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Chapter7:Intra-arterial infusional chemotherapy
Table 7.3 Comparison of pharmacologic characteristics of targeted agents active in colon cancer in regard to suitability for regional therapy
Cetuximab Bevacizumab Panitumumab
Active in colon cancer + + +
Steep dose–response curve – – –
Linear pharmacolinetics – – –
High clearance – – –
Hepatic extraction ? ? ?
revealednon-linearpharmacokinetics,withantibodydosesin
A
the range of 200–400 mg/m2 being associated withcomplete saturationof systemic clearance. A sharp decline in systemic clearance(Ml/h/kg) wasobservedwithincreasingdoses:3.09 at20mg/m2,1.16at50mg/m2,0.811at100mg/m2,0.433at 200mg/m2,and0.374at400mg/m2.
Panitumumab is a fully human monoclonal IgG2 to EGFR.43Like cetuximab,it is directed against the extracellu­larligand-bindingdomainoftheEGFR(Table7.3).However, panitumumab has shown higher anity and substantially
Systemic
delivery
↑ systemic dose = total systemic and regional receptor
B
Systemic
compartment
Regional
compartment
lower50%inhibitoryconcentrationcomparedwithcetuximab. PhaseItrialshavebeenconductedinrenalcellcancerpatients testingescalatingdosesof1,1.5,2,or2.5mg/kgweeklywithno loadingdose.44Skinrashwaspresentin100%ofpatientsatthe
2.5mg/kgdoselevel.PanitumumabPKstamodelthatincor­poratesbothlinearandsaturableEFGR-mediatedCLmecha­nisms. Panitumumab concentrations increased non-linearly withthedose,whichwasmostlikelyduetoprogressivesatura­tionofaxedEGFRsink.EFGR-mediatedCL requiresoccu­pancy of the EGFR by panitumumab before internalization. emeanestimates forlinearCLand volumeofdistribution were2.59mL/day/kgand41.8mL/kg,respectively.eparam­eters characterizing non-linear clearance were estimated at 165µg/day/kg.ehalf-lifeaveraged15.9days.Atthe2.5mg/
Systemic
compartment
↓ HAI dose = total regional and limited systemic receptor
Figure 7.4 (A) Therapeutic antibodies administered systematically at
regular doses saturate regional and systemic receptors and exhibit non-linear pharmacokinetics. (B) Therapeutic antibodies administered at low doses through hepatic arterial infusion (HAI) may exhibit linear pharmacokinetics, saturate regional receptors preferentially, and result in decreased systemic toxicity.
Regional
compartment
HAI
kgdose,theclearanceofpanitumumabwasclosetothetypical CLrangeofhumanantibodiesthatarenotsubjecttoananti­gensinkof1–4mL/day/kg,butareclearedviathereticuloen­dothelialsystem.
Regarding regional therapy, although therapeutic mono-
despiteclinicalresponse.is approachmayresultin contin­uedbenetwithoutexperiencingthedisturbingside eectof skinrash.
clonalantibodiesmaydierintheirbindingtarget,presumed mechanism of action, and main toxicity, all of them share general pharmacokinetic and pharmacodynamic proper­ties:ofnote,non-linearpharmacokinetics, verylowsystemic clearance, and receptor-mediated mechanism of action.45 erefore,increasedlocalconcentrationswithHAIoverintra­venousadministrationarenotexpected.Furthermore,evenif achieved, greater concentrations may not result in increased therapeutic eect. However, regional therapy may be useful todecrease systemic toxicity,ifhepaticextraction is demon­strated. At normally administered doses of therapeutic anti­bodies, non-linear pharmacokinetics would prevent hepatic extraction.Lowdosesoftherapeuticantibodieswillexhibitlin­earpharmacokineticsandmayenable hepaticextractionand decreased systemic toxicity when administeredthroughHAI (Figure7.4).Subjects suitableforresearchincludethosewith liver-onlymetastaseswhocannottoleratesystemicantibodies,

Combining best systemic chemotherapy with best HAI strategy

Currently, there is no better drug forHAIthanFUDRbased on pharmacologic characteristics. A series of phase I clini­caltrialshaveexaminedthefeasibilityofcombiningsystemic chemotherapywithHAIFUDR.isstrategyhasmaturedinto phaseIIclinicaltrialsthatexaminethe combinationstrategy in two clinical scenarios: unresectable liver-onlydisease and adjuvantaerliverresection.D’Angelicaetal.reportedon49 patients with unresectable liver metastatic disease. Patients couldreceiveeithersystemicoxaliplatinandirinotecanor5FU irinotecan based on the chemotherapyhistory.e primary outcomewasconversiontoresectionrate.Withamediannum­ber of 14 liverlesions,resection ratewas 47%, response rate was76%,medianprogression-freesurvivalwas13months,and
59
Section II:Principles of image-guided therapies
target
(
)
(
)
(
)
(
)
==
(
)
(
)
(
)
(
)
(
)
CQ
(
)
(
)
medianoverallsurvivalwas38months.Survival forresected patientswas80%at3years.Ofnote,treatmentoftherst24 patientsincludedsystemicbevacizumab,whichdidnotimpact outcome and was discontinued because of unexpected high biliarytoxicityrate.46UsingHAIFUDRandsystemicchemo­therapyasadjuvanttherapyaerliverresection,Kemenyetal. conductedarandomizedphaseIItrialof±bevacizumabtothe abovecombination.Primaryoutcomewasrecurrence-freesur­vival.Seventy-threepatientswhounderwentliverresectionfor metastatic colorectal cancer were randomized. With median follow-up of 30 months, the 4-year recurrence-free survival was46% and 37% for patients treated with or without beva­cizumab (P = 0.4). Despitenegativeresultsfor bevacizumab addition,theadditionofHAIandsystemicchemotherapyaer liver resection demonstrated 4-year overall survival rate of 81%and85%forbevacizumabandnobevacizumabpatients.47 eseresultsarepromisinginviewthatabout50%ofpatients hadhighclinicalriskscore.

