infn milanopcbat1.mi.infn.it/~battist/fisicamedica/lecture6_radiobiology.pdf · aspe% di...
TRANSCRIPT
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Aspe%diradiobiologia
G.Ba&stoniINFNMilano
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Interdisciplinaryaspects:PhysicsandBiology
pontheBraggpeakwhenRres~0.2mmE~4MeVLET~10keV/μm<d>~4nm
12ContheBraggpeakwhenRres~1mmE~17MeV/uLET~140kev/μm<d>~0.3nm
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Effetto microscopico dei raggi X
5 µm
e- range = 15 mm X ray = 4 MeV
LET = ΔE/ Δx espresso in
keV/µm = eV/nm
ΔE
Δx
(CortesiadiU.Amaldi)
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150 ionizzazioni/cell
(Fcell ≈20-30 mm)
Effetto microscopico dei raggi X
d = 40 eV / LETeV/nm≈ 200 nm
5 µm
e- range = 15 mm X ray = 4 MeV
LET = ΔE/ Δx espresso in
keV/µm = eV/nm
ΔE
Δx
LET elettrone 0.2 keV/µm
200 nm
(CortesiaU.Amaldi)
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res R
Kin En. d_av
Microscopic distribution of the hadronic ionizations electron 0.3 keV/μm
d = 40 eV / LETeV/nm= 130 nm
- 260 mm 200 MeV d=90 nm
20 nm 2 nm
Protons are quantitatively different from X-rays
Protons are SPARSELY IONIZING
keV/μm 0.45
- 75mm 100 MeV d=50 nm
- 4 mm 20 MeV d=15 nm
- 0.2 mm 4 MeV d=4 nm
keV/μm 0.45 0.55 2.5 10
CourtesyU.Amaldi
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Microscopic distribution of the hadronic ionizations
res R
Kin En. d_av
- 260 mm 200 MeV d=90 nm
- 75mm 100 MeV d=50 nm
- 4 mm 20 MeV d=15 nm
- 0.2 mm 4 MeV d=4 nm
20 nm
keV/μm 0.45 0.55 2.5 10
2 nm
- 260 mm 4800 MeV
d=4 nm
- 100 mm 2800 MeV
d=3 nm
- 42 mm 1800 MeV d= 2 nm
- 1 mm 200 MeV d=0.3 nm
keV/μm 10 14 20 140
SSB Å
DSB Æ
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d=130 nm
Protons: 1. more favorable dose 2. same ‘indirect effects’
30 cm
Beam of 200 MeV protons
X-rays beam
d=50 nm
d= 15 nm
d=90 nm
Protons are SPARSELY IONIZING as X-rays
CourtesyU.Amaldi
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d=130 nm
Carbon ions: 1. more favorable dose 2. ‘direct effects’
30 cm
Beam of 200 MeV protons
X-rays beam
Carbon ions are DENSELY IONIZING (higher biological effectiveness)
Beam of 4800 MeV carbon ions
d= 4 nm
d= 2 nm
d= 0.3 nm
CourtesyU.Amaldi
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EquivalentDose,RBE(Sv)
9
we are mainly concerned with supplying a prescribed physical dose to aprescribed volume. However, dose all by itself is not a very good measure ofbiologicaleffect. Itsadvantagesarethat it’seasytodefineandrela]velyeasytomeasure.(Intheearlydaysaquan]tycalledexposure,ameasureoftheioniza-onproduced,wasusedinstead.)
Thebiologicaleffectofagivendosedependsonthetypeofradia]on,thetarget]ssue, the frac]on of an organ exposed and the ]ming of dose delivery(frac]ona]on). In radiobiology, the ‘rela=ve biological effec=veness’ (RBE)of aradia]on type is defined as the ra]o of the dose of a standard radia]on,frequently60Coγrays,tothedoseoftheradia]oninques]onthatgivesthesamebiologicaleffect.
Equivalent dose has its own units: sieverts (Sv) correponding to Gy and rem(‘roentgenequivalentman’)correspondingtorad.
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TheDose-Survivaldependence
La curva di sopravvivenza previstadal modello mul]target nonrappresentabeneipun]spermentali nella regione dellebassedosidove ida]sperimentaliindicano una pendenza ≠ 0. Nondescriveinoltrelacurvaturanellaregionedelledosimedio-alte.→ Entrambe le regioni di dosesono meglio descriie da unafunzionedel]po:
S=exp(-αD-βD2)
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EfficaciaBiologicaRela]va(RBE)• RBE:rapportotraladosediunaradiazionediriferimento(DRX)e
ladosedellaradiazioneinesame(Dr)necessarieperoienerelostessolivellodell’effeiobiologicoconsiderato
0
...SFSFr
RX
DDEBR
=⎟⎟⎠
⎞⎜⎜⎝
⎛= D0
SFXR
SFp
0DDp
XR
SFSFRBE
=⎟⎟⎠
⎞⎜⎜⎝
⎛=
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Usodidiversequalitàdiradiazione.IlconceiodiRBE
12G. Battistoni 08/06/2015
EfficaciaRadiobiologica(numeropuro)
Il danno biologico è proporzionale al prodotto: RBE * Energia deposta
RaggiXRBE=1ProtoniRBE~1.112-CRBE~3-4
Aienzione:RBE=F(par]cella,Energia,LET,]podicellula,...)
