Patient release

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Chapter6:Radioembolization

Y microspheres that are usedforradioembolization are not metabolized and are registered as devices. Radioactive delivery devices generally use sealed radioactive sources that canbeindividually handledbysta.However,the90Ymicrospheres are only 20–40 µm and must be delivered through suspensioninsalinesolutionor5%dextrosesterilewaterand shouldthereforebe handledbythesametechniquesas those forradiopharmaceuticals.atis,ifthedeliverybecomescompromised,radioactivecontaminationisaconcern.erefore, stepsshouldbetakentopreventthespreadofradioactivecontamination.Forradiopharmaceuticals,an absorbentmaterial withplasticbackingisallthatisrequired.Formicrospheres, contamination prevention is accomplished by using porous material,suchassurgicaltowelsandgauze,totrapthemicrospheres.During resin radioembolization, special careshould be taken when handling any uids, such as blood or urine, fromthepatientduetothepresenceoffree90Y.

e radiation detector used to monitor for contaminationmustbesensitivetobetaradiation,suchasahand-held Geiger-Müller(GM) detector that is not using a beta radiation shield. Most government regulations consider the presenceof185Bqindicativeof contamination.us, very small amountsof material (greaterthan 1/106 of the administered microspheres)leaking fromthedeliverysystem mayproduce a sizable contamination. Following every radioembolization procedure,thestainvolvedintheprocedureroomshouldbe surveyedwithaGMdetector.Contaminationshouldbedecontaminateddowntobackgroundlevels.

transplantation. Although investigators should follow their owninstitutionalguidelinesforelapsedtimefromradioembolizationtotime of surgery ortransplantation,this should be balancedagainstthemedicalneedsofthepatient.Monitoring thepatientsurfacedoserateisatypical methodtodetermine what precautions should be followedat the time of surgery. Generally,ifthepatient’s skinsurfacedoserateis<20µSv/h, special handling of the liver and lungs by the surgeonisnot requiredatthetimeoftheprocedure.atis,leadgloves,specialinstruments,andextremityradiationmonitors(e.g.,ring badge)arenotnecessary.Radiationsafetystashouldbenotiedfortransportationandstorageoftheexplantedspecimen. Institutional experience may vary, but patients treated with radioembolizationtypicallyhavesurfacedoserates<150µSv/h at30daysregardlessofadministeredactivity.

Following surgery (resection or transplantation), the explantedliver should be placed in a formaldehydesolution or alcohol solutionforstoragein a leakproof container. e containershouldberefrigeratedwhileinstorage.Becausethe explantedlivermaycontainradioactivemicrospheres,thecontainershouldbemonitoredwithanenergy-compensatedGM detectororaportableionizationchamber.Ifthedoserateatthe surfaceofthecontainerexceeds50µSv/h,thecontainershould be placed behind lead shielding for decay in storage. While in storage, the explanted liver container should be labeled as radioactive material per local radiation safety guidelines. Institutionsshouldalsofollowgovernmentguidelinesforroom postingofareascontainingradioactivematerialordesignated radiationareas.Oncethecontainerhasdecayedfor60days,the

Patient release

e patient’s tissues usuallyprovide sucient attenuation of thebetaemissionssuchthatpatientscanbereleasedfromthe hospital without special written radiation precautions. However, thereisstillBremsstrahlungradiationproduceddue to beta interaction with the liver tissue (less than 1% of the interactions).Asaresult,typicalsurfaceradiationdose rates perreceivedactivityfrompatientswhoreceivedradioembolizationaverage0.04mSv/h/GBq,butreadingscanrangefrom

0.003to 0.135 mSv/h/GBq, depending on patientbodymass index. Toput this dose ratein perspective, a typical person receives approximately3–6 mSv/year from background ionizingradiation.Aswithotherpatientswhoreceivediagnostic radiopharmaceuticals, patients are advised to avoid contact

surfaceexposureratewillusuallybelessthan5–10µSv/husing a portableionization chamber. At that time, the pathologist mayhandlethe specimen inthe grossing lab using standard universalprecautionsandtechniques.Ifimmediatedeterminationofclearsurgicalmarginsisrequired,thevolumeoftissue handledinanalyzinga frozensectionis minimal and should notposearadiationrisktothesta.Handradiationmonitors canbeworntomonitorthestaexposure.Onceanypathologic analysisiscomplete,alltissuesshouldbeplacedintheoriginal storagecontainerandreturnedtoradioactivematerialstorage. AllareaswheretheliverspecimenwashandledshouldbesurveyedwitharadiationdetectioninstrumentsuchasaGMthin windowdetector.Readingsshouldbelessthanambientbackgroundlevels.

withthegeneralpublicforacoupleofdays.Patientsandtheir familyarealsoadvisedtoinformfuturemedicalprofessionals thatthey have undergonearadioactive procedure. As stated earlier, trace amountsof radioactivity havebeen detected in patienturine aer administration of resin microspheres. For patients who receive resin microsphere radioembolization, instructionshouldincludeushingatoilettwicefor24hours followingtreatment.

Radiation safety considerations for cases involving surgery

erewillbeinstanceswhere a patientundergoingradioembolizationbecomesa surgical candidateforresectionorliver

Radiation safety considerations in case of autopsy, burial, or cremation

NationalCouncilforRadiationProtectionandMeasurements (NCRP)reportno.155,Management of Radionuclide erapy Patients(2006),41providesguidanceregardingburialofpatients withpermanentimplantsonlevelsofradioactivitybelowwhich noprecautionsareneeded.NCRPreportno.161,Management of Persons Contaminated with Radionuclides (2010),42 also gives practical guidance to medical and mortuary personnel, although more in the context of dealing with generally contaminatedsubjects. NCRP reports are generally accepted as appropriateguidanceforuse in the absence ofregulatory

Section II:Principles of image-guided therapies

requirements. International Commission on Radiological Protectionpublication94,Release of Patients aer erapy with Unsealed Radionuclides(2005),43 provides internationalguid- anceonburial,cremation,ortheautopsyofpatientswhohave receivedtherapeuticradionuclides.