Future research

IntermsofselectionofnewdrugcandidatesforHAI,werec­ommendapharmacological-guidedapproach.Drugsneedto demonstratepharmacokinetics compatiblewith advantageif regionallydelivered.Despiteclinicalappeal,mostdrugswill notfulllpharmacologicalcriteriatobeselectedforfurther development.Intermsofclinicaldevelopment,well-designed controlled trials testing one strategy at a time are needed. Matureresultsofpreviouslydescribed phase II trials in the neoadjuvant and adjuvant setting warrant phase III trial conrmation.
Ontheotherhand,patientselectionneedstoimprovein order to solidify the indication for regional therapies. If we accept that the pattern of metastatic spread of colon cancer isneitherrandomnor completelyanatomicallymediated,we canhypothesizetheexistenceofmoleculardeterminantsofthe metastaticbehavior.Inthisregard,Kemenyetal.havereported ontheimpactofKRASmutationstatusonrecurrence-freesur­vivalandrecurrencepatternsaerliverresectionformetastatic colorectalcancer.Onacohortofpatientsthathadundergone liver resection and adjuvant HAI FUDR/LV plus systemic chemotherapy at Memorial Sloan-Kettering Cancer Center, the authors retrospectivelycorrelated KRAS mutationstatus withoutcome.FromMarch2003toJanuary2013,402patients underwent liver resection, and KRAS mutation analysis was performedon169patients:118patientswereKRAS-wild-type and51patientswereKRAS-mutant.e3-yearrecurrence-free survivalratewas46%forwild-typepatientsand30%formutant

Regional therapy pharmacology appendix

Increasedlocal concentrationsanddecreased systemic expo­sure are two dierent advantages pursued with regional therapies. It is important to realize that, even when both characteristicscanbe integratedandsummarized in a single expressioncalledoverallselectivity,eachoftheseadvantagesis independentfromtheother,astheyaredeterminedbydier­entvariables.
Increased local concentrationsatthetargetsitedependupon
whetherornotthedrug is metabolized or eliminated by the targettissue.Ifthereisnometabolismoreliminationofdrug by the target tissue, target site concentration advantage of intra-arterialdelivery(R bodyclearance(CLTB)totheregionalexchangerate(Q).
R
target
where:
C
(IA)=targetconcentrationsforintra-arterialdelivery
target
C
(IV)=targetconcentrationsforintravenousdelivery.
target
e regional exchange rate of the liver (250–1000 mL/min) is not as favorable for increased local concentrations as the exchangerateof,forexample,theperitoneum(5–25mL/min) orthearachnoidspace(0.5–5mL/min).Nevertheless,itcanbe assumedto beconstantandtherefore,inaparticularpatient, increasedlocalconcentrationsdepend only onthehighCLTB ofthedrug.
Ontheother hand,whenthetarget tissueistheexclusive routeof elimination foradrug,noincreaseinconcentration canbeachievedifthesamedoseisgivenregionallycompared withsystemically:
R
Decreased systemic exposuretothedrugdependsontheextent ofmetabolismoreliminationofthedrugduringtherst-pass eect.Itimpliesbiotransformationtolessactiveproductsand/ orexcretionby the hepatobiliary system. InthecaseofHAI, thefractionextractedduringtherstpass,alsocalledhepatic extraction ratio, can be estimated from the HA level – HV level/HAlevel.
Hepaticextractionratio=HAlevel–HVlevel/HAlevel
erefore,thedecreasedsystemicconcentrationadvantage forintra-arterialdelivery(R thefractionextractedduringtherstpass:
)dependsontheratioofthetotal
target
target
=
IV
C
target
C
target
systemic
A
CL
=+1
TB
Q
reg
=1
IV
)canbeexpressedintermsof
CI
=
C
target
1,7
patients(P=0.005).Patternsofrecurrencedieredaccording toKRASstatus:thecumulativeincidenceofbonemetastasis was 2% vs. 13.4% (P <0.01), brain metastases2% vs. 14.5% (P = 0.0533), and lungmetastases 33.2% vs. 58% (P < 0.01) for wild-type vs. mutant KRAS patients respectively.48 is researchsupportstheconceptthatthereareindeedmolecular determinantsofmetastaticspread.erefore,itmaybe pos-
Overall selectivity(Rd) summarizes the combined advan- tageofincreasedlocalconcentrationsanddecreasedsystemic exposure:
sibletodevelopmolecularbiomarkerstoidentifyandexclude
R
fromtherapeuticregionalstrategiesthosepatientswithapro­pensityforextrahepaticspread.
==
d
R
R
target
systemic
R
C
C
systemic
C
CC
reg/ IV
target target
reg
systemic
systemic
systemic
//IV
systemic
IA
IV
E
1
−
CL
=1+
TB
1
E
−
60
Chapter7:Intra-arterial infusional chemotherapy
E
1 −
VS
KS
m
(
)
(
)
Whenthetargettissueistheexclusiverouteofeliminationfora drug,noincreaseinlocalconcentrationscanbeachieved,and theadvantageislimitedtodecreasedsystemicexposure.
1
R
=
d
bedescribedusingarithmeticorlogarithmicscaleplots.Inthe naturallogarithmicplot,ifthedistributionphaseisneglected, thedecreaseinconcentrationduringtheterminalelimination phase is near-linear. is implies that a constant fraction of drugdoseremaininginthebodyiseliminatedperunittime (rst-order kinetics). e rate constant for the elimination
Advantageofregionaltherapystandsonlyaslongasthedose rateuseddoesnotsaturateeitherCLTBorhepaticextraction. isisapotentialproblemwithdrugsthatexhibitnon-linear pharmacokinetics. With higher dose rates, the CLTB and thehepaticextractionactuallydiminishandtheadvantage islost.
Drugsthatmustbeactivatedatasiteotherthanthearterial
infusionsitehavenoregionaldeliveryadvantage.
Finally,itshouldbenotedthat,althoughpharmacokinetic parameters may allow a selective increase in hepatic tumor exposure, the crucial target eect of a particular drug (e.g., DNAincorporationofathymidineanalog)mightalsoexhibit non-linearkinetics.Inthiscase,theimpactonwhatactuallyis mostimportant– the drug eect – ratherthantheincreased drugconcentration,mightbelessselectiveathighthanatlow doserates.isistheconceptoftissue-relatedpharmacokinet­icsandtakesintoaccountnotonlysaturatingpharmacokinet­icsinthe tumorbutalso in systemic tissues. If, athigh dose rates,theplateaufortheeectishigherinsystemictissuesthan forthetumoritself,lossofregionalselectivityisobserved.

