Thisprotocoliscurrentlybeingreviewed.

Bytheendofthisprotocol,youwillhave:

1. Gainedabasicknowledgeofbonemarrowtransplantation

2. LearntthereasonswhyTBIisprescribed

3. Understoodsomeofthesideeffectsonthepatient

4. UnderstoodthetreatmentconsiderationsforTBI

5. Beengivenexamplesofdifferenttreatmenttechniques

WhyisTBIused?

Totalbodyradiation(TBI)wasfirsttrialledinthe1920s.Itwasadministeredatalowdose(0.10.25Gy)severaltimesaweektotreatmalignanciesofthelymphoma.Today,TBIisstillprescribedatalowdoseforspecificdiseasessuchasnonHodgkin'sLymphoma1.Inmodernradiationtherapycentres,TBIismorecommonlyusedinpreparationforabonemarrowtransplant.

BoneMarrowTransplantation

Bonemarrowtransplantation(BMT)iswidelyusedasatreatmentforhaematologicalmalignanciessuchasleukaemia,aswellasseverecombinedimmunoandenzymedeficienciesdisordersandhaemopoieticsystemdisorderssuchasaplasticanaemia

RadiationOncology,Physics,TotalBodyIrradiation(TBI)

ID: 000490 Approved:24 May 2010 Last Modified: 16 Feb 2012 Review Due:31 Aug 2012

Target Audience: ThisprotocolisaimedatprovidinginformationonTotalBodyirradiation(TBI)forthefollowing:

n MedicalPhysicsRegistrarsn RadiationOncologyRegistrarsn RadiationTherapists

Overview: n ThisprotocolisdesignedtoprovideanoverviewoftheclinicalindicationsforTBI,thetheoryandpractiseofTBI,thedifferentsetupuptechniquesused,andtheconsiderationsfortreatment.ItwillalsobrieflydescribetheprocessofbonemarrowtransplantationandsomeofthesideeffectsexperiencedbythepatientafterreceivingacourseofTBI.

n LowdoseTBIisbeyondthescopeofthisprotocol.

Key References: n AAPMreport17(outdatedbutworthreading)n Galvin,J.M.,Report:AAPM2001Meetingsn ESTRO,EULEPandEBMT,ProceedingsoftheInternationalMeetingonPhysical,

BiologicalandClinicalAspectsofTotalBodyIrradiation,Radiotherapy&Oncology,Supplement18(1),1990

Additional Resources: n AustralianBoneMarrowDonorRegistryn AustralianBoneMarrowTransplantFoundationn CurrentOpinioninOncology,Supplement21(1),pp146,2009

ProtocolObjectives:

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2.

However,notallpatientsaresuitableforaBMT.ConsiderationsforaBMTincludethephysicalhealthofthepatient,diagnosisandthestageofthedisease3.

ApatientwhoisreceivingaBMTiscalledarecipient,andthehealthybonemarrowisgivenbyadonor.Therecipientismatchedwithasuitabledonorbytissuetyping.Thisisdonebyestablishingthehumanleucocyteantigentype,whichisawhitebloodcellmarker,fromabloodsample3.

Insomecases,thedonorsbonemarrowundergoesaprocesstoremoveharmfulTlymphocytes,knownasTcelldepletion.TheseTcellscausegraftversushostdisease,wherethedonorscellsrecognisetherecipientscellsasforeignandmountanimmuneresponsetorejectthem.

Thebestpossibledonorisanidenticaltwinhoweverthereisonlya2535%chancethatafamilymemberwillprovideagoodmatch.Atransplantthatcomesfromanotherpersonisreferredtoasanallogeneictransplant,orasyngeneictransplantifthedonorisanidenticaltwin4.

Anautologoustransplantisonewherethepatientsownstemcellsareused.Thismaybedoneifthediseaseisinremissionordoesnotinvolvethebonemarrow.Thepatientsstemcellsaretakenandstored,thenreturnedtothepatientafterchemotherapyand/orradiationtherapy4.

Clinicalindicationsfortotalbodyirradiation

TBIisusedinaradiationoncologysettingasaconditioningregime.ItistypicallyprescribedforpatientsrequiringaBMT,withtheaimofincreasingthesuccessofthetransplantintherecipient5,6.