If an autopsy must be performed on the corpse, special precautionsmayberequiredifthe activity exceeds thelimits set for cremation.However,microspherebrachytherapywith

Y microspheres usually only involvessignicant quantities intheliver.erefore,anautopsycouldbeperformedwithout thepathologistexceedingthelimitsforradiationexposureto thegeneralpublicifthelivercanbeexcised andsetasidefor radioactivedecay.Ifanautopsyisperformedwithin34daysof treatment,thepathologistmay want totake the conservative approachandremovetheliverandlungspriortoperforming theautopsytoreduceanyextensiveexposure(lessthan1hour).

Forpostmortempatients,therewouldbenoradiationsafety restrictionsonembalmingorburialasitisextremelyunlikely thatembalmersand funeral workers would receive radiation dosesinexcessofthe publicdoselimitof1mSv/year.Inthe USA,acrematoriummayacceptacorpseiftheradioactivityis lessthan74MBqforallradionuclides.43Individualstateregulationsmaypreventcremationbasedon contaminatesintroducedduringthemanufacturingprocess.Foratypicalpatient whowasadministered1.5GBqof90Ymicrospheres,thecorpse mayhavetobestoredifdeathoccurredwithin12daysofthe microsphere brachytherapy treatment. is is a minor considerationthatshould be decided onacase-by-casebasis.As statedabove,the conservative approach would be toremove theliverandlungsforradioactivedecaystorage.

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Chapter6:Radioembolization

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32. SmitsML,NijsenJF,vandenBoschMA,LamMG,VenteMA, HuijbregtsJE,etal.Holmium-166radioembolizationforthe treatmentofpatientswithlivermetastases:designofthephase IHEPARtrial.J Exp Clin Cancer Res2010;29:70.PubMed PMID:20550679.PubmedCentralPMCID:2903532.

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37. DezarnA,CessnaJT,DeWerdLA,FengWZ,GatesVL,Halama J,etal.RecommendationsoftheAmericanAssociationof PhysicistsinMedicineondosimetry,imaging,andquality assuranceproceduresfor(90)Ymicrospherebrachytherapy inthetreatmentofhepaticmalignancies.Med Phys2011; 38:4824–4845.

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Chapter

Principles of intra-arterial infusional chemotherapy in the treatment of liver

Background

erationalefor regionalchemotherapyis to maximize drug concentrationsandtumordruguptakeinthetargetorganand minimizesystemictoxicity.1Forregionaldrugdeliverytosuccessfullyimpact relevantoutcomes,severalimportantprinciplesregardingtumorbiology,drugpharmacology,anddelivery systemsmustbefullled.2emodeloflivermetastasisfrom colorectalcancercomplieswiththeseprinciples,as colorectal cancerhasaregionalpatternofdissemination, with the liver being the only site of metastatic disease for long periods of time in some cases.3 Other salient featuresinclude theselectivesupplyofbloodtolivermetastasesbythe hepatic artery4 andavailabilityofactivedrugswithsuitablepharmacokinetic properties.

therapy will be reviewed. Desirable pharmacokinetic and pharmacodynamic characteristics of drugs considered for evaluation in the hepatic arterial infusion (HAI) model of regional drug delivery will be discussed, using oxuridine (FUDR)asamodel,inthecontextofpatientswithcolorectalliver-onlymetastases(CRLM).Also,anevaluationofthe pharmacologyofcurrentlyapprovedagentsforthetreatment ofmetastaticcoloncancer and their hypotheticalvaluefor regional drug delivery will be performed.Resultsof phase IandphaseIItrialsofHAIwiththesedrugs,ifavailable,will beexplainedintermsofthepreviouslyestablishedpharmacologicrationale.Finally,foractivedrugsnotalreadytested, acriticalanalysiswillbedoneoftheavailablepharmacokineticsdatatodeterminethelikelihoodofsuccessfulincorporationofthesedrugstoHAI-basedtherapeutics.Weprovide anappendixwithbasicpharmacologydenitionstoenhance comprehensionforthereaderwhoisnotfamiliarwiththese concepts.

metastases from colorectalcancer

Fidel David Huitzil Melendez and NancyKemeny

In this chapter, pharmacological concepts of regional

Pharmacologic concepts useful in understanding and evaluating potential advantages of regional delivery for specicdrugs

eultimategoalofregionaltherapyistoimprovethe therapeutic index by increasing ecacy and decreasing systemic toxicity. Hepatic arterial therapy relies on two important assumptions:

1. Regionaldeliveryofthedrugleadstoincreasedlocalconcentrationandthereforeincreasedtherapeuticresponse.

2. Regional delivery ofthedrug leads to decreased systemic exposureandreducedsystemictoxicity.

esuitabilityofanyspecicdrugforregionaltherapycanbe evaluatedbytheextenttowhichitfulllstheseassumptions.

Regional delivery of the drug leads to increased local concentration

AsdescribedbyCollins,1increasedlocalconcentrationdepends ontheratiooftotalbodyclearanceforaparticulardrug(CLTB) to the regionalexchange(Q) for a particular body compartment:CLTB/Q.Inthemodelofhepaticarterydrugdelivery,as the regional exchange rate is constant (100–1,000 mL/min), thelocalconcentrationforaparticulardrugdependsuponits totalbodyclearance.Higher CLTBresultsin higher local concentrations.erefore,therearetwopossiblescenarios:drugs with clearance exhibiting rst-order kinetics even at much higherdosesthanthosenormallyusedforsystemictreatment, anddrugsthatexhibitzero-orderkineticswhenanattemptto increase the dose is made.Only the rst ones will fulll the assumption that regional delivery of the drug will result in increasedlocalconcentrations(Figure7.1).