Pharmacology appendix

49–52
Pharmacokinetics refers to the mathematical analysis of the timecourseofdrugconcentrationsinthebody.Itsimportance liesintheassumptionthatthemagnitudeofapharmacologic eectofagivendrugdependsonitsconcentrationatitssiteof action.erefore,factorsdeterminingdrugconcentrationatits siteofactionsuchasabsorption,distribution,metabolism,and eliminationarewithintheeldofstudyofpharmacokinetics.
Kinetic models are useful for the purpose of the study of pharmacokinetics.ebodyisconceivedasconsistingofsev­eralinterrelatedcompartments.A central compartment con­sisting of extracellular uid space and well-perfused organs (e.g.,liver,kidneys)iscommonlydistinguishedfromaperiph­eral or tissue compartment consisting of poorly perfused organs and tissues (e.g., muscle or fat). Aer a single-dose intravenousinjection of a drug, a two-compartment kinetic modelwilldepictconcentrationsdeclining in two phases: an initialrapid(alpha) distributionphaseandaterminalslower (beta)eliminationphase.ealphaphaseisdominatedbydis­tributionofdrugfromthecentralto theperipheralcompart­mentand terminates when thereis equilibrium betweenthe twocompartments.Formostdrugs,distributionoccursmuch morerapidlythanelimination,andthereforethe distribution term becomes zero aer onlya smallportion of the dose is eliminated.ebetaphaseisdominatedbyeliminationofdrug fromthecentralcompartment.
Eliminationreferstotheremovalofdrugfromthebody. erearetwoprocessesinvolvedin elimination:metabolism (mainly by the liver)and excretion (mainly by the kidneys). e plasma–drug concentrations over time relationships can
phaseKEcanbecalculatedforanydrug.However,ifadrugis giveninadoselargeenoughtoexceedthecapacityofenzyme systems to eliminate a constant proportion of the drug, the resultisthataconstantamountperunitoftimeiseliminated rather than a constant fraction (zero-order kinetics). In this case,therateisindependentoftheconcentration.
Metabolismreferstothedisappearanceofadrugwhenitis
changedchemicallyintoanothercompound,calledmetabolite. Drugmetabolisminvolvesthealterationofthechemicalstruc­ture of thedrug, commonlyby an enzyme. e change gen­erallyinvolvesconversionintoamorepolar formthatcanbe morereadilyexcretedintheurine.Forsomedrugs,metabolism means conversion into an active species. Metabolic reactions arecommonlyclassied as phase I or phase II.Phase I reac­tionsincludeoxidations,reductions,andhydrolyticreactions. Manydrugoxidationreactionsarecatalyzedbythecytochrome P450-dependentmixed-functionoxidasesystem.PhaseIIreac­tionsinvolveconjugationsthattakeplacebycouplingthedrug moleculetoanendogenoussubstituentgroup,sotheresulting productwillhavegreaterwatersolubilityorothermodications thatleadtoenhancedrenalorbiliaryelimination.Conjugation mayoccur withglucuronate,activatedglycine,acetate,sulfate, andother groups.e metabolicrateofreactionisdependent ontherelationofthemaximumrateofreaction(V
),thecon-
max
centrationofthedrug(S)andtheMichaelisconstant.isrela­tionshipisdescribedbytheequation:
rate of reaction=
(
max
)
+
Ofnote,duringzero-orderkinetics,whenenzymesystemsare saturated,V=V
andthereforetheratebecomesconstant.
max
Excretion refers to the removal of a drug from the body
without chemical changes. Elimination occurs primarily by renalmechanismsintotheurine.
Pharmacokinetic parameters summarize the pharma-
cokineticsofadrug,integratinginformationonmetabolism, excretion,and distribution, and expressing themin a stand­ardizedformtoallowcomparisonsbetweendrugs.Important pharmacokinetic parameters include clearance, volume of distribution,bioavailability,andhalf-life.Ultimately,pharma­cokineticparametersofagivendrugareusedtocalculatedos­ingregimens.
Drug clearanceisdenedasthevolumeofbloodclearedof
drugperunittime(e.g.,mL/min)anddescribestheeciency ofeliminationofadrugfromthebody.Totalbodyclearance ofadrugissimplythe sumofclearancesacrosstheorgansof elimination,either bymetabolismorbyexcretion. erefore, totalclearance=renalclearance+hepaticclearance.Clearance relatestherateofeliminationofdrug(mg/min)totheplasma concentrationofdrug(mg/mL)and,therefore,isexpressedas volumeperunittime(mL/min).
61
Section II:Principles of image-guided therapies
rate of elimination of drug (mg/min)
(
)
(
)
=
.
(
)
DR
D


TD
L=
plasma concentratipoon of drug (mg/mL)
Clearance is an independent pharmacokinetic parameter. It does not depend on the volume of distribution, half-life, or bioavailabilityandisconstantforaparticulardruginaspecic patient.e clinicalutilityofclearanceisthecalculationof a maintenancedoserate,accordingtotheformula:
Maintenance dose rate mg/h target concentration mg/L c
At rst-order kinetics, every drug has one only clearance value,independentof the plasmaconcentrationof thatdrug. However, during zero-order process, when the enzyme sys­temsaresaturated,therateofeliminationbecomesconstant. Accordingto the formula, therefore, with a constantrate of eliminationandincreasingplasmaconcentrationsofthedrug, the clearance actually decreases. is concept is relevant to understandwhytheadvantageofregionaltherapyislostdur­ingzero-orderkinetics.Astheadvantageisdirectlydependent onclearanceofdrug,increasingdosesresultinreducedclear­anceand,therefore,reducedadvantage.
Volume of distributionisanindependent pharmacokinetic
parameter that replaces the determination of the actual vol­umeinwhichdrugmoleculesaredistributedwithinthebody, asthiscannotbemeasured.us,theapparentvolumeofdis­tribution(Vd)isdenedastheproportionalityfactorbetween theconcentrationofdruginblood orplasma(mg/L)andthe totalamountofdruginthebody(mg)anditis expressed in volumeunits.
Vdcanbecalculatedfromthetimezeroconcentration(C0)
aerintravenousinjectionandthedose(D):
Co=D/V
eclinicalutilityderivesfromthecomparisonoftheappar­ent Vd with typical body water volumes. Plasma estimated volumeis 3 L, extracellular compartment estimated volume is15L,andtotalbodyestimatedvolumeis45L.Whenadrug bindsextensivelytoplasmaalbumin,Vdapproximatesthenor­malplasma volume.Ifa drug is extensively bound to tissue sitesbutweaklytoplasmaproteins,theVdcanachievevalues as high as 15,000 L or40,000 L. Provided that samplingto determineVdislimitedtoplasma,Vdvaluescangreatlyexceed thetotalbodyvolume.
eadditionalclinicalutilityoftheVdisthecalculationofa
loadingdoseaccordingtotheformula:
× llearance L/h
d
Asadependentpharmacokineticparameter,itsvalueisdirectly proportionaltoVdandinverselyproportionaltoclearance:
t
=(0.693×Vd)/Cl
1/2
e clinical utility of half-life is multiple: calculation of the durationofadrugeect,doseintervals,timerequiredtoelimi­natethedrug,andtimerequiredtoachieve“plateau”concen­trationsduringrepeatedormaintenancedosingwithadrug.
Pharmacodynamics refers to the study of the biological
eect of any drug, including mechanisms of actionatphysi­ological,biochemical,andmolecularlevels.
Concentration–response relationships refer to the quanti-
cationofthe amount of drug necessaryto produce a given response,andareusuallyexpressedasarithmetic orlogarith­miccurves.Concentrationassumesthesteady-statedruglevel achievedduringaconstantinfusion.Whenthedrugisgivenas abolus,thenconcentrationshouldbeinterpretedasthearea undertheconcentration(asopposedto peak concentrations) versustimecurve,orC×T.Additionally,asonerarelyknows theconcentrationofdrugattheactivesite,itisusuallyneces­sarytoworkwithdose–responserelationships.
Receptor theoryexplainstheconceptofreceptorsassitesof
action,aconceptthatiscriticaltounderstandingdose–response curves.Foralmostall drugs, themagnitudeofthe pharmaco­logicaleectdependsonthe concentrationsofbothdrugand receptorsat the target tissue. Itassumes that, at higher drug concentrations,a higher extentofreceptoroccupancyoccurs. Inaddition, the extent of receptoroccupancy determines the extent of pharmacological eect in a manner depicted by an S-shapedcurve.Atthe middle ofthecurve,themagnitudeof responseincreasesinanearlylinear manner withprogressive increasesindrugconcentrationandreceptoroccupancy.Atthe rightextremeofthecurve,wherethemaximaleectisachieved, even large increases in drug concentration result in minor increasesofthepharmacologiceect.esamephenomenon isobservedatthelesideofthecurve,neartheminimal-eect zone,whererelativelylargeincreasesindrugconcentrationpro­duceonlyamodestincreaseinpharmacologiceect.
Occupationofa receptorby a drug isdetermined by the
concentrationofthedrug(D)anditsanityconstant(KD)and itisindependentofthetotalreceptornumber(RT).eanity constantisaxedparameterandrepresentstheconcentration ofdrug at which half of the receptorsareoccupied.Low KD meanshighanityandhighKDmeanslowanity.erefore, theproportionofdrugbound,relativetothemaximumpro­portion that could be bound (fractional occupancy), can be estimatedwiththefollowingformula:
Loadingdose(mg)=Css(mg/L)×Vd(L)
Vdisindependentofclearance,half-life,orbioavailability.
Half-life(t
trationofdrugtodecrease by half. ere areseveralwaysin whicht graphoflogC(t)versustime.Itsvaluecanalsobedetermined fromtheslopeofthelogCpovertimeplot:
1/2
canbedetermined.Itcanbereaddirectlyfromthe
1/2
62
)isdenedasthetimeittakesfortheconcen-
t
=0.693/Kel
1/2