Thisisachievedthroughleukaemiacellkill,eradicatingtherecipientsbonemarrowandprovidingasufficientdegreeofimmunosuppressiontoavoidgraftrejectionintherecipient7,8.Thedonorshealthybonemarrowistheninfusedintotherecipientoverseveralhours3.

AsuccessfulBMTisachievedwhenthedonorsbonemarrowattachestothecavitiesintherecipientslargebonesandbeginstoproducenormalbloodcells3.

Effectonthepatient

Thepatientmayexperiencesideeffectsfromthechemotherapyandradiationtherapy,suchashairloss,nausea,vomiting,hairlossanddiarrhoea.Inadditiontothis,complicationsmayarisefromtheBMT,suchasgraftversushostdisease,rejectionorinfection.ThepatientmayevenrelapsefollowingaBMT3.

Prescription

FractionationinTBIisusedtoexploitthedifferencesinrepaircharacteristicsbetweenleukaemicandnormallungcells9.ManydosefractionationregimesarecurrentlyinuseinAustralasiaandinternationally.Bierietal(2001)conductedastudythatassessedthe5yrsurvivalrateforpatientsprescribedwith10,12and13.5Gy.Allpatientsweregivenabidailyfractionation(bd),over3days.The5yrsurvivalrateforeachofthoseprescriptionswere62,55and46%respectively.

Fractionationwasfoundtoinducelesstoxicityinthepatientsnormaltissues(lung,liver,lensetc)thanaprescriptionof10Gyinasinglefraction.However,insituationswithagraftTcelldepletion,ahigherrateofgraftfailuresafterfractionatedregimeswasobserved,indicatingthatthe1012Gyfractionatedschedulescouldbecomedetrimental.Increasingthedosetoovercomethereducedefficacyofthelowerdoseschedulewouldinturnincreasetoxicity7.Ahigherdosegiveninlargerfractions,eg16Gyin8bd,mayreducetheriskofleukaemicrelapseatthecostofincreasedmorbidity6,10.

12Gyin6bdiscommonlyconsideredastandardregime11,whereasintheUK14.4Gyin8bdisincreasinglyprescribed6.Otherfractionationscheduleshavebeenclinicallyusedforexample,9Gyin3dailyfractionsand12Gyin4dailyfractionsforpaediatriccases12.

Thedoseisnormallyprescribedtothepatientsmidlineattheumbilicusorpelvisregion.ICRU50(1993)recommendsadoseaccuracyof+7%to5%howevermanyRadiationOncologistsarewillingtoacceptupto10%accuracyasTBIisconsideredaspecialtechnique.

Underdosageincreasestheriskofarelapsewhilstoverdosage,particularlyincriticalstructures,increasestheriskofmorbidity.Theeffectofoverdosageinthelimbshasnotyetbeenstudied6.

Energy,beamspoileranddosehomogeneity

TBITechniques

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Photonbeamenergiesbetween4MVand18MVarecommonlyusedinTBI.Thewidthofthepatientisaconsiderationwhenselectingbeamenergyduetothetissuelateraleffect13.Fora52cmseparationattheshouldersofalargeadult,theentrancedosecanbeupto25%higherthanmidlinedosefora6MVbeamat500cmSSD.Reducingtheseparationto30cmreducesthedosedifferentialtoapproximately10%14.ThismaybeachievedthroughuseofanAP/PAfieldarrangement,ratherthanabilateral.Also,raisingtheenergyto15MVreducesthisdifferentialtolessthan15%.

Forpatientswiththickness35cm,higherenergiesshouldbeconsidered13.

However,increasingthebeamenergyalsoincreasestheskinsparingeffectinherentinphotonbeams,withthedepthofmaximumdose(dmax)progressingfurtherintothepatient.Henceabeamspoilerisusedtoincreasetheentrancedose,sonamedbecauseitspoilsthebeam.

ThebeamspoileristypicallymadeofperspexandmaybemountedontheTBItreatmentcouchorstandaloneasamoveablescreen.Thethicknessissuchthattheentrancedoseisraisedtowithin90%oftheprescribeddose13.