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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DRUG A

DRUG B

C L E A R A N C E

DOSE

↑ DOSE = ↑ LOCAL CONCENTRATION ↑ DOSE ≠ ↑ LOCAL CONCENTRATION

Figure 7.1 Regional delivery of drug A (ﬁrst-order kinetics, constant clearance

despite the dose) can result in increased local concentrations compared to systemic concentrations. Regional delivery of drug B (zero-order kinetics, clearance decreases after a certain dose level) will not result in increased local concentrations if the dose is administered at high doses, limiting the potential advantage of increased eﬃcacy.

C L E A R A N C E

DOSE

Increased local concentration leads to increased therapeutic response

eparadigmthatincreaseddoseofadrugwillresultinincreased biologiceecthasbeenchallengedbytheavailabilityoftargeted agentsforthetreatmentofcancer.6Mostcytotoxicdrugsacton DNAor tubulin and exhibit a sigmoidal steep dose–response curve, and dose selectionis based onmaximaltolerateddose. However, for targetedtherapies,moreis notnecessarilybetter. Pharmacodynamiceect isthoughttobetheresultofreceptor occupancy and saturation.Optimal target inhibitionoccurs at aspecicdrugconcentration,andincreasingthedosewillnot increasetheeect.Furthermore,atuseful drugconcentrations, themaximumtolerateddosemaynothavebeenreached.Asthis hasbeen recognized, the needfornewstrategiestodenethe clinicallyactivedoselevelforthiskindofdrugsisevident.e traditionalphaseItrial,usefulforcytotoxicdrugdoseselection, doesnotaccomplishthegoalfortargetedagents.Otherparameters,includingpharmacokineticendpointssuchasachievinga predenedtargetplasma levelordirectmeasurementoftarget inhibition,maybemorerelevant.erefore,thepotentialbenet for increased therapeuticresponse through increased local concentrationsisrelevantforcytotoxicdrugs,butmaynotbeas importantfortargetedagents(Figure7.2).

Regional delivery of a drug leads to decreased systemic exposure

Decreasedsystemicexposuretothedrugdependsontheextent ofmetabolismoreliminationofthedrugduringrst-passeect. InthecaseofHAItherapy,thehepaticextractionratiocanbe estimatedfromthe[hepaticarterial(HA)levelofadrug–hepaticvenous(HV)levelofadrug]/HAlevel.Onlydrugs with highhepaticextractionwillpotentiallyresultindecreasedsystemicexposure.Ifhepaticextractionexhibitslinearpharmacokineticsevenat highdoses,thismayallowdoseescalationin thesearchforagreatertherapeuticbenet.However,ifhepatic extraction exhibits non-linear pharmacokinetics, dose escalationwillresultindecreasedhepaticextractionratio,withloss oftheadvantageofdecreasedsystemicexposure.7Additionally,

Chapter7:Intra-arterial infusional chemotherapy

A CYTOTOXIC DRUG B TARGETED AGENT

R E S P 0 N S E

DOSE DOSE

↑ LOCAL CONCENTRATION =

↑ THERAPEUTIC EFFECT

Figure 7.2 For drugs exhibiting a steep dose–response curve, an advantage

in therapeutic eﬀect can be obtained by increasing local concentrations of the drug. For drugs that exert their optimal biological eﬀect at a speciﬁc drug concentration, no advantage in therapeutic eﬀect can be expected by increasing local concentrations.

R E S P 0 N S E

↑ LOCAL CONCENTRATION ≠

↑ THERAPEUTIC EFFECT

forsomedrugs,rst-passmetabolismresultsingenerationof activemetabolites.Nodecreased systemic exposure toactive metabolitescanbeexpectedforthesedrugs(Figure7.3).

Although the potential advantagesof increased local concentrationanddecreasedsystemicexposuredependondierent variablesandarethereforeindependent,thecombinedadvantageofregionaltherapycanbeexpressedwithCollins’formula:

Advantage1

HA flow rate 1

Total body clearance of the drug

−−

fraction of drug extracted across liver

Finally,eectiveregionaldrugdeliveryrequiresotherdrug propertiestobeconsidered,suchasstabilityatbodytemperature,highsolubilityin order to be infusedinsmallvolumes, andcompatibilitywithtitanium,stainlesssteel,siliconerubber, andpolyurethane.

Pharmacological suitability for hepatic arterial infusion of dierent active drugs in colorectalcancer

Floxuridine (5-uoro-2’-deoxyuridine)

Fluoropyrimidinesareactiveincolorectalcancerthroughinhibitionofthymidylatesynthase.8FUDR,aeruptakebyafacilitated diusion transport system, undergoes phosphorylation intothe active nucleotideFdUMPby the enzyme thymidine kinaseattheintracellularlevel.Negativelychargednucleotides cannotleavethecellandaccumulationoftheactivedrugwithin the cell occurs. FdUMP and 5,10-methylen-tetrahydrofolate form a stable ternary complex with thymidylate synthetase, inhibitingthetransformationofdUMPintodTMP,akeystep forde-novopyrimidinesynthesis.

In-vitro studies in multiple humancolorectal cancer cell lineshaveshownthatFUDRismoreeectivethan5-uorouracil (5FU),asshownbyahighratioofthehalfmaximalinhibitory concentration(IC50)of5FUoverFUDRonamolarbasis.e dose–eect curveis sigmoidal and potentiationofFUDRby leucovorinwasmorepronounced.Inaccordancewithcellcycle

Section II:Principles of image-guided therapies

Hepatic artery

Regional delivery of a drug leads to decreased systemic exposure

Hepatic

extraction

Hepatic vein

mucocutaneoustoxicityand diarrhea observedwiththeprolongedinfusionandmoreleucopeniaobservedwiththebolus.