=
R
where:
DR=drug–receptorcomplex RT=totalnumberofreceptors
[DR]/[RT]=fractionaloccupancy [D]=drugconcentration
KD=anityconstant.

+ K
D
Chapter7:Intra-arterial infusional chemotherapy
D

()
TD B
e concept of antagonists is also derived from the receptor theory. Competitive antagonists will compete for the same bindingsiteonagivenreceptor.Whenbothdrugsarepresent and competing, theagonist occupancy is determined by the formula:
DR

=
R
[]
++
DK BK
1 /

14. GrageTB,etal.Resultsofaprospectiverandomizedstudyof hepaticarteryinfusionwith5-uorouracilversusintravenous 5-uorouracilinpatientswithhepaticmetastasesfrom colorectalcancer:aCentralOncologyGroupstudy.Surgery 1979;86(4):550–555.
15. IyerL,RatainMJ.Clinicalpharmacologyofcamptothecins. Cancer Chemother Pharmacol1998;42Suppl:S31–S43.
16. AbigergesD,etal.PhaseIandpharmacologicstudiesofthe camptothecinanalogirinotecanadministeredevery3weeksin
antagonismis surmountable. With two drugs competing for thesamebindingsite,thedrugwiththehigherconcentration relativetoitsanityconstantwilldominate.
Ultimately, it is implicit from the formula that competitive
Otherimportantconceptsderivedfromthereceptortheory includepartialagonists,sparereceptors(signalamplication), receptordesensitization,andsupersensitivity.
cancerpatients.J Clin Oncol1995;13(1):210–221.
17. HerbenVM,etal.PhaseIandpharmacokineticstudyof irinotecanadministeredasalow-dose,continuousintravenous infusionover14daysinpatientswithmalignantsolidtumors. J Clin Oncol1999;17(6):1897–1905.
18. OheY,etal.PhaseIstudyandpharmacokineticsofCPT-11 with5-daycontinuousinfusion.J Natl Cancer Inst1992;84 (12):972–974.