èil“dato”piùdelicatoperilradioterapista
Daindagare!!!
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Notesull’RBE
àL’RBEdiunaradiazionenonèunagrandezzaunivoca……madipende:- dalladefinizioneusataperilcalcolo;- dall’effeiobiologicoconsiderato(p.e.:sopravvivenzaoinduzionedi
mutazioni);- dallivellod’espressioneconsideratoperundatoeffeiobiologico;- dallalineacellulareconsiderata.
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Dipendenzadallivellod’espressione
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RBEvsLET
(Skarsgards, Physica Medica 14, Suppl 1,(1998)1-19)
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RBEvsLET
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CHAPTER 1. INTRODUCTION 14
Figure 1.4: Correlation between physical and biological dose, cell survival andRBE. Top picture shows the physical and biological dose for a spreadout Braggpeak ranging from 6 to 10 centimeter. The corresponding cell survival is shownin the middle picture and the RBE in the bottom picture. (after [Wey03], imagefrom [Cre06])
a uniform load with dose over the whole tumour) ranging from 6 to 10 centimeters. Thecorresponding cell survival is shown in the middle picture and the RBE in the bottom picture.It is worth to note that the RBE is energy dependent and therefore, the physical dose in theBragg Peak is not constant in order to reach constant biological dose.
The knowledge of the the spatial dependency of ρ, Φ, LET and RBE for all Nz projectilesthat can be created by nuclear fragmentation, leads to a realistic description of the biologicaldose:
Dbiol(r) =1
ρ(r)
Nz!
z=1
E"
0
Φ(z,E, r) LET (z,E) RBE(z,E) dE (1.5)
Range straggling and lateral scattering
When a charged particle is traversing a medium it undergoes not only the already mentionedinelastic collisions with the atomic electrons but also elastic Coulomb scattering with thenuclei of the target. This happens frequently and is therefore, called multiple Coulomb scat-
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PerfareunSOBPuniforme...
Tsujii2007
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OxygenEnhancementRa]o
ioniadaltoLEThannounOERmoltoinferiorerispeioairaggiX
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JRadiatRes.2014Sep;55(5):902–911.LauraAntonovicetal.
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La]picaa&vitàdelradiobiologosperimentale
0 2 4 6 8 101E-3
0,01
0,1
1
LN229 cells 6 MeV photons 50 keV/ µm C ions 95 keV/ µm C ions 218 keV/ µm C ions
Sur
vivi
ng fr
actio
n
Dose ( Gy )Coloniedicellulediglioblastomaumanoformatedacellule
irraggiate(asinistra)enon(adestra).
Incubazionedeicampionia37°Cper14giorniIrraggiamentodeicampioni
Campionifissa=ecolora=
Cellulecol=vateinvitropreparateperl’irraggiamento
CurvediSopravvivenzacellularevsDose
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Field10x10 cm2, 33x33 spots,
scanning step 3 mm
In collaboration with INFN groups (LNL, Mi, Na, Rm3, ISS)
EsempidimisureeffeiuatealCNAO
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Survival curves – Protons: cells HSG
RBE value 1.1
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Horizontal beam of carbon ions 3 animals per field
In vivo experiments
In collaboration with NIRS and UniPv
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Results ü Survival curves of cells crypts in 3 SOBP positions
Carbon beam at CNAO is biologically
identical to the ones in NIRS and GSI
(difference in RBE < 7%)
Facility Beamposition
D10(Gy) VarianceD10
RBE10 Variance(%)
Cobalt-60γrays
--- 14.86±0.08(*)
NIRS Proximal 10.38(+) 1.44(*) Middle 9.46(+) 1.57(*) Distal 8.29(+) 1.80(*)
GSI Proximal 10.21(+) 1.47(*) Middle 9.40(+) 1.63(*) Distal 8.37(+) 1.80(*)
CNAO Proximal 9.85 5.1%NIRS3.5%GSI
1.51 4.7%NIRS2.7%GSI
Middle 9.75 3.1%NIRS3.7%GSI
1.52 3.18%NIRS6.7%GSI
Distal 8.5 2.5%NIRS1.5%GSI
1.75 2.78%NIRS2.78%GSI
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L’importanzadiavereadisposizioneunmodelloradiobiologico
• PergliioniloRBE(Rela]veBiologicalEffec]veness)puo’cambiareanchediunfaiore3passandodalplateaualpiccodiBragg
• LemisuresperimentalichefornisconoilvaloredelloRBEinfunzionedel]podicellulaeperdiversecondizionidiirraggiamento(speciediione,Energia,profondita’nelmezzo)sonopiuiostolimitate.