Electronsaregeneratedinthelinearaccelerator(linac)headandattypicalTBItreatmentdistances(>300cm)progressivelylosetheirenergy,whilstmoreelectronsaresimultaneouslygeneratedinair.Thespoilerservestoabsorborscatterelectronsgeneratedinthelinacheadandairittheninturnsbecomesasourceofelectronsgeneratedbythephotoninteractions.Theseelectronshaveawideangulardistributionandhavetheeffectofincreasingdoseinthebuildupregion.Thepatientistypicallypositioned1030cmawayfromthespoilerthisseparationdistanceaffectstheprofileattheentrysurface15.

Thespoilerisalsousedtohomogenisethedosetothepatient.Ideally,thepatientwouldreceivetheprescribeddoseuniformlyacrossthewholebody.Thisisverydifficulttoachieveclinicallyduetothevaryingwidthsofthepatientscontours13.Therearemanydifferentmethodsusedtocompensateandcorrectforthevariationsincontourandanatomy,aswellasshieldcriticalstructures.

Criticalstructuresandtissuecompensators

Materialssuchasperspex,ricebags,sandbagsorthegelatinelikebolusareregularlyusedtohomogenisethepatientscontours(figure1)andassistinshieldingcriticalstructuressuchasthelung,liverandkidneys.

(a) (b)

Figure1:Anexampleofa)bolusbagsandb)perspexblocksusedinsomedepartmentstoshieldthepatient'sheadinbilateraltreatment

Stripsoflead,cerrobendorlowmeltingpointalloyblocksmayalsobeusedtofurtherprotectcriticalstructures13.Often,thepatientsownarmsandhandsareusedasshielding:inabilateraltreatment,thepatientsarmsmaybepositionedalongtheirside,providingfurtherlungshielding(figure2).

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Radiation Oncology, Physics, Total Body Irradiation ( TBI )

(a) (b)

Figure2:Patientinlateralpositionwith(a)armscrossedoverchestforgreaterlateralchestexposure,and(b)witharmsbysideto'shield'lateralchest.

Whencriticalstructuressuchaslungsandliverareshielded,anelectronbeammaybeusedtoboostthedosetothoseregionstoreducetheincidenceofrelapse16.

Doserate

LatetermcomplicationsfromaBMTandTBIconditioningregimeincludeinterstitialpneumonitis,cataracts,renaldysfunctionandgraftversushostdisease.Whilstradiationalonemaynotaccountforthese,manystudieshaveinvestigatedtherelationshipbetweendoserateandspecificcomplications.

Doserateisasignificantconsiderationintheonsetofrenalcomplications,withdoserates

SomecentresimagethepatientwithaCTscanoftheentirebodyorcertainlevelswithinthepatienttoobtaininformationforatreatmentplanningsystem(ifused)ortomanuallycalculateseparationanddeviseshieldingpositions.Xraysmayalsobeusedtomarkoutlungshieldingpositions.

Itisimportanttonotethatwhendevisingshielding,thepatientshouldbescannedorxrayedinthetreatmentpositionduetotheshiftinanatomywhenlyingsupineorsideways,orstanding.

MonitorUnits(MU)maybegeneratedusingatreatmentplanningsystemormanualcalculation.Insomecentres,MUisnotcalculatedandthetreatmentdeliveryisbasedontheionchamberreadingatthepatientsgroin,correctedforambientpressure,temperatureandpatienttemperature.

Dosimetry

InvivodosimetryforTBIisofrelevanceinreportingthedosedeliveredandmostimportantly,thedosehomogeneityduringeachtreatmentfraction.Itisalsousedtoverifypatientpositionandthereproducibilityofthesetup5.ThereareseveralfactorstoconsiderwhenchoosingadosimetertoperforminvivodosimetryforaTBIpatient.Theseconsiderationsareconsistentwiththerequirementsofaninvivodosimeterforanytypeofpatientmeasurement.

Someconsiderationsinclude:

n inherentbuildupinthedosimetern accuracyn reproducibilityn doserate,n fieldsize,n angular,n SSDandn temperatureindependencen linearityn easeofuseandreadoutn postirradiationfadingn andphysicalsize20

Thermoluminescencedosimeters(TLDs)areoftenusedinTBIastheyconformwellwiththerequirementsofinvivodosimetersandhaveasmalluncertaintyofupto2.5%21.ThethicknessaTLDchipisrepresentativeofthesensitivelayersoftheskin.HoweverTLDsarelabourintensivetoprepare,readoutandcalibrate,andrequiresomephysicalspaceforthesupportinghardware20.