In-vitro studies have shown a sigmoidal dose–response curve to FUDR9 and the pharmacokinetics of FUDR is linearandnotsaturated,even atdoseratesthataregreaterthan usedclinically.5eCLTBforFUDRhasbeenestimatedtobe 15,000–25,000mL/min.ehepaticextractionratioofFUDR rangesfrom0.69to0.92whenthedoseisadministeredintravenouslyasdeterminedby HAlevels– HV levels/HA levels.

However, with HAI, FUDR hepatic extraction is 0.94–0.99.

SystemicFUDRconcentrationsduringHAIswereonly25%of correspondingsystemiclevelswithperipheralvenousadministration(Table7.1).

Notsurprisingly,withthispharmacokineticprole,HAIof FUDRinpatientswithlivermetastasesfromcolorectalcancer hasconsistentlyresultedinhigherresponserateswhen com-

Hepatic artery

Regional delivery of a drug does not lead to decreased systemic exposure

Hepatic extraction

Hepatic vein

pared with systemic administration of eitherFUDR or 5FU. Inrandomized studies comparing HAI to intravenousdelivery ofuoropyrimidines,increased mediansurvivalwasalso observedwithHAItherapy,ifcrossoverwasnotallowed.Using Collins’formula,thecalculatedadvantageforFUDRadminis-

Hepatic artery

(Inactive drug)

Activating

metabolism

Hepatic vein (Active metabolite)

trationbyHAIis1,200-foldintermsofdrugexposurethanby systemicadministration.

5-Fluorouracil

As a uorinated pyrimidine, 5FU has proven activity in colorectal cancer and shares the mechanism of action with FUDR, inhibiting thymidylate synthase through the formation of FdUMP.8 However, the metabolic route is somewhat dierent. e predominant activation step for 5FU is

Regional delivery of inactive drug does not prevent systemic exposure to active metabolite.

Figure 7.3 In the hepatic arterial infusion model, decreased systemic

exposure to an active agent depends on the hepatic extraction ratio for that particular drug. (A) Drugs with high hepatic extraction will result in decreased systemic exposure and potentially less systemic toxicity. If hepatic extraction exhibits linear pharmacokinetics, and the eﬀect is dose-dependent, dose can be increased looking for a combined beneﬁt of increased eﬃcacy and decreased systemic exposure. (B) Drugs with low hepatic extraction will not result in decreased systemic exposure. If the drug exhibits non-linear pharmacokinetics when administered at high doses, the advantage of decreased systemic exposure will decrease as the dose is escalated. (C) If the drug is activated in the liver, decreased systemic exposure to active metabolites cannot be expected.

its phosporibosylation to 5-uoridine-5′-monophospate (FUMP),areactioncatalyzedbytheenzymeorotatephosphoribosyl transferase (OPRT), requiring the phosphate donor 5-phosporibosyl-1-pyrophosphate as a cosubstrate. FUMP is subsequently converted to 5-uorouridine-5′-diphosphate (FUDP) by a pyrimidine nucleoside monophosphate kinase. From here, FUDP can be further converted into 5-uorouridine-5′-triphosphate (FUTP), capable of RNA incorporationand responsiblefor5FUtoxicity. On the other hand,FUDPcanbeconvertedto5-uoro-2′-deoxyuridine-5′- diphosphate (FdUDP) by ribonucleotide reductase and ultimately to 5-uoro-2′-deoxyuridine-5′-monophosphate (FdUMP).Activemetabolites can be converted back to 5FU

specicity,prolongedexposureofhumancell lines to FUDR greatlyenhances growth inhibition. However,when the duration of exposure is prolonged, the inuence of leucovorin modulationisdecreased.

AnimaltumormodelshaveshownthatFUDRyieldsbetter therapeuticecacythan5FUwhen studiedinvariousschedulesandindierentcolontumors.

Early clinical trials comparing systemic FUDR and 5FU showed mixed results in terms of response rates. Overall, they were considered equivalent. A comparison of the mode ofadministrationofFUDRshowedthattherapidintravenous injectionwassuperiortothe24-hourconstantinfusion,with signicantlyhigherresponserates.Adistincttoxicitypattern was observed with each mode of administration,with more

andfree5FUcanbedegradedbydihydropyrimidinedehydrogenase(DPD),thelevelofexpressionofwhichcanaltertoxicity,butnotantitumoractivity.

5FUhasdemonstratedantitumoractivityinvitro,intumor modelsandinclinicaltrials.isantitumoractivityispotentiated by leucovorin. e drug is active in multipledierent schedules, including bolus administration and continuous infusionadministration.5FUhasdemonstratedincreasedsurvivalintheadjuvantsetting.10Inmetastaticdisease,numerous studiesshowincreasedsurvivaloverbestsupportivecare.

Similarto FUDR,invitrostudieshaveshownasigmoidal dose–responsecurve.However,converselytowhatisobserved with FUDR, 5FU doeshave signicant saturable,non-linear pharmacokinetics and therefore, total body clearance and

Chapter7:Intra-arterial infusional chemotherapy

Table 7.1 Comparison of the pharmacokinetic proﬁle of ﬂoxuridine (FUDR) and 5-ﬂuorouracil (5FU) in regard to suitability for regional therapy

5,7,10

Hepatic

(L/min)

FURD 15–25 0.69–0.92 0.95 0.25 Yes 1,200-fold

5FU

20 mg/kg/day as a constant infusion.

270 mg/kg/day short infusion.

CLTB = total body clearance; IV = intravenous; HAI = hepatic arterial infusion.

2 0.8 No 40

0.5 0.1 No 2.2

hepaticextractiondecreaseathighdoserates.11Atadoserate

extraction after IV dose

of 20 mg/kg/day as a continuous infusion, CLTB is approximately2000mL/min.Atadoserateof270mg/kg/day,CLTBis approximately500mL/min.Ithasbeenobservedthatclearance aerintravenousadministrationdependsonthemodeofinfusion.HigherCLTBvaluesrangingfrom5.41to57.9L/minwere observed with continuous venous infusion of 750–1,000 mg over8hours.Hepaticextractionatdoserateof20mg/kg/day asacontinuousinfusionis80%butdecreasesto10%atadose rate of 270 mg/kg/day. Others have estimated an extraction ratio ranging from 0.22 to 0.45 aer peripheral intravenous administrationandahepaticextraction rangingfrom19% to 51%withHAI.5Systemic5FUconcentrationsduringHAIwere only59%ofcorrespondingsystemiclevelswithperipheralvenousadministration.

