TreatmentPlanning

G.BattistoniINFNMilano

Thetreatmentplanningprocess

Individualpatient Radiotherapytreatmentunits

Beamdata:radiationquality,PDD,profiles,...

Patientdata:CTscan,outlines

Optimizationofsourceorbeamplacement

Dosecalculation

Localizationoftumorandcriticalstructures

Preparationoftreatmentsheetandrecordandverifydata

Simulation

3

About the patient:

•  Target location •  Target volume and shape •  Secondary targets - potential tumor

spread •  Location of critical structures •  Volume and shape of critical structures •  Radiobiology of structures

4

About the machine:

•  Beamdescription(quality,energy)•  Beamgeometry(isocentre,gantry,table)•  Fielddefinition(sourcecollimatordistance,applicators,collimators,blocks,MLC)

•  Physicalbeammodifiers(wedges,compensator)•  Dynamicbeammodifiers(dynamicwedge,arcs,MLCIMRT)

•  Normalizationofdose

TreatmentPlanninginhadrontherapy(Effective) Dose Optimization

Imaging: CT scan and/or PET-CT)

Electron density

Intensity, position and energies to be delivered

to patient

Radiobiology: RBE parameters OER (not yet…) TreatmentPlanning

SystemNuclear Physics: Dose vs Depth hadrone/nucleus scattering: fragments etc.

Radiotherapist: identification of Target Volume and of Organs at Risk

Inverseplanningperscansioneattiva

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Input:

• Hounsfieldnumbers(dallaCT)deivoxelsincuièsuddivisol’interovolumeanatomico

• Identificazionedapartedelclinicodelvolumedatrattareeladosedasomministrareedegliorgan-at-risk(OAR)eladosemassima

Sipuòscriverelafunzione-costodaminimizzareecomeesempiosipuòusarelaseguente:

ovelasommasieseguesututtiivoxelsdiinteresse(mTeOAR)eDi

brappresentaladosebiologicafornitaalvoxeli-esimo

Esempio1-D

Parecchifascicontribuisconosuunmedesimovoxel:

• dafascichearrivanodalmedesimocampodiirraggiamento

• dadifferenticampi

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• dilèladosefisicaunitariarilasciatadalfasciol-esimosulvoxeli-esimo

• flèlafluenza(dadeterminare)delfasciol-esimo

• RBEièilrelativebiologicaleffectivenesssulvoxeli-esimomediatosututtiifascicherilascianodosesulvoxeli-esimo

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Sipuòriscriverelafunzione-costointerminidisopravvivenzapiuttostochedidose:

oveSirappresentalasopravvivenzadelloi-esimovoxelmediatasututtiifascicherilascianodosesulmedesimovoxel.Assumendo:

• relazionefrasopravvivenzaedosedeltipolineare-quadratica:

)exp( 2DDS βα −−=• leseguentirelazionipermediarea e bsuicampimisti

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doseunitariarilasciatanelvoxeli-esimo

radiobiologia

radiobiologiadeiraggiXperlalineacellulare

GSItreatmentplanningpackageTRiP98

Conventionalone-dimensionalscalingofpencilbeam

Ifthetwoionizationpotentialsarenearlythesame

IftheratioofstoppingpowerbetweenwaterandthemediumSwmzwisassumedtobeindependentoftheprotonenergyoneeasilyderivesthescalingrelation:

zmcanbeexpressedusingtheWaterEquivalentPathLengthapproach:

This1Dpathlengthscaling,istransferredtothelateralfluenceLm(r,z,E0)accountingformultipleCoulombscattering:

zm:depthinthemediumzw:depthwater.

WaterEquivalentPathLenght(WEPL)Approximation

Treatment Planning System

TPS is directly related to scanning modality and RBE evaluation model

Need to include management of moving organs and integration of in-room imaging

(TPS used at CNAO)

SyngoTPScalculation(HIT)ThankstoA.Mairani

Acube3x3x3cm3inwaterstartingatadepthof7cm

protonsBeamspacingΔX,ΔYis3mm,ΔZis2mm15“slices”(energies)from97.53to116.85MeV121beams/sliceTotalno.ofparticles:4.77915E+09Lastslice(116.85MeV)at~10cmofdepth:σx,y=1.37cmatisocenter1.71766E+09totalparticles,1.4196E+07particles/beam(1.2780e+08particlesin0.3cmx1cm2)Firstslice(97.53MeV)at~7cmofdepth:σx,y=1.61cmatisocenter1.45296E+08totalparticles,1.412E+06particles/beam(1.0807e+07particlesin0.3cmx1cm2)

