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Chapter5:Tumor embolotherapy and chemoembolization
A
A
B
B
Figure 5.6 Preparation of a mixture of Lipiodol and doxorubicin. (A) Pumping
method used to mix Lipiodol and doxorubicin with two syringes connected via a three-way stopcock. (B) Light photomicrograph shows the formation of oil-in-water-type emulsion with variable-sized (10–50 μm) water droplets containing doxorubicin hydrochloride in the oil base.
Figure 5.7 Basic concept and ideal endpoint of subsegmental Lipiodol
chemoembolization. (A) The diagram illustrates the exclusive arterial supply for encapsulated nodular hepatocellular carcinoma (HCC) and mixed arterial and portal venous supply for the portion of extracapsular invasion and small HCC without capsule formation. (B) After injection of sufficient amount of a mixture of Lipiodol and anticancer drug through a tumor-feeding artery, the tumor neovasculature and the peripheral portal veins around the tumor are filled with
oftheemulsioncanbemoreenhancedbyadjustingthespecic gravity of the contrast medium dissolving chemotherapeutic drugsclosetothespecicgravityofLipiodol.
35
Subsegmental chemoembolization
ebloodsupplyoflivertumorsisdependentontheirdevel­opmentalstages and growth patterns. Whereas encapsulated nodular HCCs are totally supplied by the hepatic artery, well-dierentiated or early HCCs, small nodular tumors (i.e., daughter nodules), intrahepatic metastases, and the extracapsular inltrating edges of advanced HCCs are sup­pliedbyboththeportalveinandthe hepatic artery.
36,37
Even in advanced-stage disease, most liver metastases have a dis­tinct portal blood supply to the tumor periphery.
38,39
 ese tumors with portal blood supply may therefore be resistant tointra-arterialembolotherapy,whichiswhyitis important tosimultaneouslychemoembolize hepaticarterialandportal venoussupplies.Ifa sucientamountofLipiodol-anticancer drugemulsionisinjectedtothetumor-feedingartery,Lipiodol carrying an anticancer drug accumulates not only in the
the emulsion. Subsequent hepatic artery embolization (arrows) may result in the effect of combined arterial and portal blockage, and tumor fraction with mixed arterial and portal venous supply can be treated effectively by the combined effect of high-dose chemotherapy and ischemia.
tumor vessels but also in the peripheral portal veins sur­roundingthetumorthrougharterioportalcommunicationsor tumor-drainingveins.Subsequentparticulateembolizationof tumor-feedingarterycancausethecompletedevascularization ofthetumor.isis the basicconcept and ideal endpointof subsegmental or ultraselective Lipiodol chemoembolization forsmallhepatictumors40(Figure5.7).
Drug-eluting bead TACE (DEB-TACE)
Another recent strategy for improving the pharmacokinetic proleandtherapeuticeectofTACEistheuseofdrug-eluting beads (DEBs).41 DEBs are biocompatible, non-resorbable PVA-based microspheres that can be loaded with various chemotherapeutic agents42(Figure 5.8). e loaded beads can occlude the feeding vessels of the tumor, while the
39
Section II:Principles of image-guided therapies
AB C
Figure 5.8 DC Bead spheres. (A) A bottle
of DC Bead spheres (doxorubicin-capable beads, Biocompatible, UK) of 100–300-mm size. (B) A bottle containing DC Beads after mixing with doxorubicin solution for 1 hour. (C) Microscopic view of DC Beads of 100–300 mm. (D) Microscopic view of red-tinged
D
DC Beads containing doxorubicin after soaking in drug solution.
chemotherapeuticagent is released in a slow and controlled manner,achievingahigherandmoresustainedreleaseofdrug directlyintothetumorandalowreleaseofdrugintothesys­temiccirculationtoreducesystemictoxicity.
Currently, two types of microsphere are clinically avail­able: the DC Bead microspheres (Biocompatibles, Farhan, UK) and superabsorbent polymer-based HepaSphere/ QuadraSphere microspheres (Merit Medical, South Jordan, UT).eDEBsrangeinsizefrom100to900μm,andsmaller beaddiametersachieveamoredistalembolizationandamore extensivenecrosisascomparedwithlargerbeads.43Preclinical andclinicalstudieshavedemonstratedthatDEB-TACEresults inhighertumorconcentrationsandlowersystemicconcentra­tions of doxorubicin compared to conventional TACE. Ina multicenter,randomized,prospectivephaseIIstudy,sig­nicantreductions in livertoxicityand drug-related adverse eventswere shown for DEB-TACEover conventional TACE. Irinotecan DEBs administered in TACE have also been reportedtobeactiveandsafeinpatientswithlivermetastases fromcolorectalcancer.
47
eweakpointofconventionalTACEisthattherehasbeen a wide variability in the choice of chemotherapeutic agents, dosage,embolizingagents,andproceduraltechniques.Because ofthis substantial heterogeneity of TACEprotocols, conven­tionalTACEhasbeencriticizedasanon-standardizedmethod and surrounded by substantial controversy in the treatment ofHCC.However,DEB-TACEprovidesarelativelystandard­izedprotocol,aswellaslevelsofconsistencyandrepeatability thatarenotavailablewithconventionalTACE,andoersthe opportunity to implement a standardized approach to HCC treatment.
46
42,44–46
Superselective catheterization and C-armCT
DuringTACE,asuperselective(i.e.,segmentalorsubsegmen­tal)approachisrecommendedwheneverpossible.Recenttech­nological advances in C-arm CT and microcatheter systems haveimprovedthetechnical success ratesforthesuperselec­tiveor ultraselectivecatheterizationoftumor-feedingarteries (Figure5.9).Microcathetersareavailableinvariablesizes,from thelargerbore (outerdiameter3F) tovery small bore(2For lower).Amicrocathetershouldbenavigatedtoanappropriate position,withembolizationperformedasselectivelyaspossi­bletoavoidthenecrosisofnon-targetliverparenchyma.
C-arm CT is a recent technical breakthrough in digital
subtraction angiography systems that makes it possible to
obtain multiplanar CT-like images and three-dimensional volume-rendered or maximum-intensity-projection images fromasinglerotationalacquisition.48C-armCTcanprovide valuableinformationabout the arterial supplyto tumors not visible on conventional angiography, and about the blood supplyoftumorslocatedindicultareassuchasthecaudate lobe.49Itcanalso allowoperatorstoidentifyandcharacterize tumorsthat are not clearly characterized on angiographyor cross-sectionalimaging,48aswell astodierentiatepseudole­sions(e.g.,arterioportalshunts)fromtumors.50C-armCTis also helpful for detecting extrahepatic supply and avoiding chemotherapeutic delivery to the extrahepatic arteries that supply other organs. Several studies have demonstrated the usefulnessofC-armCTduringchemoembolization,inthatit providesadditionalinformationthatisnotavailableinconven­tionalangiographyimages andincreasesoperatorcondence incatheterpositioning.
48
40
A CB
D
Chapter5:Tumor embolotherapy and chemoembolization
FE
G
Figure 5.9 A case of superselective chemoembolization for multinodular hepatocellular carcinoma using C-arm computed tomography (CT). (A) Celiac
arteriogram shows multiple hypervascular tumors in the liver. (B) Maximum-intensity projection image obtained by C-arm CT shows all hypervascular tumors with their feeding arteries. (C, D) Superselective chemoembolization was performed using 2F-tip microcatheter under the guidance of C-arm CT. (E) Postchemoembolization spot image shows compact Lipiodol uptake within the tumors and their surrounding portal veins. (F, G) Non-contrast CT images obtained on the same day after chemoembolization show subsegmental distribution of Lipiodol uptake, along with compact Lipiodol uptake within the tumors (arrows) and surrounding portal veins.