References

1. CollinsJM.Pharmacologicrationaleforregionaldrugdelivery.
J Clin Oncol1984;2(5):498–504.
2. KemenyNE.,etal.Intra-arterialchemotherapyforliver
tumors.InBlumgartLH,ed.Surgery of the Liver, Biliary Tract and Pancreas.Philadelphia,PA:SaundersElsevier,2007; pp.1321–1337.
3. WeissL,etal.Haematogenousmetastaticpatternsincolonic
carcinoma:ananalysisof1541necropsies.J Pathol1986;150 (3):195–203.
4. SigurdsonER,etal.Tumorandliverdruguptakefollowing
hepaticarteryandportalveininfusion.J Clin Oncol1987;5 (11):1836–1840.
5. EnsmingerWD,etal.Aclinical–pharmacologicalevaluation
ofhepaticarterialinfusionsof5-uoro-2′-deoxyuridineand 5-uorouracil.Cancer Res1978;38(11):3784–3792.
6. ArteagaCL,BaselgaJ.Clinicaltrialdesignandend pointsforepidermalgrowthfactorreceptor-targeted therapies:implicationsfordrugdevelopmentandpractice.Clin Cancer Res2003;9(5):1579–1589.
7. EnsmingerWD.Intrahepaticarterialinfusionof chemotherapy:pharmacologicprinciples.Semin Oncol2002;29 (2):119–125.
8. vanLaarJA,etal.Comparisonof5-uoro-2′-deoxyuridine with5-uorouracilandtheirroleinthetreatmentofcolorectal cancer.Eur J Cancer1998;34(3):296–306.
9. ParkJG,etal.Enhancementofuorinatedpyrimidine-induced cytotoxicitybyleucovorininhumancolorectalcarcinomacell lines.J Natl Cancer Inst1988;80(19):1560–1564.
10. RagnhammarP,etal.Asystematicoverviewofchemotherapy
eectsincolorectalcancer.Acta Oncol2001;40 (2–3):282–308.
11. WagnerJG,etal.Steady-statenonlinearpharmacokineticsof 5-uorouracilduringhepaticarterialandintravenousinfusions incancerpatients.Cancer Res1986;46(3):1499–1506.
12. BoublilJL,etal.Continuous5-dayregionalchemotherapyby 5-uorouracilincoloncarcinoma:pharmacokineticevaluation. Br J Cancer1985;52(1):15–20.
13. GoldbergJA,etal.Pharmacokineticsandpharmacodynamics oflocoregional5uorouracil(5FU)inadvancedcolorectalliver metastases.Br J Cancer1988;57(2):186–189.
19. vanRielJM,etal.Continuousadministrationofirinotecanby hepaticarterialinfusion:aphaseIandpharmacokineticstudy. Clin Cancer Res2002;8(2):405–412.
20. vanRielJM,etal.Continuousinfusionofhepaticarterial irinotecaninpretreatedpatientswithcolorectalcancer metastatictotheliver.Ann Oncol2004;15(1):59–63.
21. FiorentiniG,etal.Irinotecanhepaticarterialinfusion chemotherapyforhepaticmetastasesfromcolorectal cancer:resultsofaphaseIclinicalstudy.Tumor i2001;87 (6):388–390.
22. DesoizeB,MadouletC.Particularaspectsofplatinum compoundsusedatpresentincancertreatment.Crit Rev Oncol Hematol2002;42(3):317–325.
23. KweekelDM,GelderblomH,GuchelaarHJ.Pharmacologyof oxaliplatinandtheuseofpharmacogenomicstoindividualize therapy.Cancer Treat Rev2005;31(2):90–105.
24. KornmannM,etal.Oxaliplatinexertspotentinvitro cytotoxicityincolorectalandpancreaticcancercelllinesand livermetastases.Anticancer Res2000;20(5A):3259–3264.
25. RaymondE,etal.Oxaliplatin:areviewofpreclinicaland clinicalstudies.Ann Oncol1998;9(10):1053–1071.
26. RothenbergML,etal.Superiorityofoxaliplatinand uorouracil-leucovorincomparedwitheithertherapyalonein patientswithprogressivecolorectalcanceraeririnotecanand uorouracil–leucovorin:interimresultsofaphaseIIItrial. J Clin Oncol2003;21(11):2059–2069.
27. TournigandC,etal.FOLFIRIfollowedbyFOLFOX6orthe reversesequenceinadvancedcolorectalcancer:arandomized GERCORstudy.J Clin Oncol2004;22(2):229–237.
28. GrahamMA,etal.Clinicalpharmacokineticsofoxaliplatin:a criticalreview.Clin Cancer Res2000;6(4):1205–1218.
29. KernW,etal.PhaseIandpharmacokineticstudyofhepatic arterialinfusionwithoxaliplatinincombinationwithfolinic acidand5-uorouracilinpatientswithhepaticmetastasesfrom colorectalcancer.Ann Oncol2001;12(5):599–603.
30. GuthoI,etal.Hepaticarteryinfusionusingoxaliplatinin combinationwith5-uorouracil,folinicacidandmitomycin C:oxaliplatinpharmacokineticsandfeasibility.Anticancer Res 2003;23(6D):5203–5208.
31. MancusoA,etal.Hepaticarterialcontinuousinfusion(HACI) ofoxaliplatininpatientswithunresectablelivermetastasesfrom colorectalcancer.Anticancer Res2003;23(2C):1917–1922.
63
Section II:Principles of image-guided therapies
32. FiorentiniG,etal.Oxaliplatinhepaticarterialinfusion chemotherapyforhepaticmetastasesfromcolorectal cancer:aphaseI–IIclinicalstudy.Anticancer Res2004;24 (3b):2093–2096.
33. DucreuxM,etal.Hepaticarterialoxaliplatininfusionplus intravenouschemotherapyincolorectalcancerwithinoperable hepaticmetastases:atrialofthegastrointestinalgroupofthe FederationNationaledesCentresdeLutteContreleCancer. J Clin Oncol2005;23(22):4881–4887.
34. LeviF,HebbarM,SmithD,LepèreC,FocanCNJ,etal.Final resultsofrstEuropeanphaseIItrialofintravenouscetuximab (Cet)andhepaticarteryinfusionofirinotecan,5-uorouracil, andoxaliplatininpatients(pts)withunresectableliver metastasesfromwtKRAScolorectalcancer(LM-CRC)aer systemictreatmentfailure(OPTILIV,NCT00852228).In 2013 Gastrointestina Cancers Symposium.2013.SanFrancisco, CA:JournalofClinicalOncology.
35. BouchahdaM,GrimaldiMCE,ChatelutE,Innominato PF,PaintaudG,etal.Chronomodulatedhepaticartery infusion(HAI)ofirinotecan,5-uorouracil(5-FU),and oxaliplatin(l-OHP)plusintravenous(iv)cetuximab(Cet) (Chrono-Optiliv)inpatientswithunresectablelivermetastases fromwtKRAScolorectalcancer(LM-CRC)aertreatment failure(EuropeanphaseIItrialNCT00852228).In2013 ASCO Annual Meeting.2013.Chicago,IL.
36. FiorentiniG,etal.Intra-arterialinfusionofirinotecan-loaded drug-elutingbeads(DEBIRI)versusintravenoustherapy (FOLFIRI)forhepaticmetastasesfromcolorectalcancer:nal resultsofaphaseIIIstudy.Anticancer Res2012;32 (4):1387–1395.
37. SalmanHS,CynamonJ,JagustM,etal.Randomizedphase IItrialofembolizationversuschemoembolizationtherapyin previouslytreatedpatientswithcolorectalcarcinomametastatic totheliver.Clin Colorectal Cancer2002;2(3):173–179.
38. ChenX,etal.Quanticationofirinotecan,SN38,andSN38G inhumanandporcineplasmabyultrahigh-performanceliquid chromatography-tandemmassspectrometryanditsapplication tohepaticchemoembolization.J Pharm Biomed Anal2012; 62:140–148.
39. LuJF,etal.Clinicalpharmacokineticsofbevacizumabin patientswithsolidtumors.Cancer Chemother Pharmacol2008; 62(5):779–786.
40. ChungKY,etal.Cetuximabshowsactivityincolorectalcancer patientswithtumorsthatdonotexpresstheepidermalgrowth
factorreceptorbyimmunohistochemistry.J Clin Oncol2005;23 (9):1803–1810.
41. ScaltritiM,BaselgaJ.eepidermalgrowthfactorreceptor
pathway:amodelfortargetedtherapy.Clin Cancer Res2006;12 (18):5268–5272.
42. BaselgaJ,etal.PhaseIstudiesofanti-epidermalgrowthfactor receptorchimericantibodyC225aloneandincombinationwith cisplatin.J Clin Oncol2000;18(4):904–914.
43. CohenuramM,SaifMW.Panitumumabtherstfullyhuman monoclonalantibody:fromthebenchtotheclinic.Anticancer Drugs2007;18(1):7–15.
44. RowinskyEK,etal.Safety,pharmacokinetics,andactivityof ABX-EGF,afullyhumananti-epidermalgrowthfactorreceptor monoclonalantibodyinpatientswithmetastaticrenalcell cancer.J Clin Oncol2004;22(15):3003–3015.
45. LoboED,HansenRJ,BalthasarJP.Antibody pharmacokineticsandpharmacodynamics.J Pharm Sci2004; 93(11):2645–2668.
46. D’AngelicaMI,etal.PhaseIItrialofhepaticarteryinfusional andsystemicchemotherapyforpatientswithunresectable hepaticmetastasesfromcolorectalcancer:conversionto resectionandlong-termoutcomes.Ann Surg2015;261 (2):353–360.
47. KemenyNE,etal.RandomizedphaseIItrialofadjuvanthepatic arterialinfusionandsystemicchemotherapywithorwithout bevacizumabinpatientswithresectedhepaticmetastasesfrom colorectalcancer.J Clin Oncol2011;29(7):884–889.
48. KemenyNE,etal.KRASmutationinuencesrecurrence patternsinpatientsundergoinghepaticresectionofcolorectal metastases.Cancer2014;120(24):3965–3971.
49. BrodyT.Introductionsanddenitions.InWeckerL,Minneman KP,eds.Brody’s Human Pharmacology,Philadelphia:Elsevier Mosby,2005;pp.3–8.
50. SomogyiA.Clinicalpharmacokineticsandissuesin therapeutics.InWeckerL,MinnemanKP,eds.Brody’s Human Pharmacology.Philadelphia:ElsevierMosby,2005;pp.41–56.
51. HollenbergP.Absortion,distribution,metabolism,and elimination.InWeckerL,MinnemanKP,eds.Brody’s Human Pharmacology.Philadelphia:ElsevierMosby,2005;pp.27–39.
52. MinnemanKP.Receptorsandconcentration–response relationships.InWeckerL,MinnemanKP,eds.Brody’s Human Pharmacology.Philadelphia:ElsevierMosby,2005;pp.9–25.
64
Section II
Chapter
Imaging in interventional oncology:Role of image guidance
8
François Cornelis and Stephen B. Solomon