Slice Numb.0 2 4 6 8 10 12 14 16

No.

of P

artic

les

0

200

400

600

800

1000

1200

1400

1600

1800

610×Particles vs Slice

protons

12CBeamspacingΔX,ΔYis2mm,ΔZis2mm14“slices”(energies)from186.57to223.56MeV/u225beams/sliceTotalno.ofparticles:2.03959E+08Lastslice(223.56MeV/u)at~10cmofdepth:σx,y=0.64cmatisocenter7.5102E+07totalparticles,3.33787E+05particles/beam(8.345E+06particlesin0.2cmx1cm2)Firstslice(186.57MeV)at~7cmofdepth:σx,y=0.69cmatisocenter7.2631E+06totalparticles,3.2280E+04particles/beam(8.07E+05particlesin0.2cmx1cm2)

12C

Slice Numb.0 2 4 6 8 10 12 14

No.

of P

artic

les

0

10

20

30

40

50

60

70

80610×

Particles vs Slice

Thecompleteplaniscomposedby2opposedfields,12C.

DoseprescriptionascalculatedbySyngoTPS

Beam1=272571648particlesBeam2=239598608particles

Unesempiodicalcolosuunverocasopaziente

EnergyNominalBeamSpotsperSlice[n]Energy[MeV/u]Slice[n]:1137.282

2140.7223144.1034147.43 35150.71 56153.94 77157.12 88160.26 109163.35 1510166.41 2811169.43 7112172.41 10313175.37 16314178.28 21915181.17 24916184.03 23617186.86 23418189.66 23519192.43 23120195.18 229

EnergyNominalBeamSpotsperSlice[n]Energy[MeV/u]Slice[n]:21 197.91 23222200.61 22823203.29 19324 205.95 18125208.58 17426211.19 18627213.79 18028216.36 17229218.91 16630221.45 15431223.96 13532226.46 12333228.94 10534231.34 8835233.79 7236236.22 4937238.63 3338241.03 1439243.42 4

Totalno.ofspots:4542

TreatmentDescription:Beam1

•  GrosstumorvolumeorGTV•  ClinicaltargetvolumeorCTV•  PlanningtargetvolumeorPTV•  OrganatriskorOAR

•  TheGTVisthegrossdemonstrableextentandlocationofthetumor.

•  TheCTVisavolumeoftissuethatcontainsademonstrableGTVand/orsubclinicalmalignantdiseasewithacertainprobabilityofoccurrenceconsideredrelevantfortherapy.

•  ThePTVisageometricalconceptintroducedfortreatmentplanningandevaluation.Itistherecommendedtooltoshapeabsorbed-dosedistributionstoensurethattheprescribedabsorbeddosewillactuallybedeliveredtoallpartsoftheCTVwithaclinicallyacceptableprobability,despitegeometricaluncertaintiessuchasorganmotionandsetupvariations.

•  TheOARorcriticalnormalstructuresaretissuesthatifirradiatedcouldsuffersignificantmorbidityandthusmightinfluencethetreatmentplanningand/ortheabsorbed-doseprescription.

23

Target delineation ICRU 50 & 62

� GrossTumorVolume(GTV)=clinicallydemonstratedtumor

ClinicalTargetVolume=GTV+areaatrisk(eg.potentiallyinvolvedlymphnodes)

24

Need to keep in mind

•  Always a 3D problem •  Different organs may respond differently to

different dose patterns. •  Question: Is a bit of dose to all the organ

better than a high dose to a small part of the organ?

thecorrectdosetothecorrectvolume

Dose Volume Histograms are a way to summarize this information

0

20

40

60

80

100

120

0 20 40 60 80Dose (Gy)

Vol

ume

(%)

Comparisonofthreedifferenttreatmenttechniques(red,blueandgreen)intermsofdosetothetargetandacriticalstructure

Target dose

Critical organ

27

The ideal DVH •  Tumor:

–  High dose to all –  Homogenous dose

•  Critical organ –  Low dose to most of the

structure

100%

dose

100%

dose

TCPmodelling

TCP=“long-term”localcontrol~sigmoidalD50=localcontroldosefor50%ofcases(alsocalledTDC50)γ50proportionaltoslopeodTCPvsDosecalculatedatD50