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Section II:Principles of image-guided therapies
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31. NakajoM,KobayashiH,ShimabukuroK,etal.Biodistribution andinvivokineticsofiodine-131Lipiodolinfusedviathe hepaticarteryofpatientswithhepaticcancer.J Nucl Med1988; 29:1066–1077.
32. KanZ,SatoM,IvancevK,etal.Distributionandeect ofiodizedpoppyseedoilintheliveraerhepaticartery embolization:experimentalstudyinseveralanimalspecies. Radiology1993;186:861–866.
33. RaoulJL,HeresbachD,BretagneJF,etal.Chemoembolization ofhepatocellularcarcinomas:astudyofthebiodistribution andpharmacokineticsofdoxorubicin.Cancer1992; 70:585–590.
34. NakamuraH,HashimotoT,OiH,etal.Transcatheteroily chemoembolizationofhepatocellularcarcinoma.Radiology 1989;170:783–786.
35. SakaguchiH,UchidaH,NishimuraY,etal.Pharmacokinetic studyofAdriamycinintheemulsionmixedwithLipiodol– dierenceresultingfromcompositionandmethodsof preparation,andbehavioraermesentericarterialinjectionin rat.Gan To Kagaku Ryoho1991;18:1349–1355.
36. GosekiN,NosakaT,EndoM,etal.Nourishmentof hepatocellularcarcinomacellsthroughtheportalbloodow withandwithouttranscatheterarterialembolization.Cancer 1995;76:736–742.
37. WakasaK,SakuraiM,KurodaC,etal.Eectoftranscatheter arterialembolizationontheboundaryarchitectureof hepatocellularcarcinoma.Cancer1990;65:913–919.
38. StrohmeyerT,HaugebergG,LierseW.Angioarchitecture andbloodsupplyofmicro-andmacrometastasesinhuman livers.Ananatomic–pathologicalinvestigationusinginjection techniques.J Hepatol1987;4:181–189.
39. TaniguchiH,DaidohT,ShioakiY,etal.Bloodsupplyand drugdeliverytoprimaryandsecondaryhumanlivercancers studiedwithinvivobromodeoxyuridinelabeling.Cancer1993; 71:50–55.
40. MiyayamaS,MatsuiO,YamashiroM,etal.Ultraselective transcatheterarterialchemoembolizationwith a2-ftipmicrocatheterforsmallhepatocellular carcinomas:relationshipbetweenlocaltumorrecurrenceand visualizationoftheportalveinwithiodizedoil.J Vasc Interv Radiol2007;18:365–376.
41. MoriseZ,SugiokaA,KatoR,etal.Transarterial chemoembolizationwithdegradablestarchmicrospheres, irinotecan,andmitomycin-Cinpatientswithlivermetastases.J Gastrointest Surg2006;10:249–258.
42. VarelaM,RealMI,BurrelM,etal.Chemoembolizationof hepatocellularcarcinomawithdrugelutingbeads:ecacyand doxorubicinpharmacokinetics.J Hepatol2007;46:474–481.
43. GonzalezMV,TangY,PhillipsGJ,etal.Doxorubicin elutingbeads-2:methodsforevaluatingdrugelutionand in-vitro:in-vivocorrelation.J Mater Sci Mater Med2008; 19:767–775.
42
Chapter5:Tumor embolotherapy and chemoembolization
44. LewisAL,TaylorRR,HallB,etal.Pharmacokineticand safetystudyofdoxorubicin-elutingbeadsinaporcinemodel ofhepaticarterialembolization.J Vasc Interv Radiol2006; 17:1335–1343.
45. PoonRT,TsoWK,PangRW,etal.AphaseI/IItrialof chemoembolizationforhepatocellularcarcinomausinganovel intra-arterialdrug-elutingbead.Clin Gastroenterol Hepatol 2007;5:1100–1108.
46. LencioniR,deBaereT,BurrelM,etal.Transcathetertreatment ofhepatocellularcarcinomawithdoxorubicin-loadedDCbead
48. TognoliniA,LouieJ,HwangG,etal.C-armcomputed
tomographyforhepaticinterventions:apracticalguide.J Vasc Interv Radiol2010;21:1817–1823.
49. WallaceMJ,MurthyR,KamatPP,etal.ImpactofC-armCTon
hepaticarterialinterventionsforhepaticmalignancies.J Vasc Interv Radiol2007;18:1500–1507.
50. SzeDY,RazaviMK,SoSK,etal.ImpactofmultidetectorCT hepaticarteriographyontheplanningofchemoembolization treatmentofhepatocellularcarcinoma.Am J Roentgenol2001; 177:1339–1345.
(DEBDOX):technicalrecommendations.Cardiovasc Intervent Radiol2012;35:980–985.
47. AlibertiC,TilliM,BeneaG,etal.Trans-arterial chemoembolization(TACE)oflivermetastasesfromcolorectal cancerusingirinotecan-elutingbeads:preliminaryresults. Anticancer Res2006;26:3793–3795.
43
Chapter

