoprovideaddi­tionalinformationabouttumorphysiology.Dynamiccontrast enhancementtechniques measure ratesof contrast enhance­mentinaparticularareatoidentifyviabletumor.MRI arte­rialspinlabelingisanothermethod for measuring perfusion of a particular area without administering contrast.50 All of thesetechniquesattempttoaddphysiologicinformationtothe standardanatomic
126
formationofCTandMR.
Immediate reduction in FDG uptake may be correlated with tumor necrosis induced by the ablative technique.
56,117
However, rapidly the central zone of necrosis is surrounded by an outer zone of congestion, which shows inammatory changeswithinafewdays,causedbytherecruitmentofneu­trophils, lymphocytes, andmacrophages.
127–130
 erefore, the
periphery of thenecrotic zone shows increased FDG uptake
fordaysandmaydisturbtemporarilytheresultsofsubsequent
PETbyincreasingthefalse-positiverate.Aer 3 months the roleof PETCTtoassesstheresponseaerablationhas been foundtobeofsignicantclinicalvalue. responseasaleadingindicatoroftumorresponsemaybeeven morepredictiveofoutcomethanmorphologiccriteria.Itisin thiscontextthatthePERCISTcriteriawereproposedin2009 to rene and validate quantitative approaches to monitor­ingPETtumorresponse.NewPETimagingtracersmayhave increasedspecicitythatcandistinguishposttherapyinam­mationfromactualresidualtumor.Severaltargetshavealready beendeterminedandimagedusingexistingPETradiopharma­ceuticals,suchastissuehypoxia,apoptosis,andincreasedcell proliferation,butnewbiologicalimagingtargetsarecurrently stillbeinginvestigated. as thymidine can be labeled with positron-emittingisotopes fordetectingtumorproliferation.Antibodiesthatspecically targetcancercellscanbelabeledwithPETisotopesaswell. isincreasedimagingspecicitymaybe useful in assessing posttherapytumorbeds.
Other new molecular imaging techniques that provide increasedtumorspecicitymayultimatelyplayaroleiniden­tifyingresidualdiseaseaerimage-guidedtherapy.esetools willhelpimprovethesetherapiesbyprovidingincreasedcon­dence of success and an earlier opportunity to intervene if residualviabletumorremains.

Summary

Imagingplays a critical role in interventionaloncology pro­cedures.Imagingallowspreprocedureplanning,tooldelivery guidance,intraproceduralmonitoring,andposttherapyassess­ment.Eachoftheseareasisevolving.Imagefusionandrobot­ics,forexample,representtwoareas ofpotentialapplicability tointerventionaloncologyprocedures.Asimagingequipment becomesmorecustomizedtothetaskofimage-guidedtherapy, itislikelythat these procedures will becomesaferandmore eective.