SemiconductorsarealsowidelyusedforTBIdosimetry,withmuchresearchstillbeingconductedtocontinuallyimprovetheirphysicalandresponsecharacteristics.Metaloxidesemiconductorfieldeffecttransistors(MOSFETs)havebeenusedforTBIdosimetry.Reproducibilitywithin3%oftheentranceandexitdose,andagreementwithin3.9%ofTLDreadingshavebeenachieved20,22.Semiconductordiodesallowforimmediatedosereadings,howevercaremustbetakenduetotheirangularandenergydependence23.

Otherdosimetersincludeopticallystimulatedluminescence(OSL),whichhastheadvantageofbeingeasiertohandlethanTLDs,andtheselfdevelopingGAFchromicfilm(figure5).GAFchromicEBTfilmhasbeenfoundtoagreewithTLDresultswithin6.7%foratypicalpatientmeasurement24.

(a) (b)

Figure5:(a)CutpiecesofGAFchromicEBT2filmusedforinvivodosimetry(b)pointdensitometerusedtoreadoutfilm.

Dosimetersareplacedatsomeofthefollowingpositions:head,neck,sternalnotch,chest,abdomen,pelvisandankles.Dosimetersmayalsobeplacedbetweenthethighsnearthegroinasasubstituteforpatientmidline.Anionchambermayalso

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Radiation Oncology, Physics, Total Body Irradiation ( TBI )

beusedatthispositiontoallowdirectcomparisontoprescribeddose25(figure6).

(a) (b)

Figure6Anexampleofanionchamber(a)placedatgroinwithGAFchromicEBT2filmattached,and(b)connectedtoelectrometertomonitordosedelivered.

TBIonCobalt60

TBImaybeperformedonaCobalt60unit.Variousmethodsincludeusingastationarybeaminconjunctionwithamovingcouch26,orplacingthepatientinastretcheronthefloor27.ThepatientassumesaproneandsupinepositionfortheAP/PAfields.

RadiationSafety

MostTBItreatmentsareperformedwithahighenergylinearaccelerator,withthegantryat90oor270oandthecollimatorat45owithjawsfullopentogivethemaximumfieldwidthpossible.Giventheextendedtreatmentdistance,therequirednumberofMUtodelivertheprescribeddoseforTBIcanbeupto36timesmorethanifthepatientwereatisocentre28.

WhilstscatterfromtheisocentreisnotaconcernforTBI,moreradiationwillbedirectlyincidentontheprimarybarrierbehindthepatient.AnextensiontotheNCRPbarrierdesignformulahasbeenproposed,whichseparatesdirect,leakageandscatterforthelinearacceleratorworkloadcomponents28.

References

1. Safwat,A.,Y.Bayoumi,H.Akkoush,etal.2004."AphaseIItrialofadjuvantlowdosetotalbodyirradiationinnonHodgkin'slymphomapatientsfollowingstandardCHOP."ActaOncol43(5):480485.

2. Gratwohl,A.1990."Bonemarrowtransplantation:indicationsandtechnique."RadiotherOncol18Suppl1:39.3. "AustralianBoneMarrowDonorRegistry(ABMDR)."Linktoexternalarticle 4. "ArrowBoneMarrowTransplantFoundation."Linktoexternalarticle 5. Briot,E.,A.DutreixandA.Bridier.1990."Dosimetryfortotalbodyirradiation."RadiotherOncol18Suppl1:16

29.6. Gilson,D.andR.E.Taylor.1997."Totalbodyirradiation.ReportonameetingorganizedbytheBIROncology

Committee,heldatTheRoyalInstituteofBritishArchitects,London,28November1996."BrJRadiol70(840):12011203.

7. Cosset,J.M.,T.Girinsky,E.Malaise,etal.1990."ClinicalbasisforTBIfractionation."RadiotherOncol18Suppl1:6067.

8. Bieri,S.,C.Helg,B.Chapuis,etal.2001."Totalbodyirradiationbeforeallogeneicbonemarrowtransplantation:ismoredosebetter?"IntJRadiatOncolBiolPhys49(4):10711077.

9. O'Donoghue,J.A.,T.E.WheldonandA.Gregor.1987."Theimplicationsofinvitroradiationsurvivalcurvesfortheoptimalschedulingoftotalbodyirradiationwithbonemarrowrescueinthetreatmentofleukaemia."BrJRadiol60(711):279283.