Principles of radioembolization

6
Vanessa L. Gates, Riad Salem, and Robert J. Lewandowski

Introduction

Radioembolization is dened as the administration of micron-sized embolic particles loaded with a radionuclide using percutaneous transarterial techniques. Fluoroscopic guidance,angiographicendpointsofembolizationand stasis, and the need to modify this based on angiographic ndings makesthistreatmentatrueembolizationprocedure.Dosimetry planning,theadministrationanddeliveryofradiationonthe microscopiclevel,themodicationofthedosebasedontumor and hepatic volume, in addition to the required knowledge ofradiation eects on tissuemake this a brachytherapypro­cedure.Radioembolizationthereforecombinesradiationwith embolization.
Investigations into yttrium-90 (90Y) and other radionu­clidesaspartofamicrosphereorparticleforthetreatmentof cancerdatebacktothe1960s.
1,2
Initialstudiesof resin90Yin humanswerereportedinthelate1970s.eseminalworkin a canine liver model demonstrating the safety andfeasibility ofusing90Ytherapyforhepaticmalignancieswasreportedin the late 1980s.
3,4
 Human studies of90Y microsphere therapy in liver applicationsfollowedfrom the late 1980s through to the1990s.
5–12
eseinvestigationsestablishedthesafetyof90Y for intrahepatic applicationsas well as the tolerance of nor­malparenchymatoradioembolization.Itshouldbenotedthat dierentdisciplinesuse slightly dierentnamesforradioem­bolization: microsphere brachytherapy, microbrachytherapy, hepaticintra-arterialradiotherapy,andselectiveinternalradia­tiontherapy. e termradioembolizationwillbeusedinthis chapter,asitisthepreferredtermperSocietyofInterventional Radiologystandardsdocument.
13