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123. MerkleEM,NourSG,LewinJS.MRimagingfollow-up aerpercutaneousradiofrequencyablationofrenalcell carcinoma:ndingsin18patientsduringrst6months. Radiology2005;235(3):1065–1071.
124. SuhRD,WallaceAB,SheehanRE,HeinzeSB,Goldin JG.Unresectablepulmonarymalignancies:CT-guided percutaneousradiofrequencyablation–preliminaryresults. Radiology2003;229(3):821–829.
125. KamelIR,BluemkeDA,EngJ,LiapiE,MessersmithW,Reyes DK,etal.eroleoffunctionalMRimagingintheassessment oftumorresponseaerchemoembolizationinpatients withhepatocellularcarcinoma.J Vasc Interv Radiol2006;17 (3):505–512.
126. ChenC-Y,LiC-W,KuoY-T,JawT-S,WuD-K,JaoJ-C,etal. Earlyresponseofhepatocellularcarcinomatotranscatheter arterialchemoembolization:cholinelevelsandMRdiusion constants–initialexperience.Radiology2006;239(2):448–456.
127. OkumaT,OkamuraT,MatsuokaT,YamamotoA,Oyama Y,ToyoshimaM,etal.Fluorine-18-uorodeoxyglucose positronemissiontomographyforassessmentofpatients withunresectablerecurrentormetastaticlungcancersaer CT-guidedradiofrequencyablation:preliminaryresults.Ann Nucl Med2006;20(2):115–121.
128. OkumaT,MatsuokaT,YamamotoA,HamamotoS,Nakamura K,InoueY.Assessmentofearlytreatmentresponseaer CT-guidedradiofrequencyablationofunresectablelung tumoursbydiusion-weightedMRI:apilotstudy.Br J Radiol 2009;82(984):989–994.
129. OkumaT,MatsuokaT,OkamuraT,WadaY,YamamotoA, OyamaY,etal.18F-FDGsmall-animalPETformonitoring
thetherapeuticeectofCT-guidedradiofrequencyablation onimplantedVX2lungtumorsinrabbits.J Nucl Med2006;47 (8):1351–1358.
130. YamamotoA,NakamuraK,MatsuokaT,ToyoshimaM, OkumaT,OyamaY,etal.Radiofrequencyablationinaporcine lungmodel:correlationbetweenCTandhistopathologic ndings.AJR2005;185(5):1299–1306.
131. KuehlH,AntochG,BockischA,ForstingM.Wherethereisno PET/CT.Eur J Radiol2008;67(2):372.
132. DonckierV,VanLaethemJL,GoldmanS,VanGansbekeD, FeronP,IckxB,etal.[F-18]uorodeoxyglucosepositron emissiontomographyasatoolforearlyrecognitionof incompletetumordestructionaerradiofrequencyablationfor livermetastases.J Surg Oncol2003;84(4):215–223.
133. LangenhoBS,OyenWJG,JagerGJ,StrijkSP,WobbesT, CorstensFHM,etal.Ecacyofuorine-18-deoxyglucose positronemissiontomographyindetectingtumorrecurrence aerlocalablativetherapyforlivermetastases:aprospective study.J Clin Oncol2002;20(22):4453–4458.
134. WahlRL,JaceneH,KasamonY,LodgeMA.FromRECIST toPERCIST:evolvingconsiderationsforPETresponse criteriainsolidtumors.J Nucl Med2009;50Suppl 1:122S–150S.PubMedPMID:19403881.PubmedCentral PMCID:2755245.
135. HomanJM,GambhirSS.Molecularimaging:thevisionand opportunityforradiologyinthefuture.Radiology2007;244 (1):39–47.PubMedPMID:17507723.
136. vanWaardeA,JagerPL,IshiwataK,DierckxRA,ElsingaPH. Comparisonofsigma-ligandsandmetabolicPETtracersfor dierentiatingtumorfrominammation.J Nucl Med2006;47 (1):150–154.
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Section II
Chapter

Novel developments in MR assessment of treatment response after locoregional therapy

9
Kelly Fábrega-Foster, Neda Rastegar, Jean-François H. Geschwind, and Ihab R.Kamel
Introduction:MultiparametricMRI
Precise and early assessment of treatment response is critical aerlocoregionaltherapy.Inpatientswithunresectabletumors, magneticresonanceimaging(MRI)representsanimportanttool forposttreatmentfollow-up.Itsadvantages includetheabsence ofionizingradiationandasophisticatedrepertoireofanatomic, functional,andmolecularimaging techniques.Multiparametric MRIcombinesseveralofthesetechniquesin ordertooptimize tumorcharacterizationandenablesuperiorassessmentoftreat­ment response. e goal of multiparametric MRI is to permit elucidation of a “tumor-imaging phenotype” by maximally exploitingthesetechniques.1etumor-imagingphenotypemay assistinpredictingandassessingresponsetoavarietyofantican­certherapies.Posttreatmentimaging parameterssuchasaltera­tionsincontrastenhancementandapparentdiusioncoecient (ADC)valuesmayserveastreatmentresponsebiomarkers.
Widespreadreliance on imagingbiomarkersoftreatment responsedemandsacertaindegreeofscienticrigor.eideal imagingbiomarkermustsatisfyatleastfourcriteria.First,it must permit early assessment of treatment response, allow­ingtimelymodicationoftreatmentregimensandpreventing unnecessarytoxicitytopatients.Second,itmustenablerepro­ducible quantications of treatment response. is presup­posesaclearappraisalofmeasurementerrorsuchthatchance variation can be reliably distinguished from true response. ird,itmustbecapableofcontendingwithtumorheteroge­neity.Tumorsrepresentintrinsicallycomplexandheterogene­ous ecosystems, a fact reected in their treatment response. Variabledegrees of posttreatmentnecrosismay be seen in a singletumor. Targetedretreatmentoftumorsdepends onthe imagingmodality’sabilitytorepresentthisvariabilitywithhigh delity.Fourth,itmustbeable to predict not only surrogate endpoints,butalsosurvival.Surrogateendpointsincludealter­ationsinlesioncharacteristicsovertime,betheseanatomicor functional.eoptimalendpoint,however,ispatientsurvival.
Cross-sectionalassessmentoftreatmentresponsehastradi­tionallybeenbasedonanatomicimagingcriteria.3Stratication of patients into response categorieshas relied on changesin tumor size, with measurements obtained in the axial plane. elimitationsoftheseanatomiccriteriahaveencouragedthe use of functional and molecular imaging biomarkers in the
responseassessment. e repertoireof functional MRI tech­niquesincludes:diusion-weightedMRI(DW-MRI),dynamic anddual-phasecontrast-enhancedMRI(DCE-andCE-MRI), MRIspectroscopy,andpositronemissiontomography(PET) MRI.4 Together,anatomic and functional techniques provide a more comprehensive assessment of treatment response. Increasingappreciationforthespatialandtemporalheteroge­neityoftumorsandtheirtreatmentresponsehasculminatedin theuseofvolumetricfunctionalMRIforresponseassessment. Inthistechniquefunctionalimagingtechniquesareappliedin athree-dimensionalsetting.
is chapter aims to introduce the reader to multipara­metricMRI as a means of assessing treatmentresponseaer transarterial chemoemboliztion (TACE) in patients with liver tumors. In our discussion of functional techniques, we will focus on the two most commonly employed techniques forresponseassessment,namely DW-MRIandCE-MRI.We willalsodiscussthenovelapplicationofthesetechniquesina three-dimensionalsetting,the volumetricapproachtoassess­mentoftreatmentresponse.