Example:TCPcurveforD50=60Gy,γ50=1.5

Forstandardfractioning:D50:20Gyto100Gyγ50:1-4Gy

γ 50=D dTCPdD D=D50

TCPPoissonModelHyp:Onlyclonogeniccellscanregrowthetumor

N=numberofclonogenes;SF(D)=fractionofclonogenssurvivingatdoseD

TCP ~e−N SF (D)

TCP~e−N SF2D/2

TCPLQ ~e−N e

−αD 1+d / α β{ }⎛⎝⎜

⎞⎠⎟

⎛⎝⎜

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D50~2Log Log2

N⎛⎝⎜

⎞⎠⎟

Log SF2( )

γ 50~ Log22

Log NLog2

⎛⎝⎜

⎞⎠⎟

ProblemiSofttissuecelldensity~109cells/ccDetectabletumors1cc(100cctumorsarecommon)ifN~numberofcells➞N≥109➞𝛾50≥7.3Observations:𝛾50~2

2possibilesolution(notutuallyexcluive!!)1.  TCPiscontrolledbyafewradioresistentclonoves2.  TCPisapopulationaverge:(inter-tumor)differenttumorshavedifferentradiosensitivity(intra-tumor)clonogeswithinatumorvaryinradiosensitivity

Summaryofradiationeffects

•  Targetinradiotherapyisbulktumourandconfirmedand/orsuspectedspread

•  Needtoknowbotheffectsontumourandnormaltissues•  Normaltissuesneedtobeconsideredasawholeorgan•  Radiationeffectsarecomplex-detaileddiscussionof

radiationeffectsisbeyondthescopeofthecourse•  Modelsareusedtoreducecomplexityandallow

predictionofeffects...

normaltissues

•  Sparingofnormaltissuesisessentialforgoodtherapeuticoutcome

•  Theradiobiologyofnormaltissuesmaybeevenmorecomplexastheoneoftumours:– differentorgansresponddifferently–  thereisaresponseofacellorganizationnotjustofasinglecell

–  repairofdamageisingeneralmoreimportant

Differenttissuetypes

•  Serialorgans •  Parallelorgans(e.g.lung)

Tissuesmaybeconsideredtohavefunctionalsubunits(FSU),whereeachsubunitperformssomeofthefunctionofthatorgan.

each FSU performs its functionrelatively independently of the others.Such tissues are considered parallel,and examples include the lung, liverandkidney.

each FSU is critical for the functionofotherFSUs.EachFSUiscriticalforthefunctionofotherFSUs.These organs are considered serial,and include the spinal cord andgastrointestinaltract.

Differenttissuetypes

•  Serialorgans •  ParallelorgansEffectofradiationontheorganisdifferent

In thesetissues, thetotalvolume irradiated isvery important in determining the outcome.Forexample, the liver is capableof sustaininglife even if half its volume is made non-functionalbyradiation.

In these tissues, it is vital thatradiation dosage dose not exceedtolerance at any point. Forexample, loss of one FSU of thespinal cord will lead to loss of allFSUscaudaltothatpoint.

DisclaimerWarning:theconceptofserialandparallelarrangementofFSUs isnot entirely correct, asmany tissues have both serial and parallelcomponents.Forexample,thelungsrelyonthetracheaandairways(serial arrangement) to function. The FSUs of the brain have bothserial and parallel components. It is possible to lose part of theoccipitalcortexandstillhavevision,butifthatpartisthefoveathenfunctionwillbecriticallyimpaired.

DoseVolumeeffects

•  Themorenormaltissueisirradiatedinparallelorgans–  thegreaterthepainforthepatient–  themorechancethatawholeorganfails

•  Ruleofthumb-thegreaterthevolumethesmallerthedoseshouldbe

•  Inserialorgansevenasmallvolumeirradiatedbeyondathresholdcanleadtowholeorganfailure(e.g.spinalcord)

EquivalentUniformDoseTheconceptofequivalentuniformdose(EUD)(Niemierko1997)providesasinglemetric for reporting non-uniform tumor dose distributions. It is defined as theuniform dose that, if delivered over the same number of fractions as the non-uniformdosedistributionofinterest,yieldsthesameradiobiologicaleffect.PhenomenologicalformulareferredtoasthegeneralizedEUD,orgEUD:vi is the fractional organ volume receiving a dose Di and a is a tissue-specificparameter thatdescribes the volumeeffect. For a→–∞,gEUDapproaches theminimumdose;thusnegativevaluesofaareusedfortumors.Fora→+∞,gEUDapproachesthemaximumdose(serialorgans).Fora=1,gEUDisequaltothearithmeticmeandose.Fora=0,gEUDisequaltothegeometricmeandose.gEUD is often used in plan evaluation and optimization because the samefunctionalformcanbeappliedtobothtargetsandOARswithasingleparametercapturingthedosimetric“essence”ofthebiologicalresponse.