Mechanism of radioembolization

Radioembolizationoflivertumortakesadvantageoftheunique vascularsystemoftheliver.14Innormallivertissue,approxi­mately 70–80% of the organ’s blood ow is supplied by the portalvein,andthehepaticarteryaccountsfortherest.is contrastswithbothhepatocellularcarcinoma(HCC)andmet­astatictumorstotheliver,whichhaveapproximately80–100% oftheirblood owsuppliedbythehepaticartery.isdier­enceinperfusionisexploitedbyradioembolization,whereby
radioactivemicrospheresdopedwitharadionuclideareused toproduceintentionalmicroembolizationofthetumorcapil­lary bed in the livertumor(s)by delivering the microspheres throughthehepaticarteryand,subsequently,selectivelytarget­ingmalignantdisease.
e microembolic eect of radioembolization is due to capillary blockage; theaveragesize of rst-levelcapillaries is approximately7μmandtheaveragemicrosphere size ranges from 25 to 32 μm. Sincethe range in the number ofmicro­spheresis1–80millionmicrospherespertherapeuticadmin­istration, the percentage of rst-level capillaries blocked is
0.1–11%. Depending on the number of administered micro­spheres,theemboliceectcanrangefrommildtomoderate.
Presently, the radiation therapy portion of radioemboli­zationis due tothepresenceof90Y.90Yisabeta-emitterwith anaverageenergy of 0.9267 ± 0.0008 MeV and ahalf-life of
2.6684 ± 0.0013 days.15 e maximum range of the90Y beta radiationinwateris 11 mm.16 Ninetypercent of the emitted energy is absorbed withina sphere of water with aradiusof
5.3 mm.17 us, this radionuclideisideal for localized treat­ment. For completeness, it should be noted that90Y decays over99.98%ofthetimeviaβ−decaytothegroundstateof90Zr. Asmallfractionoftheradionuclide(~0.01%)β−decaystothe excited0+stateof90Zr,whichsubsequentlydecaystotheground stateviainternalconversion,internalpairproduction(e+e–),or two-photonde-excitation.eminisculeinternalpairproduc­tionbranchingratiois(31.86±0.47)×10–6andmightbeuseful forthe non-destructive assay of90Y or for monitoring of the depositionofthemicrosphereswithintheliver.
18–20
Eectsfromradiationarerelatedtotheradiationabsorbed dose(dose), which is the energyabsorbedper mass of tissue given in units of Gray (Gy). e schema developed by the Medical Internal Radiation Dose (MIRD) Committee of the SocietyofNuclearMedicineisthecurrentdosimetrystandard for radioembolization.
13,21–23
 is dosimetry method assumes auniformdistributionoftheactivitythroughoutthe mass of interest (treatment mass). For beta-particle decay, it is also assumedthatthereisnoproductionofBremsstrahlungandthat allofthedecayenergyiscompletelyabsorbedwithinthemass. eradioactivesourceispermanentlyimplantedinthepatient with no removalfrom the region,so theeective half-life is
Interventional Oncology, Second Edition, ed. Jean-François H.Geschwind and Michael C.Soulen. Published by Cambridge University Press. ©Cambridge University Press2016
44
Chapter6:Radioembolization
A
(kg)
AA AA
rL
.=++
simplythe radioactivehalf-life. Using all these assumptions, theequationforcalculatingthedosebased on the treatment activity(A)andthetreatmentmass(m)isgivenas:
(Gy) 49.38
D
= . Equation(1)
(GBq)
m
e doses to tumor,lung,andnormal liver tissue can be further calculated based on the partition model, which is describedbyHoet al.
24,25
Assumethatalloftheadministered
activityisdepositedinthenormalliver,tumor,orlungsgiving:
TotalNormalLiver Tumo
Equation(2)
ung
However,currentreportingstandardsusethehepaticlobar dose(i.e.,thedosetotissuesuppliedbytherighthepaticartery, le hepatic artery, or middle hepaticartery) so that clinical resultscanbecomparedbetweeninstitutions.
13