Ofnote,extractionratiosmayalsodieraccordingtothe modeofadministration.Bolusadministrationof1,000 mgof 5FUviathehepaticarteryresultsin0.11extractionratiowhile a5-dayinfusionof500–900mg/m2/dayresultsin0.93extractionrate.Whentheinfusionrateisincreasedto900–1,500mg/ m2/day,theextractionratiodecreasesto0.44.

Overall,5FUpharmacokineticsisnotassuitableasFUDR pharmacokineticsforHAI.eregionaladvantageofHAIover systemicadministrationof5FUisonlyabouttwo-tosixfold.11 Acomparisonoftheresultantareaundertheplasma5FUconcentrationaerintrahepaticarterialbolusinjectionandintravenousadministrationdidnotshowanydierence.13Results fromarandomizedclinicaltrialcomparingHAIwithsystemic administration of 5FU did not show a signicant dierence intermsofresponserate,timetoprogression,durationofthe response,andsurvivalrate.

Irinotecan

Irinotecan (CPT-11) inhibits DNA synthesis by inhibiting topoisomerase I activity, an enzyme overexpressed in colorectal cancer.15 CPT-11 undergoes sequential metabolism to SN-38bytissueandserumcarboxylesteraseandtoSN-38Gby hepatic uridine diphosphateglucuronosyltransferases.SN-38 is the active metabolite of CPT-11, with 100- to 1,000-fold greaterantitumoractivitythan CPT-11.SN-38Gis the inactive metabolite. SN-38 and SN-38G undergo signicant biliary excretionandenterohepaticcirculation.SN-38G may be deconjugated to form SN-38 by intestinal β-glucuronidase. ecytochrome P450 3A4 (CYP3A4)isalso involved in the metabolismofCPT-11,resultingin theformationofAPC,a

Hepatic extraction after HAI dose

Systemic concentration after HAI/ systemic concentation after IV Linear PK

Advantage of regional therapy

metabolite500-foldlesspotentthanSN-38intermsofantitumoractivity.Finally,CPT-11,SN-38,andSN-38Gcanexistas alactoneform(intactlactonering, active) and as a carboxylateform(openring,inactive).Whenadministeredorally,the molarratioofSN-38areaunderthecurve(AUC)/CPT-11is at least threefold greater than aer intravenous administration,indicatinga higher exposureofSN-38dueto rst-pass metabolism.

CPT-11exhibitsnon-linearpharmacokinetics.e molar ratioofSN-38/CPT-11decreasesathigherdoses,possiblydue tosaturationofconversionofirinotecantoSN-38.emetabolicratioofSN-38/CPT-11hasalsobeenshowntobesignicantlyhigheraera low-dosecontinuousinfusionofCPT-11 thanaerahigh-dose,shortinfusionofCPT-11.Non-linear pharmacokinetics can be explained by the saturation of carboxylesteraseandglucuronidationpathways.

epharmacokineticsofCPT-11has been reportedfora varietyofdosagesandschedules.

As a result of non-linear pharmacokinetics, clearance dependsondoseandmodeofadministration.Doseescalation from100to750mg/m2administeredbytheintravenousroute resulted in approximately 50% reduction in CPT-11 clearance,from26to12L/m2/h.16Formultipledosagesandschedulesusing30–90-minuteintravenousinfusions,the clearance rangesfrom232to352mL/min/m2.eadministrationofa low-dosecontinuousintravenousinfusionover14daysevery 3 weeks at a dose rate ranging from 7.5 to 17.5 mg/m2/day resultedinaclearanceof28.2L/hour.17Asecondstudyof5-day intravenouscontinuousinfusion of CPT-11atdoses ranging from25to40mg/m2/dayresultedin clearanceranging from

47.4 to 101.6 L/hour. is increase in clearance with lower doses administeredas a continuousinfusionis in agreement withnon-linearpharmacokinetics.

Regardinghepaticextraction,noformalstudiesmeasuring levelsatthehepaticveinsandhepaticarteryhavebeendone. efactthathepaticmetabolismofCPT-11resultsinanactive compound makes hepatic extraction of the drug dicult to incorporateintotheassessmentofregionaldeliveryadvantage. e non-linear pharmacokinetics predicts that, with higher doserates,theclearanceofthedrugisactuallydiminished,preventinganyadvantage.Also,therst-passmetabolismresults in an active metabolite. erefore,a high hepatic extraction mayparadoxicallybedeleteriousforanyadvantageofregional therapy, as it results in increased systemic exposure to the activemetabolite.