• Ilpassaggiodacampidisegmen]monoenerge]ciasovrapposizionedicampimul]plinone’facilmenteriproducibilesperimentalmente
• Necessita’diunmodellopers]mareloRBEinfunzionedi:ione,energia,profondita’,lineacellulareefinalmentedicampimul]pli
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Introduc]ontotheLocalEffectModel(GSI)
TreipotesibasilaridelLocalEffectModel(LEM):1. L’effeiobiologicoe’interamentedeterminatodalladistribuzione
localedelladosedentroilnucleocellulare
2. Il danno biologico dipende solo dal valore di aspeiazione deladeposizione di energia. Non c’e’ differenza per quanto riguardal’effeiodovutaadosedepositatalocalmentedaraggiXedaioni/protoni: In ul]ma analisi l’energia e’ deposta in ogni caso daglieleironisecondariemessi
3. Il nucleo cellulare e’ omogeneo, con densita’ e radiosensibilita’costante
M. Scholz et al (GSI)
Ilmodellononsiproponedidefinireimeccanismidiina%vazionecellularemadidareunas=madeglieffe%medidocu=adunadoselocale
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0/
)(2
===
rDDrDo
o r<rminconrmin=10nm(]picamente)
r>rmax
rmaxe’calcolatoinfunzionedellamassimaenergiatrasferibileall’eleirone=gEd cong=0.05,d=1.7oveEe’l’energiapernucleonedelloioneincidente
Doe’calcolatoimponendochel’integralesiaparialladosedepositata
rmin<r<rmax
DistribuzioneRadialedellaDose
Andamentodell’energiamediadepositatainfunzionedelladistanzardallatraieioriadiunapar]cellaionizzante(assedellatraccia)
Ledifferenzetrapar=cellecaricheefotonidevonoessereaTribuitealledifferen=dipendenzespazialidelladeposizionedienergia
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SuccessivaparametrizzazionepubblicatadaigruppiGSI
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EsempioperioneCa3MeV/u
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Schema]zzazionedelnucleocellulare
Soloilnucleocellularee’assuntocomebersagliobiologicamenterilevanteModellizzatocomecilindrodiareaAnuclealtezzahnuclconasseparallleoallatraieioriadegliioniTipicamente:Rnucl~5.5μm(celluleCHO)
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Schema della deposizione di dose La dose locale, per un dato numero di ioni incidenti, in ogni punto del nucleo cellulare si ottiene sommando i contributi delle singole tracce
Il modello individuera’ l’effetto biologico locale corrispondente ad una data dose (locale) avvalendosi di una curva dose-effetto relativa ai raggi X
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La sopravvivenza di una coltura cellulare irraggiata con raggi X è SX=n/ntot n: numero medio cellule che non subiscono danni ntot : numero totale cellule componenti la coltura
Inattivazione cellulare induzione eventi letali
Sopravvivenza cellulare assenza di eventi letali Nlet
Calcolodellaprob.disopravvivenza
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• La probabilità di avere k eventi letali è
• La probabilità di non avere eventi letali, ovvero di sopravvivenza è
Calcolodellaprob.disopravvivenza
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Nell’ipotesifondamentedelmodelloperlaqualel’effeiobiologicoderivante dalla deposizione locale e’ indipendente dal ]po diradiazione possiamo estendere il ragionamento ancheall’irraggiamentoconioni.
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4008/06/2015G.Ba&stoni
Assumendoquindicheallastessadoselocalecorrispondalostessodannolocalepossiamoscrivere:
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Implementazione• curvadisopravvivenzaperX,SX,infunzionedelladose,D,
perraggiXsecondoilmodelloL-Q(Linear-Quadra]c):doveαXβXDcutesmaxdipendonodallalineacellulare
− ln(SX) =α XD + βXD2
α XDcut + βXDcut2 + smax(D −Dcut )
D<Dcut
D>Dcut
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EsempiodeiparametriperraggiX(dapubblicazioneGSI)
4208/06/2015G.Ba&stoni
Tissue aX (Gy-1)
bX
(Gy-2) Dcut
(Gy) smax
(Gy-1) Rnucl
(mm) Human brain
0.1 0.05 30 3.1 5
CHO 0.228 0.02 30 1.34 5.5 Pig lung 0.068 0.017 15 0.57 2 Pig skin 0.017 0.003 15 0.1 3 Rat CNS 0.1 0.05 30 3.1 5 Adenoid 0.016 0.022 22 0.98 3 Chordoma 0.1 0.05 30 3.1 5
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Inalto:distribuzionedidosediunfasciodiioniC+6
Inbasso:confrontomisuresopravvivenza(pun])ecalcolo(linea)percelluleCHO
Qualcheconfronto:
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Confronto con dati sperimentali a 270 MeV
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LEMEvolu]on
4508/06/2015G.Ba&stoni