Radioembolic material

Currently, two90Y-microsphere products are available com­mercially worldwide: one is composed of90Y-doped resin (SIR-Spheres;SirtexMedical,NorthSydney,Australia)andthe other incorporates90Y in a glass matrix (eraSphere; BTG, Ottawa, Canada) (Table 6.1).
26,27
 eraSphere was approved in1999 by the Food andDrug Administration(FDA)under a HumanitarianDevice Exemption(HDE) for the treatment ofunresectable HCC in patients who can haveappropriately positionedhepaticarterialcatheters.Medicalprofessionalsare directedtoFDAguidancedocumentsonHDEsforusesindis­easesotherthanHCC.
SIR-Spheres® were granted full premarketing approval in 2002 by the FDA for the treatment of colorectal metastases in conjunction with intrahepatic oxuridine (FUDR). Both
GiventheFDAapprovalforbothdevices,theiruseindisease statesotherthanthestrictindicationrepresentsthepracticeof medicine.Inotherwords,theuseofthistherapyforindications other than HCC orcolorectal liver metastases is not experi­mental,butrathersupportedbyamplephaseIIdata.
Neithertypeofmicrospheredemonstratessignicantleach-
ingof90Y,inwhichthedosetothebonemarrowwouldexceed
0.05 Gy. For glass microspheres, the percent total yttrium presentduetodissolutionofthe glass rangesfrom0.02%to
0.13%.28eSIR-Spheresusermanualdiscussesresinmicro­sphereproperties.Ofnoteisthattraceamountsofradioactiv­ity,25–50kBq/L/GBqdelivered,havebeendetectedinpatients’ urineduetothefree90Yproducedinthelabelingprocessof resinmicrospheres.
Because90Y is dicult toimage,other radionuclides and material have been investigated. Of particular interest is holmium-166(
166
Ho).
166
Hopoly-l-lacticacid(PLLA)micro-
spheresareuniquebecausetheirdistributioncanbeimagedin vivowithbothsingle-photonemissioncomputedtomography (SPECT) (80.6 keV gamma 6–7%) and magnetic resonance imaging. e therapeutic eect is due to two beta particles thatareemittedwithmaximumenergyof1.77and1.85MeV.
166
Ho-PLLAmicrospheresareproducedfollowinggoodmanu-
facturingpracticeguidelines,asdescribedpreviouslybyNijsen
29–31
etal. apydose 540 mg of
Foreachpatient,a scout dose of 60 mg andather-
165
Ho-PLLAmicrospheresarepacked in high-densitypolyethylenevialswhichareirradiatedseparately in a nuclear reactor.Each therapeutic vial contains approxi­mately33 millionmicrospheres,with theaverageactivityper microspherebeing 450 Bq.
32,33
 e density of PLLA is simi­lartoresinmicrospheres,1.4 g/cc,andthesizeis 30±5µm. Currently,
166
Ho-PLLA-microspheres are not commercially
available.
devices are approved for the treatment of liver neoplasia in Europe.eraSphereisalsoapprovedforthetreatmentofliver neoplasiainCanada.SIR-Sphereshaveabroadapprovalforuse inIndia,Australia,andseveralothercountriesintheFarEast.

Indications and contraindications

Success in treatment of tumors in the liver by radioemboli­zation relies on the presence of appropriateindications that
Table 6.1 Properties of commercially available yttrium-90 (90Y)
microspheres
ensure patients receive benecial evidence-based therapy. Since each microsphere product has dierent treatment approvalcriteriaandproperties,eachcaseshouldbeindividu-
Description item SIR-Spheres TheraSphere
Sphere material Resin Glass
Sphere diameter (μm)
Activity in single vial (GBq)
Number of spheres per vial
Density (g/cm3) 1.6 3.29
90
Y activation mode Sr-90 generator Reactor
Mean calibrated activity
per sphere (Bq)
Shelf-life 24 hours after
20–60 20–30
3 3–20 (in 0.5-GBq
increments)
40–80 × 10
55 2,500
calibration
6
1.2–8 × 10
12 days after calibration
6
ally evaluated to determine which product is best suitedfor thediseasepresentation.Someofthemostgeneralindications for radioembolization, as detailed in the Radioembolization Brachytherapy Oncology Consortium (REBOC) report and European Association of Nuclear Medicine (EANM) guide­lines,includeunresectable hepaticprimaryormetastaticdis­ease, liver-dominant disease, and life expectancy of at least 3months.
34,35
Fromthemostrecentguidelines(EANMguidelines35)for
SIR-Spheres,thefollowingisalistofspeciccontraindications:
• markedlyabnormalexcretoryliverfunctiontests
• ascitesorclinicalliverfailure
• abnormalvascularanatomythatwouldresultinsignicant
reuxofhepaticarterialbloodtothestomach,pancreas, orbowel(determinedbypretreatmentangiogram). NotethatinadvertentdeliveryofSIR-Spherestothe
45
Section II:Principles of image-guided therapies
gastrointestinaltractorpancreaswillcauseacute abdominalpain,acutepancreatitis,orpepticulceration. InadvertentdeliveryofSIR-Spherestothegallbladdermay resultincholecystitis
• lungshuntingofthehepaticarterybloodowgreater than20%(determinedbypretreatmentintra-arterial technetium-99mmacro-aggregatedmicrosphere
99m
(
Tc-MAA)scintigraphy).Notethathighlevelsof implantedradiationand/orexcessiveshuntingtothelung mayleadtoradiationpneumonitis
• disseminatedextrahepaticmalignantdisease
• arelativecontraindicationconcernsprevious
andmaybeused in the assessment of treatmentresponse.If patientsarereceivingchemotherapy,itisimportanttodiscon­tinuethetreatments2–3weeksbeforethebeginningoftreat­mentwith90Ytoclearlyidentifytheagentresponsibleforany subsequenttherapeuticresponse.Moreimportantly,itisessen­tial to identify those patients receiving agents known to be radiationsensitizers,suchas 5-uorouracil,capecitabine,and gemcitabine.Radiationhepatitis,apotentiallyfatalcomplica­tion,is a theoreticalconcernforpatientsreceivingradioem­bolization,particularlyifitisusedconcurrentlywithradiation sensitizers.Pleaserefertomanufacturerdocumentationforthe mostcurrentindicationsandcontraindications.
external-beamradiationtherapytothemajorvolumeof theliver
• patientstreatedwithcapecitabinewithin2months priortoradioembolizationorwhowillbetreatedwith capecitabineatanytimefollowingtreatmentwith SIR-Spheres
• mainportal-veinthrombosis
• patientstreatedwithangiogenesisinhibitorsthat couldaectthequalityofthebloodvesselsandinduce complicationsduringangiography.
Similarly,thefollowingisalistofspeciccontraindicationsfor eraSpherefromthe most recent guidelines (EANM guide­lines35)forradioembolization:
• anydepositiontothegastrointestinaltractthatmaynotbe correctedbyangiographictechniques
• inthecaseofshuntingtothelungsthatcouldresultin deliveryofgreaterthan30Gytothelungsfromasingle treatmentor50Gyfromalltreatments.Ofnoteisthat radiationpneumonitishasbeenseeninpatientsreceiving dosestothelungsaslowas22Gywhenthepatienthas beenconcurrentlytreatedwithradiosensitizingagent
• inthecaseofsevereliverdysfunctionorpulmonary insuciency
• inltrativetumortype
• “bulkdisease”(tumorvolume>70%ofthetargetliver