Section II:Principles of image-guided therapies

Investigatorshavetried to overcomethenon-linearpharmacokineticspitfallbyusingthecontinuousadministrationof CPT-11by HAIat low dosesover5 days. ey also hypothesizedincreasedantitumoralactivityasaresultofanincreased activemetabolitethatisprimarilyactiveintheS-phaseofthe cellcycle.InaphaseItrial,patientswithlivermetastasesfrom solidtumorsreceivedHAIofCPT-11at15–25mg/m2/dayfor 5daysevery3weeksbycontinuousHAI.19Patientsreceivedone cycleofintravenousCPT-11rst.CLTBofCPT-11wassignicantlyhigherwithHAIthanwithintravenousadministration (11.3vs. 8.7 L/h/m2;P = 0.008); themetabolic ratio ([SN-38 total/CPT-11total]× 100)wasincreased withHAIcompared with intravenous administration (16.2 vs. 11.3; P = 0.015). During intravenous administration, the steady-state concentrationsofCPT-11increasedlinearlywiththedose(r=0.536; P=0.032),whereasthesteady-stateconcentrationsofSN-38 didnotsignicantlyincrease withthedose.eoppositewas trueforHAI:thesteady-stateconcentrationofCPT-11didnot increase with the dose, whereas the steady-state concentrationsofSN-38showedasignicantlinearcorrelationwiththe dose(r=0.566;P=0.035).CLTBwasindependentofthedose infused.edose-limitingtoxicitieswerediarrheaandneutropeniaata dose level of25mg/m2/day.Of note,thestudydid notincludeanarmtoevaluatesystemicirinotecancontinuous infusion.Inordertodeterminetheecacyofthisschedulein aphase II trial, 25pretreatedpatientswithcolorectalcancer metastatictotheliverweretreatedwithHAICPT-11at20mg/ m2for5days.20Partialresponseratewas13.6%.Majortoxicities werevomitinganddiarrhea,withoutsignicanthematological toxicity. e authors discussed that systemic distribution of themetaboliteSN38andfailureofentrapmentintothe liver metastaseswereresponsiblefor the lack ofsuperiorityofthe HAIapproach.

Fiorentinietal.21reportedthe resultsofa phaseIstudy evaluating a 30-minute HAI of irinotecan administered every3weeks.Grade4diarrhea,neutropenia,andabdominal pain wereobserved. e maximum tolerated dose was 240mg/m2,andtherecommendeddoseforphaseIIstudies was200 mg/m2every3 weeks.eseresultshardlysupport anadvantageofHAIirinotecangiventhatthesystemicrecommendeddoseforirinotecanevery3weeksis300–350mg/ m2. Nonetheless, 12 patients were treated with irinotecan admisteredviahepaticarterycatheterinaphaseIItrial.e dosewas200mg/m2ina30-minuteinfusionevery3weeks. Four partial responses were observed. Despite regional administration,systemictoxicitywasreported:vepatients experienced grade 2diarrhea and six patientshadgrade 2 myelosuppression.

Oxaliplatin

Oxaliplatin is a platinum analog with antitumoral activityinadvancedcolorectalcancer.Itwasrstsynthesizedin Japan as a diaminociclohexane (DACH) oxalatoplatinum compound.

Oxaliplatin is a prodrug that is activated by conversion to monochloro, dichloro, and diaquo compounds by non-enzymatic hydrolysis, resulting in displacement of the

oxalategroup.eaquated derivativesofoxaliplatinareconsideredtobethebiologicallyactivespecies,capableofadduct formationwithvarioussuldeandaminogroups.

ecytotoxicactivityofoxaliplatinisinitiatedbyformation of a DNA adduct between the aquatedoxaliplatinderivative anda DNAbase.Initially,onlymonoadductsareformed,but eventuallyoxaliplatinattachessimultaneouslytotwodierent nucleotidebases,resultinginDNAintrastrandcross-links.e modicationofthethree-dimensionalstructureofDNAwill resultininhibitionofDNApolymerization.Ontheotherhand, aerDNAadductformation,tumorcellswillactivatecellular repair mechanism. ese mechanisms involveenzymes containing several amino and sulfur groups. Oxaliplatin can be covalently bound to these repair enzymes and can therefore impairtheirfunction. Ultimately,thecombinationof inhibitionofDNApolymerizationandinhibitionofDNArepairwill resultinsubstantialDNAdamage,activationofapoptoticpathways,andcelldeath.Cellulardetoxicationprocessescompeting with DNA adduct formation include conjugation of the aquatedcompoundto glutathione, methionine,andcysteine. e conjugatedproductsaresubsequentlyexcreted from the cellandeliminatedfromthebody.Inaddition,aera 2-hour infusion of oxaliplatin,70% of the drug is bound to plasma proteins(mostlyalbumin),therebylosingitsantitumorpotentialand,5daysaerasingleinfusion,thisfractionincreasesto about95%.

Preclinicalevidencesuggestsasteepdose–responsecurveto oxaliplatininhumancoloncarcinomacells.Freshlyexplanted tumorspecimensfrompatientswithisolatedliver metastasis fromcolorectaloriginwereexposedto0.1,1,10,and100µg/ mLofoxaliplatinfor2hours.Alltumorspecimensshowedsignicantconcentration–responseeects.

e clinical activity of oxaliplatin in advanced colorectal cancerhasbeendemonstratedinseveralsettings.25Asasingle agent,theobjectiveresponserate to oxaliplatinis20–24%in untreatedpatientsand 10% in 5FU-pretreatedpatients.With oxaliplatinin combinationwith 5FU, the objective response rate is 51% in untreatedpatients. In patientswith advanced colorectalcancerrefractoryto 5FU,thecombinationof5FU/ leucovorin(LV)/oxaliplatinyields a responserateof 21–25%. Aertumorprogressionon5FU/LV/CPT-11,theresponserate is9.9%or15%.

26,27

Regarding pharmacokinetics, discrimination between boundandfreeplatinuminbloodandplasmausuallyoccurs. Ultralterableplatinum(comprisingnon-protein-bounddrug and biotransformationproductsin plasma water)is thought torepresentalltheplatinumspecieswithantitumorandtoxic properties in the circulation. erefore, plasma ultraltrate representsthe most relevant matrix when considering pharmacologicalactivity.

e PKs of platinum in ultraltrate are triexponential, characterized by short initial α and β distribution phases (0.28 and 16.3hours, respectively) followedby a long terminalγphase(273hours).eshortinitialαandβphases likelyrepresenttherapidclearanceofintactoxaliplatinand the reactive dichloro-, monochloro-, and diaquo-DACH platin intermediates into tissues and/or removal from the

Chapter7:Intra-arterial infusional chemotherapy

Table 7.2 Comparison of pharmacologic characteristics of chemotherapy agents active in colon cancer in regard to suitability for regional therapy