Introduction

Advancesinmedical imaging havecreatedthe opportunity for minimally invasive, image-guided oncologic care by allowing: (1)procedure planning; (2) device delivery; (3)intraprocedure monitoring;and(4) therapyassessment.Althoughmostcurrent image-guided therapy still utilizes standard diagnostic imaging equipment,interventionaluseofimagingequipmenthasinfact dierentprioritiescomparedwithdiagnosticusesofsuchequip­ment. erefore, interventional procedures prioritize imaging equipmentthat:(1)providesreal-timeimaging;(2)lowersradia­tiondose;and(3)providesgreaterphysicianaccesstothepatient. In contrast to diagnostic imaging, lower image quality is an acceptablecompromiseforreal-timeimagingforinterventional procedures.Patientshavealreadyundergonehigh-qualitydiag­nosticimagingwhentheyarereferredtointerventionaltherapies. Moreover,high-qualitydiagnosticimagingmayrequiremoretime andmoreradiationdosethanfastimagingofarestrictedregion ofinterestasperformedforimageguidanceofinterventions.
Although current imaging systems provide some of the required features for interventional procedures, none pro­vides all of them. Ultrasound (US) is a real-time, multipla­nar technique, but islimited in terms of detectionor tumor visualization. Computed tomography (CT) provides partial accessandcanbeusedtoguideproceduresintermittently,but exposes patients and sta to ionizing radiation.
1,2
 Moreover, CTisprimarilyatwo-dimensional(2D)planartool;real-time, three-dimensional(3D)imagingisnotyetfullyintegratedinto interventional CT applications. Magnetic resonance imaging (MRI)seemstobethemostreliabletechnique,allowinginter­ventionstobeperformedfortumorsthatarevisibleonlywith MRI,suchasincaseofso-tissuetumors,andprovidesther­mal monitoring of ablations, limitedandMRtoolcompatibilityislacking.
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 but access to MRI systemsis
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However,using these techniques, recent intervention-focused improvements havehelpedbroadentheapplicationsofimage-guidedtherapy.
diagnosticimagingstudyavailablemustbeevaluated.Inmany cases,theevaluationrequiresanassortmentofimagingstudies. SomemaybeanatomicstudiessuchascontrastCTorMR,and otherstudiesmaybephysiologicstudiessuchaspositronemis­siontomography(PET) or single-photon emission computed tomography(SPECT). Comparison of all these studieshelps to direct the therapy(Figure 8.1 and Figure 8.2). e imag­ingcomponentofthe patientevaluationpriorto aprocedure includesansweringthefollowingbasicquestions:(1)Isthepro­ceduretechnicallyfeasible?(2)Whatisthebestapproachtothe target?(3)Arethereanyanatomicvariants?and(4)Whatare thepotentialdeleteriouseectstonearbystructures?
Althoughradiationoncologistsemploysophisticatedplan­ningsystemstooptimizetheirprocedures,similarsystemsfor interventionaloncologyarestill in their infancy.One appro­priateexampleofinterventionaloncologyplanningismapping overlappingablationspriortoanablationprocedure.isplan­ningcanhelpensureadequatetumorcoverageandavoidance ofcriticalstructures.Mathematicalmodels havebeenusedto predictnecessaryablationoverlapping.
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Inafeasibilitystudy, robotshavebeen used to implementan overlappingablation plan.11 Other examples of interventional oncology planning using imaging include 3D CT hepaticarteriographyprior to chemoembolization12 and technetium-99m (
99m
Tc) macroag­gregated albumin (MAA) imaging prior to selective intemal radiationtherapy.
Anotheraspectofplanningmayincludesimulationsystems thatallowthephysician tonotjustreviewimagesbut also to workwithinstrumentsinavirtualprocedure.Patient-specic computersimulationscanmodel the ablativezoneusing data obtainedfrompre-andintraoperativeimagingandtreatment parameters.Recently, many institutions have begun applying simulationsowareanddevicestoallowphysicianstheoppor­tunity to “practice” prior to an actual procedure.13 Although mostof these simulation systems are stillnascent,itis likely thattheywillplayanincreasingroleinthefuture.

Imaging for procedure planning

erstcriticalapplicationofimaginginanyimage-guidedpro­cedureor,forthatmatter,anysurgicalprocedureisintheplan­ningphase.Inthisapplication,themostrelevant,high-quality
Interventional Oncology, Second Edition, ed. Jean-François H. Geschwind and Michael C.Soulen. Published by Cambridge University Press. ©Cambridge University Press2016