10. Hui,S.K.,R.K.Das,B.Thomadsen,etal.2004."CTbasedanalysisofdosehomogeneityintotalbodyirradiationusinglateralbeam."JApplClinMedPhys5(4):7179.

11. Adkins,D.R.andJ.F.DiPersio.2008."Totalbodyirradiationbeforeanallogeneicstemcelltransplantation:isthereamagicdose?"CurrOpinHematol15(6):555560.Linktoexternalarticle

12. Kornguth,D.G.,A.Mahajan,S.Woo,etal.2007."Fludarabineallowsdosereductionfortotalbodyirradiationinpediatrichematopoieticstemcelltransplantation."IntJRadiatOncolBiolPhys68(4):11401144.

13. Khan,FM.2003.ThePhysicsofRadiationTherapy:Lippincott,Williams&Wilkins,USA.4thEd.14. Galvin,J.M.2001."AAPM2001MeetingReports."Linktoexternalarticle 15. Kassaee,A.,Y.Xiao,P.Bloch,etal.2001."Dosesnearthesurfaceduringtotalbodyirradiationwith15MVX

rays."IntJCancer96Suppl:125130.16. Shank,B.,R.J.O'Reilly,I.Cunningham,etal.1990."Totalbodyirradiationforbonemarrowtransplantation:the

MemorialSloanKetteringCancerCenterexperience."RadiotherOncol18Suppl1:6881.17. Cheng,J.C.,T.E.SchultheissandJ.Y.Wong.2008."Impactofdrugtherapy,radiationdose,anddoserateon

renaltoxicityfollowingbonemarrowtransplantation."IntJRadiatOncolBiolPhys71(5):14361443.

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18. Oya,N.,K.Sasai,S.Tachiiri,etal.2006."Influenceofradiationdoserateandlungdoseoninterstitialpneumonitisafterfractionatedtotalbodyirradiation:acuteparotitismaypredictinterstitialpneumonitis."IntJHematol83(1):8691.Linktoexternalarticle

19. Greig,J.R.,R.W.MillerandP.Okunieff.1996."Anapproachtodosemeasurementfortotalbodyirradiation."IntJRadiatOncolBiolPhys36(2):463468.

20. Best,S.,A.RalstonandN.Suchowerska.2005."ClinicalapplicationoftheOneDosePatientDosimetrySystemfortotalbodyirradiation."PhysMedBiol50(24):59095919.

21. Palkoskova,P.,H.Hlavata,P.Dvorak,etal.2002."Invivothermoluminescencedosimetryfortotalbodyirradiation."RadiatProtDosimetry101(14):597599.

22. Scalchi,P.andP.Francescon.1998."Calibrationofamosfetdetectionsystemfor6MVinvivodosimetry."IntJRadiatOncolBiolPhys40(4):987993.

23. Williams.J.R,Thwaites.D.R.2000.RadiotherapyPhysics:Inpractice:OxfordUniversityPress,USA.24. Su,F.C.,C.ShiandN.Papanikolaou.2008."ClinicalapplicationofGAFCHROMICEBTfilmforinvivodose

measurementsoftotalbodyirradiationradiotherapy."ApplRadiatIsot66(3):389394.25. Lancaster,C.M.,J.C.CrosbieandS.R.Davis.2008."Invivodosimetryfromtotalbodyirradiationpatients

(20002006):resultsandanalysis."AustralasPhysEngSciMed31(3):191195.26. Zabatis,Ch,T.Koligliatis,S.Xenofos,etal.2008."Dosimetryintranslationtotalbodyirradiationtechnique:a

computertreatmentplanningapproachandanexperimentalstudyconcerninglungsparing."JBuon13(2):253262.

27. Evans,M.D.,R.X.Larouche,M.Olivares,etal.2006."Totalbodyirradiationwithareconditionedcobaltteletherapyunit."JApplClinMedPhys7(1):4251.

28. Rodgers,J.E.2001."RadiationtherapyvaultshieldingcalculationalmethodswhenIMRTandTBIprocedurescontribute."JApplClinMedPhys2(3):157164.

Thecurrencyofthisinformationisguaranteedonlyupuntilthedateofprinting,foranyupdatespleasecheckwww.eviq.org.au

02Apr2013

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