Anatomic biomarkers

Anatomic metrics such as alterations in size are the tradi­tionalmeansofassessingtreatmentresponseaerlocoregional therapy. In 1979, the World Health Organization (WHO) denedobjectivecriteriafortumorresponsein anattemptto standardize reporting in solid tumors. is response assess­mentwasbasedontwo-dimensionalmeasurementsobtained intheaxial plane.ese measurementswerethenutilizedto stratifypatientsintofourcategories:completeresponse,partial response,stabledisease, and progressionof disease. A major limitationoftheWHOcriteriawaswidevariabilityinselection andmeasurementoftargetlesions.
e Response Evaluation Criteria In Solid Tumors
2
(RECIST)criteriarepresentedanattempttoaddresstheselimi­tations.InRECIST,unidimensionalmeasurementsobtainedin theaxialplanereplacedtwo-dimensionalmeasurementsinan attempttoavoidpropagatingmeasurementerrorsbyobtaining theproductoftwoseparatemeasurements.Specicsizecriteria wereintroducedtostandardizeselectionoftargetlesionsand newthresholdsweredenedforstraticationofpatientsinto
5
Interventional Oncology, Second Edition, ed. Jean-François H. Geschwind and Michael C.Soulen. Published by Cambridge University Press. ©Cambridge University Press2016
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Section II:Principles of image-guided therapies
responsecategories.3Asitbecameclearthatchangesintumor size could grosslyunderestimate treatment response early in theposttreatmentperiod,RECISTandWHObecameincreas­ingly obsolete.6 e subsequent introduction of functional metrics like contrast enhancement into the response assess­mentrepresentedanattemptto avoidthepotentialpitfall of relyingsolelyonanatomicmetricsin the earlyposttreatment period.
In2001,theEuropeanAssociationfortheStudyoftheLiver (EASL) redened the standards for measurement of target lesionsin thecaseofhypervascularhepatocellularcarcinoma (HCC)bylimitingmeasurementstothearteriallyenhancingor viableportionsoftumors.iswasanacknowledgmentofthe importanceoftumornecrosisasapotentialconfounderinsize measurements, particularly early aer therapy, when treated lesionsmayremainstableinsizewhilehavingundergonesub­stantialnecrosis.LikeWHO,EASLreintroducedthepractice ofobtainingbidimensionalmeasurementsinthe axialplane.7 emorerecentmodiedRECIST(mRECIST)criteriacom­binethestrengthsoftheoriginalRECISTcriteriawiththoseof EASL.InmRECIST,thereisareturntounidimensionalmeas­urementsobtainedin theaxialplane,anemphasis on earlier assessmentsoftreatmentresponse,introductionofnewcrite­riaforselectionoftargetlesions,andnew methodsforimage acquisition.
8
motion in tissues is neither entirely free nor entirely ran­dom. Instead, it is restricted by various components of the intra- and extracellular environment, such as blood vessels, cells and organelles, and extracellular macromolecules. MRI allowsvisualizationoftheseimpedimentstowatermotionby utilizingdiusion-sensitizinggradientsinthe pulsedesignof T2-weightedspin-echosequences. e strengthandduration ofthesediusionsensitizinggradientsaredenotedbytheir“b value.”Inmosttissues,theimpediments to watermotionare isotropic,meaningthatthey arenotdirectionallybiased.is isincontrasttotheanisotropicordirectionalimpedimentsto watermotionpresentinselecttissuessuchasthebrainorrenal tubules.esignicanceofthisisthatalimitedsamplingof bvaluesisoensucienttorepresentthediusioncharacter­istics of water molecules in tissue. On MR images, diusion restrictionis generally represented as signal brightness, with correspondingsignaldarknessonacomplementaryADCmap. e degree of diusion restriction within a tissue or lesion maybeevaluatedquantitativelyorqualitatively.eADCmap enablesquanticationofthedegreeofdiusionrestrictionby selectionofaregionofinterestwithinatargettissue.