gEUD = viDia

i∑⎛⎝⎜

⎞⎠⎟

1a

43

Classificationofradiationeffectsinnormaltissues

•  Earlyoracutereactions–  Skinreddening,erythema

–  Nausea–  Vomiting–  Tiredness

•  OccurstypicallyduringcourseofRTorwithin3months

•  Latereactions–  Telangectesia–  Spinalcordinjury,paralysis

–  Fibrosis–  Fistulas

•  Occurslaterthan6monthsafterirradiation

Classificationofradiationeffectsinnormaltissues

•  Earlyoracutereactions •  Latereactions

Lateeffectscanbearesultofsevereearlyreactions:

consequentialradiationinjury

Lateeffects•  Canoccurmanyyearsaftertreatment•  Canbegraded-lowergradesmorefrequent

TheLinearQuadraticModel

•  Cellsurvival:singlefraction:S=exp(-(αD+βD2))

(nfractionsofsized:S=exp(-n(αd+βd2))•  Biologicaleffect:

E=-lnS=αD+βD2E=n(αd+βd2)=nd(α+βd)=D(α+βd)

Biologicaleffectiveness

E/α=BED=(1+d/(α/β))*D=RE*D

•  BED=biologicallyeffectivedose,thedosewhichwouldberequiredforacertaineffectatinfinitesimallysmalldoserate(nobetakill)

•  RE=relativeeffectiveness

BEDusefultocomparetheeffectofdifferentfractionationschedules

•  Needtoknowα/βratioofthetissuesconcerned.•  α/βtypicallylowerfornormaltissuesthanfortumour

Thelinearquadraticmodel

0.001

0.01

0.1

1 0 2 4 6 8 10

Pro

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of c

ell s

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Dose (Gy)

cell kill (low α/β) cell kill (high α/β)

Thelinearquadraticmodel

0.001

0.01

0.1

10 2 4 6 8 10

Dose (Gy)

Prob

abili

ty o

f cel

l sur

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cell kill (low a/b)cell kill (high a/b)

Alphadeterminesinitialslope

Betadeterminescurvature

Ruleofthumbforα/βratios•  Largeα/βratios•  α/β=10to20

–  Earlyoracutereactingtissues

– Mosttumours

•  Smallα/βratio•  α/β=2

–  Latereactingtissues,e.g.spinalcord

–  potentiallyprostatecancer

Theeffectoffractionation

0.001

0.01

0.1

10 2 4 6 8 10

Dose (Gy)

Prob

abili

ty o

f cel

l sur

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l

cell kill (low a/b)cell kill (high a/b)fractionated (low a/b)fractionated (low a/b)

Fractionation

•  Tendstosparelatereactingnormaltissues-thesmallerthesizeofthefractionthemoresparingfortissueswithlowα/β

•  Prolongstreatment

Anoteofcaution

•  Thisisonlyamodel•  Needtoknowtheradiobiologicaldataforpatients

•  Importantassumptions:– Thereisfullrepairbetweentwofractions– Thereisnoproliferationoftumourcells-theoveralltreatmenttimedoesnotplayarole.

3.The4Rsofradiotherapy

•  RWithers(1975)

•  Reoxygenation•  Redistribution•  Repair•  Repopulation(orRegeneration)

Reoxygenation•  Oxygenisanimportantenhancementforradiationeffects(“OxygenEnhancementRatio”)

•  Thetumourmaybehypoxic(inparticularinthecenterwhichmaynotbewellsuppliedwithblood)

•  Onemustallowthetumourtore-oxygenate,whichtypicallyhappensacoupleofdaysafterthefirstirradiation

Redistribution•  Cellshavedifferentradiationsensitivitiesindifferentpartsofthecellcycle

•  HighestradiationsensitivityisinearlySandlateG2/Mphaseofthecellcycle

G1

G1

S(synthesis)

M(mitosis)G2

Redistribution

•  Thedistributionofcellsindifferentphasesofthecycleisnormallynotsomethingwhichcanbeinfluenced-however,radiationitselfintroducesablockofcellsinG2phasewhichleadstoasynchronization

•  Onemustconsiderthiswhenirradiatingcellswithbreaksoffewhours.