Floxuridine 5-Fluorouracil Irinotecan Oxaliplatin

Active in colon cancer + + + +

Steep dose–response curve + + + +

Linear pharmacokinetics + – – –

High clearance + – – –

Hepatic extraction +++ + –* +

systematiccirculationviaglomerularltration.elongterminalhalf-lifeofunboundplatinumin plasma ultraltrate probablyreects the slow release of low-molecular-weight platinumconjugates.Given thattheplatinumintheterminal elimination phase comprises almost entirely inactive platinumconjugates,αandβphasesrepresenttheclinically relevantt½valuesofactiveplatinum.No accumulationhas beenobservedinplasmaultraltrateaer130mg/m2every 3weeksor85mg/m2every2weeks.

e clearance of ultraltrable platinum decreases from

18.5±4.71L/h at85 mg/m2every 2 weeks to 9.34 ± 2.85 to

10.1±3.07L/hat130mg/m2every3weeks.Oxaliplatinappears tobeclearedequallybytissuedistributionandglomerularltration.Noformalstudyofhepaticextractionofoxaliplatinhas beenconducted.

HAIofoxaliplatinhasbeentestedinphaseIandphaseII

trials.

AninitialphaseIstudybyKernetal.29on21patientswith isolatedhepaticmetastases from colorectal cancerreporteda maximumtolerateddoseof150mg/m2every3weeksincombinationwithfolinicacid200mg/m2and5FU600mg/m2for5 consecutivedays.edose-limitingtoxicityconsistedofleucopenia,obliterationofthehepaticartery,andacutepancreatitis. Overall,toxicityconsistedofnausea/vomiting(16of21),anemia(16of21),upperabdominalpain(15of21),sensoryneuropathy(10of21),diarrhea(9of21),andthrombocytopenia(9 of21).However,severetoxicitymainlyconsistedofleucopenia (4of21),thrombocytopenia(2 of 21),hyperbilirubinemia(2 of21),pain(2of21),anddiarrhea(1of21).Responseratewas 59%inthesechemotherapy-naïvepatients.erecommended doseforphaseIIstudieswas125mg/m2.

In a subsequent phase II study by Gutho et al.,30 5 patients with isolated non-resectable colorectal liver metastases received HAI treatment with oxaliplatin at 130 mg/ m2onday1, incombinationwith 5FU (480mg/m2)andLV

allowing accurate evaluation of the toxicity prole. Severe abdominalpainwasobservedin30%ofthepatientsandwas thedose-limitingtoxicity. Four outof17patientsdeveloped hepatictoxicity,denedbyelevationofserumbilirubinand/ or alkaline phosphatase morethan twice the baseline level. Grade3toxicitiesincludedasthenia (1 of 17) and nausea (1 of17). Catheterandhepaticarterythrombosiswasobserved in1patientasanimmediatecomplicationand,asasecondary complication,arterialthrombosiswasobservedin7patients, leading to denitive interruption of HAI chemotherapy. Responseratewas46%.

Fiorentinietal.32reportedon12patientswhohadevidence ofprogressionofdiseaseonpreviousregimensandwhowere treated with HAI oxaliplatin every 3 weeks. Dose-limiting toxicityconsistedofobliterationofhepatic artery,abdominal pain,andseverehypotensionandwasobservedat175mg/m2. erefore,the recommended dose was 150 mg/m2. Ducreux etal.33treated28patientswhowerechemotherapy-naïvewith HAIoxaliplatinat100mg/m2combinedwithintravenousFU/ LV.Responseratewas64%.Neurotoxicitywasobservedin69% ofpatients.Only1patientexperiencedgrade3neurotoxicity. eauthorsstatedthatperhapsHAIoxaliplatinmaydecrease theappearanceofneuropathy.

Overall, the pharmacokinetics prole of FUDR is not sharedbyanyotheractivecytotoxicdrugincolorectalcancer.If oxaliplatinhepaticextractionisconrmedinstudiesnotusing historicalcontrols,oxaliplatinadministrationbyHAImaybe ofsomevalueintermsofreducedneuropathy.However,given thelackoflinearpharmacokinetics,no increaseinlocalconcentrationsoractivitycanbeexpected(Table7.2).Populations suitableforresearchincludepatientswithliver-onlymetastases fromcolorectalcancerwhohaveshownresponseonsystemic oxaliplatin,butcannottolerate further treatmentsas aresult ofneuropathy.PhaseIIcomparativetrialsareneededtobetter denetherealadvantageofHAIofoxaliplatin.

(140 mg/m2) fromday 1 to 5 and mitomycin C (7 mg/m2) on day 5 every35 days.A liver extraction ratio of 0.47 for oxaliplatinwasdeterminedbycomparingtheareaunderthe plasma–concentrationcurve (AUC)values in venous blood observed in the presentstudy aer administration of oxaliplatinviaHAItotheAUCvaluesobtainedaerintravenous administrationof oxaliplatininhistoricalcontrols.Mancuso etal.31reportedon17patientswithpretreatedmetastaticcolorectal cancer to the liver.Oxaliplatin20mg/m2/daybyhepaticarterialcontinuousinfusionfor5daysevery3weekswas givenasasingleagent,asopposedtopriorstudies,therefore

Hepatic artery combination chemotherapy administration

European investigators reported the results of the so-called OPTILIV study,34 a phase II trial of intravenous cetuximab andHAIofirinotecan,5FU,andoxaliplatinin64patientswith unresectablelivermetastasesfromwild-typeKRAScolorectal canceraersystemictreatmentfailure.etreatmentregimen involved biweekly administration of intravenous cetuximab at 500 mg/m2 and HAI of irinotecan at 180 mg/m2, 5FU at

Section II:Principles of image-guided therapies

2,800mg/m2,andoxaliplatinat85mg/m2.emediannumber of liver metastases was 10. e response rate was 46%. Resectionratewas28%.Medianprogression-freesurvivalwas

8.7monthsand overall survival was 25.7 months.Grade3–4 toxicitiesincludedneutropenia(40%),abdominalpain(26%), fatigue (18%), and diarrhea (16%). Plasma PK revealed the expectedcetuximablevelsandarelevantsystemicexposureto theHAIdrugs,withmediantrapezoidalAUCsof12.4μg*mn/ mL (2.6–38.5) for SN-38, 142 μg*mn/mL (96–434) for 5FU and100μg*mn/mL(37–189)forfreel-OHP.Asignicantcorrelationwas found between free l-OHP AUCandabdominal pain(P=0.016)andbetweenSN38AUCandbothneutropenia (P=0.018)andresponse(P=0.028).