4,11,12
As tumor cells undergo necrosis, they present less of an impediment to the motion of water molecules. is results in a relative decrease in diusion restriction andincrease in ADCvalue.Studieshavedemonstratedrelativedierencesin thebaselineADCvaluesoflivertumorsandbackgroundliver
Functional biomarkers:Diusion-weighted and contrast-enhancedMRI
Insofaras these traditionalparadigmsof treatment response relyonanatomicmetrics, theypossesscertainintrinsiclimi­tations. A common time interval for imaging follow-up of patientsaerlocoregionaltherapyisapproximately3–4weeks. istimeintervalallowssucienttimefordetectablechanges to take place without compromising timely modication of treatment. Maximum changes in tumor size are evident at 6 months aer therapy. Early trialsdemonstratingthe supe­rior safety and ecacy of drug-eluting bead (DEB)-TACE comparedwithconventionalTACEsawamere4%decreasein tumorsize1monthaertherapy,witha24%decreaseobserved at6monthsinpatientswithunresectableHCC.Bycontrast,a 64%meandecreaseincontrastenhancementand18%increase inADCvaluewasobservedintherst4weeks.9Otherstud­iesdemonstratedsignicantsynchronouschangesincontrast enhancementand ADCvalues 1–2 weeks aer TACE,with­out corresponding decreases in tumor size.10 DW-MRI and CE-MRIarecommonlyutilizedfunctionalMRIparametersin treatmentresponsepreciselybecause theyenableassessment of tumor response earlier than traditional anatomic metrics. eirresultsarereproducibleandthey possess theabilityto predictpatientsurvival.Wewilldiscusseachoftheseinturn.
e basic oncological premise of DWI is that malignant tissue is intrinsically more cellular and haphazardly organ­izedthanbenigntissue.esedierencesintissuemicroarchi­tecturecanbe representedinthe form of diusion-weighted imagesorADCmaps.DWIissensitivetothethermalmotion of water particles, also known as Brownian motion. Water
parenchyma,as well as dierences in the mean ADC values oflivertumorsbeforeandaertreatment.Beforetreatment, these dierences reect thedegreeof tissue necrosis in rela­tivelyhypoxicmalignant tissuescomparedwithbenignones. Aertreatment,anincrease inADCvaluereects thedegree oftissuenecrosisincitedbyintra-arterialtherapy.13ehisto­pathologicbasisofDWI-MRIasamarkeroftissuenecrosisis wellestablished.
14
eutilityofADCmeasurementasanearlybiomarkerof treatmentresponseisalsowellestablished.Intherst4weeks aerTACE,treated lesions demonstratesignicant increases inADCvalues.ereisaparadoxicaldecreaseinADCmeas­urementsintherst24 hoursaertherapy,whichisthought to reect a combination of cellular swelling and loss of tis­suewater.
10,15
Aerthispoint,ADC values increase forupto 3weeks,withthemost signicantincreasesoccurringat1–2 weeksaertherapy.At4weeks,ADCvaluesstabilizeorbegin todecreaseagain,anon-specicndingthatmayreecttumor cellrepopulationortissuebrosisandremodeling.
10,15,16
Posttreatment ADC changes possess prognostic signi­cance.Targetlesions fulllingRECISTandEASLcriteriafor partial response demonstrate increased mean ADC values compared with lesions demonstrating no change or disease progression.
13,16
Moreover,ADCvaluesoftargetlesionspriorto therapymayassistinpredictingresponsetotherapy.Colorectal livermetastaseswithhighpretreatmentADCvaluesaremore likelytorespondpoorlytochemotherapy.13Insofarastheaim of intra-arterial therapy is to induce tumornecrosis, lesions demonstratinga high pretreatmentADC value are expected todemonstrateADCincreasesoflowermagnitudeposttreat­ment.ismayportendarelativelypoorresponsetotherapy.
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