Imaging considerations

Imagingofliverdiseaseisanimportantaspectofbothdiagno­sisandfollowingpatientresponseposttreatment.efollow­ingsectionsdetailsomepossibleimagingprotocolsforvarious modalities. As with all patient-trackingstudies,consistencyin theimagingprotocolcourseisexceedinglyimportant.Alleorts shouldbemadetoimageagivenpatientwiththesameprotocols throughoutdiagnosis,treatment,andfollow-up.Localprotocols deningtheappropriateimagingmodalitytouseforagivendis­ease presentationshouldbedevelopedto preventunnecessary imagingexams.Periodic review ofsuchlocalprotocolsshould bemadetoincorporatechangesinimagingstandards.
Treatment with radioembolization is based on cross-sectionalimagesandarteriogramsforeachpatient.e workupincludesthree-phase contrastcomputed tomography (CT) and/or contrast-enhanced magnetic resonanceimaging (MRI)oftheliverforassessmentoftumorandnon-tumorvol­umes,portalvein patency,andextentofextrahepaticdisease. Serumchemicalanalysesevaluatehepaticandrenal function and determine the presence and magnitude of elevation of tumormarkers.eclinicalpracticeguidelinerecommenda­tionsforradioembolizationpublishedbytheREBOCandthe American Association of Physicist in Medicine Task Force 144 provide a good overview of the cross-sectional imaging requiredforradioembolization.
36,37
volumeormultipletumornodules)
• aspartateaminotransferaseoralanineaminotransferase >5timesupperlimitofnormal
• bilirubin>1timeupperlimitofnormal
• tumorvolume>50%combinedwithanalbumin<3g/dL
• patientstreatedwithangiogenesisinhibitorsthat couldaectthequalityofthebloodvesselsandinduce complicationsduringangiography.
In summary, the rst step in the evaluation of patients for therapyincludescollectingahistoryandconductingaphysical examination.Patientsshouldbe abletotoleratetreatment,as bestassessedbyOkuda,EasternCooperativeOncologyGroup, andKarnofskyscoreevaluation.Totalbilirubinlevelandpro­thrombintimeareimportantpredictorsofwhichpatientswill toleratetreatment.Relevantinformationtobeelicitedincludes a history of renal or hepatic failure, as well as pulmonary compromisesuch as chronicobstructive pulmonary disease. Tumormarkerssuchasalpha-fetoproteinshouldbemeasured
Base and follow-up cross-sectional imaging
Fromadiagnosticimagingstandpoint,carefulreviewofrecent CTorMRIwithin2–4weeksoftreatmentiswarranted.When the cross-sectional imagingmodality has beenreviewed and thepatienthasbeendeemedacandidate,livervolumecalcula­tionsareobtainedusingthelobarapproach.
Triple-phaseCT provides the fastest and most reproduc­ibleimaging of the liver for volume calculation.Becausethe treatmentapproachfor90Y is most commonly lobar, proper imaging and volume calculation is essential for dosimetry purposes.eabilitytounderstandhepaticanatomyrelieson thesound understandingof the Couinaud hepatic segments. Anatomically,themiddlehepaticveinseparatestherightand lelobes.Whenregionsof interestaredrawnandlobarvol­umesarecalculated,itisthemiddlehepaticvein thatshould beusedas theanatomicdelineatorbetweenthe rightandle lobes.Ifthemiddlehepaticveincannotbeseen,thegallbladder
46
Chapter6:Radioembolization
Table 6.2 Couinaud segments based on angiographic findings
39
Corresponding right hepatic target
Angiographic ndings
Standard RHA and LHA 1, 5, 6, 7, 8 2, 3, 4
Replaced RHA with flow to medial segment of the left hepatic lobe 1, 4, 5, 6, 7, 8 2, 3
Replaced RHA without flow to medial segment of the left hepatic lobe and standard LHA 1, 5, 6, 7, 8 2, 3, 4
Replaced LHA without flow to medial lobe 2, 3
Replaced LHA with flow to medial lobe 2, 3, 4
Accessory RHA 6, 7
RHA in the presence of an accessory RHA 5, 8
Middle hepatic artery (irrespective of origin) 4
RHA = right hepatic artery; LHA = left hepatic artery.
fossaandits axisrelativeto thelivermaybeused.is tech­niqueassumesstandardarterialanatomywithsinglerightand lehepaticarteries.If variantsareobservedangiographically (e.g.,anaccessoryrighthepaticartery),accurateangiographic correlationsmustbeperformed when the regionsofinterest forlobarorsegmentalvolumesaredrawn.Itmaybeusefulto use at-panel cone-beam CT to determine the volumefrom variantanatomy.
Acomprehensivereviewofhepaticarterialanatomyispro­videdbyLiuetal.38e mostcommonangiographicndings andvariants,with theirassociatedtargetCouinaudsegments (and hence required volumes), are listed in Table6.2.39 It is incumbentonthe interventionalradiologist to have a sound knowledge of these anatomic variants and their eects on dosimetryandmicrospheredistribution.
MAAshouldbefractionatedduringtheplanningangiography procedureinsuchamannerthattheentireliveris imagedin onesetting.Forexample,apatientwithareplacedlehepatic arteryshouldreceive37–74MBqofMAAinthereplacedle hepaticartery,withtheother74–111MBqadministeredinthe righthepaticartery.
CareshouldbetakenwhenadministeringtheMAAthrough the microcatheter. A similar ow rate as thatwhich will be usedfortreatmentshouldbefollowedtoavoidbackowdueto higherpressurebehindthebolusinjection.edeliveryshould beapproximately7mL/mintoavoidbackow.Timingofimag­ingaeradministrationofMAAisalso important.MAA isa radionuclide/protein structure, which has a time-dependent breakdownintosmallerparticlesoftheproteinaceousMAA, with subsequent migration of these smaller fragments via thenormalcapillary bed to the lungs and eventualexcretion