As discussed previously,5FU, irinotecan, and oxaliplatin arenotoptimaldrugsforHAadministration.isisconrmed by OPTILIV, as PK results reveal signicant systemic exposureand systemictoxicityof theregimen,suggestingnegligible regional delivery advantage.Apparently, the same results couldhavebeenobtainedwithsystemicadministrationofthe four-drugregimen.

2. Asdiscussedpreviously,thereisnopharmacokineticrationale to support hepatic artery administration of irinotecan over systemic administration. Furthermore, results ofexistingphase I studieshaveconrmedthatirinotecan hepaticarteryadministrationresultsinsystemictoxicityat usual systemic dosing levels, neglecting regional delivery advantage.

3. e pharmacokinetics of irinotecan and its metabolites aerchemoembolizationwithDEBIRIhasnotbeenfully described.38 At most, plasma concentration–time curves havebeen generated. Important pharmacokinetic parametersrelevanttoregionaladvantage,suchasclearanceand hepaticextraction,areunknown.Tumordrugconcentrationsaer DEBIRI or systemic irinotecan administration havenotbeen measured. Ultimately, clinical comparative studieswithpharmacokineticdataarenotavailable.

4. e authors do not explain how 200 mg of irinotecan administered twice achieves 13-month extrahepatic progression-freesurvivalin pretreatedpatients.isprogression-freesurvivalis notreportedevenforpatientstreated withfullcombinationsystemicchemotherapyandbiolog-

Hepatic intra-arterial infusion of irinotecan-loaded drug-eluting beads (DEBIRI)

icsintherst-linesetting.

We recommend cautious interpretation of these data. Conrmation and more pharmacologically comprehensive studiesareneeded.

Recently, an alternative approach to HAI chemotherapyhas reportedpositiveclinicaloutcomesinpatientswithliver-only metastases from colorectal cancer treated with regional therapies: chemoembolization with irinotecan-preloaded drug-eluting beads (DEBIRI). e premise is that the combinationofthe ischemic eect with thelocal delivery of the chemotherapeuticagentresultsinsynergisticantitumoractivity. Chemoembolization with DEBIRI showed responses in patients with liver metastases from colorectal cancer in a phaseIIstudyandtheresultsof a phase III study havebeen reported.Inthisprospectivemulti-institutionaltrialconducted inItaly,74patientswithlivermetastasesfromcolorectalcancerwererandomized tochemoembolizationwith DEBIRIvs. systemic5FU/LVandirinotecan(FOLFIRIregimen).DEBIRI was given twice at 200 mg once a month. All patients had receivedatleasttwolines ofchemotherapy,apparentlyexclusiveofoxaliplatinandbiologictherapy.eprimaryendpoint wassurvival: 2-yearsurvival was 56% fortheDEBIRI group and32%fortheFOLFIRIgroup(P=0.031,logrank).Median survivalwas22 and15months,medianprogression-freesurvivalwas7and4months,timetohepaticprogression was 7 and4months,andtimetoextrahepaticprogressionwas13and 9monthsforDEBIRIandFOLFIRI.

Severalobservationsarewarrantedtoputtheresultsofthis

studyincontext:

1. Ofnote,dierentfromhepatocellularcarcinoma,inpatients withlivermetastasisfromcolorectalcancer,arandomized phaseIIstudythatcomparedembolizationwith5FU-based chemoembolizationfailedtoshowincreasedresponserates orsurvivalofthecombinedapproach.37Toourknowledge, nocomparativestudyhasdemonstratedtheaddedvalueof DEBIRItoblandembolization.

Therapeutic monoclonal antibodies

Antibodiesagainstepidermalgrowthfactorreceptor (EGFR) (cetuximab and panitumumab) and vascular endothelial growthfactor(VEGF)(bevacizumab)havebeenproventobe usefulinmetastaticcolorectalcancer.

Bevacizumabisahumanizedmonoclonalantibodyagainst VEGF, an important regulator of physiologic and pathologic angiogenesis. Regarding pharmacokinetics, one study evaluateda total of 4,629bevacizumab concentrationsfrom 491 patients with solid tumors, who received bevacizumab dosesrangingfrom1to20mg/kgatadosingfrequencyrangingfromweeklytoevery3weeks.Estimatedclearance(CL) and central compartment volume of distribution (Vc) were

0.207L/dayand2.39L foratypical female,respectively.e terminalhalf-lifeestimatewasapproximately20daysforboth menandwomen.Patientswithlowserumalbuminandhigh serumalkalinephosphatasehad19and23%fasterCL,respectively,thana typical patient.Consistentwith the longeliminationhalf-life,simulationsshowedthatsimilarsteady-state exposures can be maintained when the weekly mg/kg dose rateismaintained,thereforeallowingadministrationofbevacizumabtocoincidewiththefrequencyofadministrationof thecytotoxicagents.

CetuximabisachimericimmunoglobulinG1(IgG1)monoclonalantibodythat bindstoEGFRwithhigh specicity and with a higher anity than either epidermal growth factor (EGF) or tumor growth factor-alpha (TGF-α),40 thus blockingligand-inducedphosphorylationofEGFR,theinitialstep ofacascadeofintracellulareventsrelatedtotumorcellproliferation.41PhaseItrials42withescalatingweeklydosesofC225

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