Imaging for device delivery

To aid in device delivery,the imaging equipment used would ideally provide real-time, 3D information. It also would pro­vide physiologic information indicating areas of contrast
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Section II:Principles of image-guided therapies
AB
AB C
Figure 8.2 Imaging used for planning. (A) Planning software is used to plan
overlapping thermal ablations to fully cover the tumor volume. Each circle represents the theoretical volume of necrosis from a single radiofrequency ablation. (B) Planning software can segment the hepatic arterial tree from a rotational angiographic study. By pointing to the tumor target, the software can identify the feeding branches as depicted in red.
enhancement or areas of metabolic activity. Additionally, it would provide wide access to the patient. Although current imagingtoolsmayprovidesomeofthesefeatures,they gener­allydonotideallyprovideallofthesefeatures.MostCTproce­dures,forinstance,areguidedwithoutcontrastandwithouttrue three-dimensionality.Researcheortsareunderwaytoimprove imagingequipmenttobettermeettheseinterventionalimaging requirements.efollowingareareasofactiveinvestigation.
Advances in real-time imaging
CTuoroscopyprovidesreal-timeCTimagesthatcanguide therapy,14 and it is now widely evaluated for various inter­ventionalprocedures, including the lung,abdominal organs, and the spine. mentinandoutoftheroomduringeachneedle’sincremental
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 It replaces the traditionalphysicianmove-
advancerequiredwithstandardCTinterventionsandallows theinterventionalradiologisttocontinuouslymonitorneedle placement. e downside to this technique is the increased radiationdoseandthelackofthree-dimensionality.Attempts toreduceradiationexposureduringCT uoroscopybylow­eringthe dose applied per section, by implementingangular beammodulationwhichenablesadaptionofthetubecurrent tothecourseofbeamandthepatient’shabitus,andbyprovid­ingarmextendershavebeendemonstrated.
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Ontheotherhand,MRuoroscopyalsoprovidesreal-time imaging without ionizing radiation. Its advantages over CT includetheabilitytofreelyselecttheimagingplanesalongthe needlepathway.20However, physicianaccesstothepatientin highorintermediateeldsystemsisamajorlimitation.
Figure 8.1 Impact of positron emission
tomography–computed tomography (PET-CT) imaging for CT-guided bone biopsy. (A) Axial fluorine-18-desoxyglucose PET-CT fusion image showed uptake (standardized uptake value 10.2) on the right ischial spine (arrow) with high suspicion of metastasis. (B) Axial non-contrast CT scan showed only a slight increase of density in the corresponding region (discontinuous arrow). (C) CT image showing the needle into the lesion. The pathologist concluded it was an epidermoid carcinoma metastasis.
Three-dimensionality
WhileUS,CT,andMRIarestillprimarilyusedin2D,planar mode,eortsareunderwaytomakemoreuseofpotential3D imaging. e ability to rapidly reconstruct 3D images from these2Dviewswillaidimage-guidedtherapy.
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Preliminary worksuggests that 3D imaging is benecial and assists with applicatorplacement.Oneofthelimitationstotheuseof3D imagingisthetimerequiredtocreatetheimagesandpresent themtothephysicianintheproceduresuite.eabilitytorap­idlyreconstruct3D images fromthese 2D views willfurther aidimage-guidedtherapy.
Recent advances in rotational at panel angiography (or cone-beamCT)providethereal-timeimagingofuoroscopy withintermittent,snapshot“CT-like”multiplanarimaging.
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 ProvidingtheCT-likeimagewiththepatientaccesstypicalof uoroscopywill allowmainstayX-ray uoroscopy machines totake on a more powerful role in the interventionaloncol­ogyimagingarmamentarium.Althoughvisualizationofdense structures such as bone and contrast-lled vessels is good, challenges still remain in so-tissue resolution. However, recent advances in the technology of angiographic equip­menthavemadeitfeasibletoconductrotationalangiography with a large-diameter image intensier allowing coverageof the hepatic vessels, and can be applied to chemoemboliza-
15,24,27–30
tion
(Figure8.2). Commerciallyavailablesowarecan be used to segment out thevessels feeding the tumorin 3D angiographyimagesandtherebyprovideaguidefortranscath­etertherapy.Asthesenewmachinesimprove,theymayreduce theneedforCTinmanyinterventionalprocedures.
Contrastagents
Contrastagentsalreadyplayan important role in diagnostic imaging,andnewcontrastagentsarebecomingavailable for allimagingmodalities.Contrastagentsareincreasinglybeing appliedasinteractivetoolsduringintervention.eycanhigh­light the target that is not easily visualized on non-contrast scans.Smallcontrastdosesgivenintermittentlyduringapro­cedure may sometimes be helpful (Figure 8.3). In the case of iodine contrast product, since the use of these agents is dose-limited due to renal toxicity, the volume administered duringaproceduremustbecarefullymonitored.Newfusion systemsthatallow overlayof needles on previouslyacquired enhancedCTimaging maybe able to manage contrastdose.
21
New, blood-pool, iodinated agents that stay in the vascular space for an extended time andthatarehepatocyte-selective
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AB
CD
Figure 8.3 Impact of intraprocedural contrast injection. (A) Enhanced
T1-weighted magnetic resonance sequence showing a right renal tumor (arrow). (B) Unenhanced computed tomography scan showed no lesion. (C) Contrast injection at the parenchymal time identified the lesion during the intervention. (D) The needle was inserted into the lesion.
(such as iodinated triglyceride-dual) may be used during CT-guidedinterventionstodelineatebloodvesselsthroughout theprocedureortoimprovetumorconspicuityinthefuture.
In some cases, US contrast agents can be used.33 Several ultrasonic contrast agents are currently available. ey are composedoftinybubblesofaninjectablegasin asupporting shell. Injected intravenously in a small bolus, they are con­nedtothevascularlumenuntiltheydissolve,thusimprov­ingowdetection.emicrobubbleswill remaininsystemic circulationfora certain period oftimedependingontheUS techniqueused.e diameterofthesemicrobubblesisin the orderofmicrometers,smallerthanredbloodcells.Gas,which composes the microbubbles (peruorocarbon, nitrogen), is eliminatedbythelungsthroughthealveolarbarrierwhilesta­bilizingelements(shells,surfactants)areremovedbytheliver and kidney. Today, the ultrasonic contrast agents have very good general tolerance, equivalent to MRI contrast agents. Microbubblecontrastagentsarenotnephrotoxicandtheinci­denceofallergicreactionsisverylow(1/50,000patients).e injectionscanberepeatedaerashortdelayofafewminutes. ContrastagentshavebeenusedinUStoplan,target,andmon­itorradiofrequencyablations.
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ForMRI, specicagents arebeingdeveloped.38MRIcon­trastagentsthatareaimedatKupercell uptake(superpara­magneticironoxideparticles)andagentsforthehepatobiliary tree(hepatobiliary-specic MR contrast agents) provide new toolsthatcanbeappliedtospeciccases.39Additionally,new thermosensitiveMRcontrastagentscanoeramonitoringtool duringthermal ablationby,forexample,releasingacontrast agentfromaliposomeundercertainthermalconditions.