Localization imaging (nuclear medicine imaging)
Following the mapping angiography, istered through an appropriately positioned microcatheter. rough MAA scintigraphy, the liver-to-lung shunting frac­tionisdeterminedasdescribedinthepackageinsertsforglass andresin microspheres.However,thereareseveral technical nuancestotheassessmentofshunting.Ifa patienthasasoli­taryHCCandifonlyonetreatmentisplanned,injectionofthe MAAintothearterythatisintendedforinjectionisindicated (inlobarorsegmental infusion). However,ifthediagnosis is multifocal bilobar HCC, MAA injection and lung shunting should be assessed before each treatment at the lobar level. is is because HCC tumors located in dierent lobes may shuntto varyingdegrees.Withoutthisinformation,the total cumulative pulmonary dose may be inadvertently exceeded. Inpatientswithmetastaticdisease,signicantshuntingisrare unlessthetumorburdenisveryhigh.Hence,lungshuntingcan beassessedoncewithcatheterplacementandMAAadminis­trationwithintheproperhepaticarteryatthetimeofplanning visceral arteriography. If angiographic shunting is observed, lobar MAA imaging is performed. In patients with variant anatomyinwhichwhole-livershuntingassessmentisplanned, fractionatedinjectionofMAAisrecommended.Dependingon thevariantanatomythatisidentied,the148–185-MBqvialof
99m
Tc-MAA is admin-
throughthekidneys.ebiologicalhalf-life rangesfrom4to 6 hours, with a similar shelf-life that depends onthe manu­facturer.Asa result,itisimportantthat theMAAbelabeled withinanhourofadministration.eoptimalimagingtiming windowis0–2hourspostMAAadministration;imagingmore than2hoursaerMAAadministrationcouldresultinhigher estimatesofhepatic-to-lungshunt.
Lungshuntfraction(LSF)estimatesmayalsobearticially elevatedduetothesizeoftheMAAparticles.Althoughthenor­malmanufacturedsizeofMAAparticlesis30–90μm,statisti­cally,asmallpercentageoftheseparticleswillfalloutsidethis range.Ofparticularinterestarethoseparticlesthataresmaller than8–10  μm, asthese will shuntthroughthenormal cap­illarysystem.iswillresultinanincreasein perceivedLSF. Accordingtomostmanufacturers,fewerthan10%oftheMAA particlesaresmallerthan10μm.Radiopharmaceuticalquality assuranceisimportanttolimitingerrorduetothisprocess.
AnothersourceofarticiallyelevatedLSFistheamountof freetechnetium.einterpretationoftheLSFandgastrointes­tinaluptakemusttakeintoconsiderationthepresenceofMAA aswellasfree(Tc-99m)pertechnetate(usedtolabeltheMAA particles).Uptakeinthethyroidand salivaryglandsandkid­neys,as well as diuse gastric mucosal uptake, should not be consideredshunting.Uptakein the gastric mucosa,thesmall
segments
Corresponding left hepatic target segments
47
Section II:Principles of image-guided therapies
Dm
(Gy)(kg)
49.38
×
(Gy)(kg)
49.38 (1 LSF)
×
m
bowel,orpancreasintheabsenceofsalivaryandthyroiduptake should be interpreted with caution because it may represent truegastrointestinalshunting.Again,caremustbetakeninthe MAA quality assurance program for assessingthe amount of free(Tc-99m)pertechnetatepresentinadosageofMAA.
An authorized user should not rely solelyon the SPECT imagesoftheupperabdomentracttoabsolutelyexcludegastro­intestinalshunting.Rather,itshouldbeconsideredanadjunc­tiveimagingmodality.Exclusionofgastrointestinalowshould beaccomplishedbyuseofthecombinedinformationobtained frommeticulous hepatic angiography, three-dimensionalCT angiography, and SPECT imaging. Fusion of CT and MAA SPECTimagesmaybehelpfulintheidenticationofextrahe­paticowofMAA.
Currentclinical practiceusesplanarimagingforLSF.e mostaccurateestimatefromplanarimagingusesbackground and scatter-correctedlung region of interest(ROI)and liver ROI. e net posterior counts and net anterior counts from each ROI are combinedusing the geometricmean. e LSF estimateisthenthesumofthegeometricmeanofthelelung andrightlungdividedbythegeometricmeanoftheliveradded tothegeometricmeanofthelungs.
Follow-up localization imaging can be performed using either Bremsstrahlung SPECT/CT or Y-90 positron emission tomography(PET)/CT.DuetotheinherentpropertiesofPET/ CT, Y-90PET/CT oers improved resolution and specicity whenusedforlocalization.
19,20
A
(GBq)
=
. Equation(4)
etreatmentactivityforeraSpheremayalsobereduced to accommodate lung shunted activity by incorporating the LSF(seeEquation5).
A D(GBq)
=
×−
. Equation(5)
Like SIR-Spheres, the estimated treatment activity may be further reduced for patients who have received chemo­therapy.Treatmentisnotrecommendedifthemeanlungdose exceeds30Gypertreatmentor50Gyforalltreatmentswith eraSphere.
Radioembolization:technical considerations
Microcatheters
ere are two specic considerations when deciding which microcatheter to employ for delivery of radioactive micro­spheres. To ensure adequate delivery of at least 80% of the microspheres,theinnerdiameterofthemicrocathetershould atleastbe0.5mm(0.020inch).26esecondconsiderationis thelengthofcatheter.emicrocathetermustbelongenough toallowproperconnection tothedeliverydevice.Forexam­ple,foreraSphere,the packageinsertinstructs the user to connect to the microcatheter in a vertical connection such thatgravitywillassistinpullingthemicrospheresthroughthe