Repair•  Allcellsrepairradiationdamage•  ThisispartofnormaldamagerepairintheDNA•  RepairisveryeffectivebecauseDNAisdamagedsignificantlymoredueto‘normal’otherinfluences(e.g.temperature,chemicals)thanduetoradiation(factor1000!)

•  Thehalftimeforrepair,tr,isoftheorderofminutestohours

Repair•  Itisessentialtoallownormaltissuestorepairallrepairableradiationdamagepriortogivinganotherfractionofradiation.

•  Thisleadstoaminimumintervalbetweenfractionsof6hours

•  Spinalcordseemstohaveaparticularlyslowrepair-therefore,breaksbetweenfractionsshouldbeatleast8hoursifspinalcordisirradiated.

Repopulation•  Cellpopulationalsogrowsduringradiotherapy•  Fortumourcellsthisrepopulationpartiallycounteractsthecellkillingeffectofradiotherapy

•  Thepotentialdoublingtimeoftumours,Tp(e.g.inheadandnecktumoursorcervixcancer)canbeasshortas2days-thereforeonelosesupto1Gyworthofcellkillingwhenprolongingthecourseofradiotherapy

Repopulation

•  Therepopulationtimeoftumourcellsappearstovaryduringradiotherapy-atthecommencementitmaybeslow(e.g.duetohypoxia),howeveracertaintimeafterthefirstfractionofradiotherapy(oftentermedthe“kick-offtime”,Tk)repopulationaccelerates.

•  Repopulationmustbetakenintoaccountwhenprotractingradiatione.g.duetoscheduled(orunscheduled)breakssuchasholidays.

RepopulationRegeneration

•  Alsonormaltissuerepopulate-thisisanimportantmechanismtoreduceacutesideeffectsfrome.g.theirradiationofskinormucosa

•  Radiationschedulesmustallowsufficientregenerationtimeforacutelyreactingtissues.

The4Rsofradiotherapy:Influenceontimebetweenfractions,t,andoveralltreatmenttime,T

•  Reoxygenation

•  Redistribution

•  Repair

•  Repopulation(orRegeneration)

NeedminimumT

Needminimumt

NeedminimumtfornormaltissuesNeedtoreduceTfortumour

Cannotachieveallatonce-Optimizationofscheduleforindividualcircumstances

Time,doseandfractionation

•  Needtooptimizefractionationscheduleforindividualcircumstances

•  Parameters:– Totaldose– Doseperfraction– Timebetweenfractions– Totaltreatmenttime

ExtensionofLQmodeltoincludetime:

E=-lnS=n*d(α+βd)-γT

•  γequalsln2/TpwithTpthepotentialdoublingtime

•  notethattheγTtermhastheoppositesigntotheα+βdtermindicatingtumourgrowthinsteadofcellkill

Thepotentialdoublingtime

•  thefastesttimeinwhichatumourcandoubleitsvolume

•  dependsoncelltypeandcanbeoftheorderof2daysinfastgrowingtumours

•  canbemeasuredincellbiologyexperiments•  requiresoptimalconditionsforthetumourandisaworstcasescenario

ExtensionofLQmodeltoincludetime:

E=-lnS=n*d(α+βd)-γT

IncludingTk("kickofftime")whichallowsforatimelagbeforethetumourswitchestothe

fastestrepopulationtime:

BED=(1+d/(α/β))*nd-(ln2(T-Tk))/αTp

Part3,lecture2:Highdosesinradiationtherapy 69

Evidencefor“kickoff”time

UseoftheLQmodel

•  Calculate‘equivalent’fractionationschemes•  Determineradiobiologicalparameters•  Determinetheeffectoftreatmentbreaks

– e.g.Doweneedtogiveextradoseforthelongweekendbreak?

Calculationofequivalentfractionationschemes

•  AssumetwofractionationschemesareidenticalinbiologicaleffectiftheyproducethesameBEDBED=(1+d1/(α/β))n1d1=(1+d2/(α/β))n2d2

Thisisobviouslyonlyvalidforonetissue/tumourtypewithonesetofalpha,betaandgammavalues

•  Exampleattheendofthelecture