Chapter8:Imaging in interventional oncology: Role of image guidance
Lastly,advancesinmolecularimagingarelikelytoprovide improvedtargetingopportunitiesthatarespecicandperson­alized.Forexample,new radiotracer-labeledantibodies(such ashuA33and cG250)canspecicallytargetcoloncancers or clearcellrenalcancersandguideinterventions.
43
Image registration andfusion
Image registration is dened as aligning two imaging data sets spatially to each other. Fusion is dened as overlaying them and visualizing them as one image. Image fusion may beperformedtocombinemetabolicimagingwithanatomical imaging(e.g.,uorodeoxyglucose(FDG)PETwithCT)orto combinereal-timeanatomicimagingwithnon-real-timeimag­ingofasecondanatomicimagingmodality(e.g.,USwithCT). WhilemetabolicimagingsuchasPEThashadamajorimpact ononcology,itsroleininterventionhasbeenlimitedbecause itlackstheanatomicdetail requiredforguidance.Asanother option,somehaveadvocatedusingnavigationtoolstofusethe pre-procedurePETCTwithintraprocedureCTforFDG-avid
44,45
40–42
lesions. imagesallowstheutilizationofboththeanatomicdetailofCT orMRIandthephysiologicinformationofPET. ever,has limitations due to dierencesin the position of the patientonthepre-procedurePETCTandtheproceduralCT.
imagestogainthereal-time,non-ionizingradiationinforma­tionofUSwith the exquisite anatomicdetailofa diagnostic CT. examination is shown simultaneously with real-time US are
31,32
commerciallyavailablefromdierentvendorsandhavebeen appliedmainlyforprostatebiopsy.50SimilarfusionofMRwith USand3Drotationaluoroscopywith2Duoroscopyhasalso beenexplored.eadvantageofthismethodisthatstructures thatarediculttooutlineonUSareshownontheCTorMRI images, and yet real-time US imaging can still be utilized.51 ese eorts toward multimodality image fusion may really aidinterventionalists,buttheengineeringdicultiesofimage registrationstill remainactivechallenges.52Patientbreathing, patient positioning, and even procedure/instrument-related motionpresentotherengineeringhurdles.
unenhanced CT to provide better depiction of tumor mar­ginsfortargetingasMRIfeatureshigherso-tissueresolution than CT.53 Fusion has also beenused to overlayuoroscopy withcone-beamCT,CT,orMRItoprovideadditionalguid­anceduringembolizationprocedures.54Multimodalityimage fusion may aid interventional radiologists substantially, but patient breathing, patient positioning, organ shi, and even procedure-/instrument-related motion challenge image reg­istration and fusion. e challenge of multimodality fusion is simplied when both imaging data sets are obtained on thesamepatientbedthroughtheuse ofmultimodalityimag­ingsuites.erefore,initialattemptsatusingimage registra­tionwithpre-procedurePETimages55haveledsometomove to real-time procedures performed directly in the PET CT suite CT/PETorMRanduoroscopy,arebeingusedandoereasier
Fusion,oroverlay, ofPETimageswithCTorMR
46,47
is,how-
FusionhasalsobeenappliedtoUSimagesfusedwithCT
48,49
USsystemsinwhichapreviouslyrecordedCTorMRI
Also, MR images may be fused with intraprocedural,
56–58
(Figure8.4). ese hybrids,combinationsuiteswith
67
Section II:Principles of image-guided therapies
AB
CD
Figure 8.4 Imaging used for
guiding therapy: positron emission tomography–computed tomography (PET-CT)-guided ablation according to the split-dose technique. Fusion of PET and CT can indicate which part of the anatomic changes still contains viable tumor. This can then guide therapy to the incompletely treated tumor. Fusion allows capitalizing on the best features of CT (anatomy) with the best features of PET (physiology). The arrow indicates the fluorodeoxyglucose-avid part of the tumor. (A) Axial non-contrast CT scan showed no lesion into the liver. (B) Fluorine-18-desoxyglucose PET image showed high uptake (arrow) corresponding to a metastasis. (C) PET-CT image showing the probe into the lesion. (D) Corresponding PET-CT fusion intraprocedural image after ablation. No residual uptake was observed.
imageregistrationsincepatientsremainonthesametableand inthesamepositionforbothimagingstudies.However,these hybridunitsarecostly,limitingtheirpracticality.
Navigation
Position sensors attached to medical devices can track the position of tools during a procedure and allow them to be trackedinrealtimewithimagingobtainedduringaprocedure. Trackingdisplaystheneedleorapplicatorlocationinrelation to the pre-procedural-acquired images and the coordinates ofthetool canthenbesuperimposedonpreviouslyacquired imagesorevenreal-timeimages.ereal-timepositioninfor­mation on the CT, for instance, may be a way of providing quasi-real-timeimagingwithoutionizingradiation.Itmayalso allowthephysiologicimagessuchasPETto be incorporated intoan intervention. Additionally,itmay allow out-of-plane trajectory imaging. Navigation has even been reported on cone-beamCTimagestofurtherenableproceduresinuoros­copyrooms.59However,allthesenavigationtoolsfacethesame image registration engineering challenges that image fusion
60–65
does.
erefore,manynavigationdevicesarebeingevalu-
atedwithareal-timeimagingtoolsuchasUS.
Tracking can be accomplished with mechanical arms, with optical systems, or with electromagnetic systems. Electromagnetic tracking allows trackingofinternalmedical devices,whereasopticaltracking requiresdirectline ofsight, whichislessusefulforimage-guidedtherapywhichmayutilize exibleneedles.60 Miniaturizationofelectromagnetic sensors andneedleswithsensorsintegratedinsidethetiphasenabled spatial tracking of needles. Internalized needle-tip sensors
actually track and follow the motionofthe needle itself and donotrelyontheestimationofneedlepositiononthebasisof externalneedlehubposition.iscancorrectforneedlebend­ing,organmotion,andrespiration.
Robotics
For improving needle placement during percutaneous image-guidedproceduresandlimitingdependenceuponphy­sicianexperience,dierentassistantsystemsarenowavailable. Among all of these available methods, the robotic approach oers several incomparable advantages, which explains why robotic-assistedinterventionrepresentsawide eld of inter­estformedicalengineering.66Forsurgicalapplications,robots allow greater precision and accuracy and lack tremor when compared with humans. arenowcommonlyproposed and may improvethestandard of care of patients. achievedwithrobot,withtheresultthatthesurgeondoesnot need to be in thesamelocationasthepatient.71is advan­tageofoperatingremotelymaybeimplementedforinterven­tional radiology in order to limit the radiation exposure to operators during CT- or uoroscopy-guided interventional procedures, proposed.79 ese systems also may improve manual place­mentbyreducingthenumberofneedleadjustments,leadingto betteraccuracy,80aswellasdecreasingtheinteroperatorvari­abilityexpectedbetweenexperiencedandinexperiencedinter­ventionalradiologistsbyreducingmanualdexteritydemand.81 Roboticprecisionmaybehelpfulto ensureoverlappingabla­tionsandsafeprobeseparation.isconcepthasbeenreported
67,68
 Several applications for surgery
69,70
 Telesurgical applications can be also
2,66,72–78
 although MR guidance has been recently
68
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