Determining treatment dosage (activity)

Whileunderstandingtheowdynamicsandbloodsupplyfor the tumor bed is important no matter the microsphere that isused, each type ofmicrospherehas adierentmethodfor determiningtheactivitythatistobeadministered.
microcatheterhub.
(Y-90) SIR-Sphere
SIR-Spheres must bedelivered slowly at a rate of no more than 5 mL/min, as rapid delivery may cause reux back intothe hepatic artery and subsequently other organs. e
(Y-90) SIR-Sphere
e package insert still indicates that the empirical method using tumor burden is the activity determination tech­nique.However,itisno longer the methodofchoicedueto radiation-inducedliverdiseaseduetothehigherdosagesused onlobartreatments.40ecurrentmethodforcalculatingthe activitytobeadministeredisbasedontheDebois body sur­facearea(BSA),fractionoftotalhepaticvolumebeingtreated (VRF),thefractionoftumormassburden(TMB),andthelung shuntreferencefraction (LSRF)from a table in the package insert.eestimatedtreatmentactivitymayfurtherbereduced forpatientswhohavereceivedchemotherapy.
microcatheter position must repeatedly be checked during theprocedurewithuoroscopytoensureitremainscorrectly positionedand that there isnotstagnant arterial ow with resultantreux/non-targetembolization.is is performed byinjectingcontrastmedium throughthele-handportof thedeliveryset.Attheconclusionoftheprocedure,thecath­eterisremoved.
(Y-90) TheraSphere
A complete infusion usually requires 4–12 mL/min infusion rateusingatleast30mLofsaline.Attheconclusionofthepro­cedure,thecatheterisremoved.
Treatmentactivity(GBq)=LSRF×VRF×
(BSA–0.2+TMB) Equation(3)
SIR-Sphere treatment is not recommended if the LSF%
exceeds20%.
(Y-90) TheraSphere
epackageinsertindicatesthattheMIRDmethodisusedto determinetheactivitytobeadministered(seeequation1and
equation4).

Radiation safety considerations

Radiationsafetyisanimportantconsiderationin this proce­dure,giventhepotentiallyhighexposurefromhandlingthera­peuticamountsof90Y, a beta-emitter.erefore,theprimary concern is exposure to the eyes, skin, and hands. Emissions from90Ycan travel morethan a meter in airbutaresigni­cantlyreducedby1cmofacrylic.Staintheprocedureroom duringradioembolizationshouldwearsafetygogglesorglasses andworkbehindtheacrylicshieldsprovided.
48
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