Treatment Planning - Istituto Nazionale di Fisica...
Transcript of Treatment Planning - Istituto Nazionale di Fisica...
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
222 ][][ OAROARi
biT
mi
bi DDDD
T
−+−=Χ ∑∑∈∈
Input:
• Hounsfieldnumbers(dallaCT)deivoxelsincuièsuddivisol’interovolumeanatomico
• Identificazionedapartedelclinicodelvolumedatrattareeladosedasomministrareedegliorgan-at-risk(OAR)eladosemassima
Sipuòscriverelafunzione-costodaminimizzareecomeesempiosipuòusarelaseguente:
ovelasommasieseguesututtiivoxelsdiinteresse(mTeOAR)eDi
brappresentaladosebiologicafornitaalvoxeli-esimo
Esempio1-D
Parecchifascicontribuisconosuunmedesimovoxel:
• dafascichearrivanodalmedesimocampodiirraggiamento
• dadifferenticampi
Percuilafunzione-costosiriscrivecome:
22 ])([ Tlli
l
cond
Vii DfdRBE −∗∗=Χ ∑∑
∈
• dilèladosefisicaunitariarilasciatadalfasciol-esimosulvoxeli-esimo
• flèlafluenza(dadeterminare)delfasciol-esimo
• RBEièilrelativebiologicaleffectivenesssulvoxeli-esimomediatosututtiifascicherilascianodosesulvoxeli-esimo
22 ][ T
cond
Vii SS −=Χ ∑
∈
Sipuòriscriverelafunzione-costointerminidisopravvivenzapiuttostochedidose:
oveSirappresentalasopravvivenzadelloi-esimovoxelmediatasututtiifascicherilascianodosesulmedesimovoxel.Assumendo:
• relazionefrasopravvivenzaedosedeltipolineare-quadratica:
)exp( 2DDS βα −−=• leseguentirelazionipermediarea e bsuicampimisti
∑∑
∗
∗∗=
ll
li
ll
li
li
i fd
fdαα
∑∑
∗
∗∗=
ll
li
ll
li
li
i fd
fdββ
Passandoallnlafunzionedaminimizzareè:
])([ 222TXTXl
li
li
cond
Vi ll
lii DDfdfd ∗−∗−∗+∗=Χ ∑∑ ∑
∈
βαβα
fluenze:incognitedadeterminare
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{ }⎛⎝⎜
⎞⎠⎟
⎛⎝⎜
⎞⎠⎟
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
babi
lity
of c
ell s
urvi
val
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
viva
l
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
viva
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