Radiobiology: A Briefing for the Brachytherapist · The role of radiobiology in treatment planning...
Transcript of Radiobiology: A Briefing for the Brachytherapist · The role of radiobiology in treatment planning...
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Radiobiology: A Briefing for the Brachytherapist
Marco ZaiderDepartment of Medical Physics
MSKCC, New York
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Plan of Presentation:
• Who needs radiobiology?• The nuts and bolts (kinds of effects, dose-
response curves, hits, temporal aspects, RBE and OER, cellular proliferation)
• Mechanisms of radiation action (rudiments of microdosimetry, LQ model, temporal aspects redivivus)
• Applications (equivalent treatments, radiation quality)
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The role of radiobiology in treatment planning is threefold:
• To provide information on biologically-equivalent temporal patterns of dose delivery
• To quantify the effect of radiation quality (relevant to low-energy brachytherapy)
• To guide biologically-based optimization algorithms
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Kinds of Effects:
• Stochastic (all or none): where radiation has no effect on the nature of the observed outcome; instead, it may change the probability of causing the effect.
• Deterministic: where the severity of the effect may change as a function of dosage.
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ExerciseExercise: classify the following as stochastic or deterministic
• Effect of radiation on normal tissues• Normal tissue complication probability
(NTCP)• Tumor control probability (TCP)• Answering correctly these questions
(including this one…)
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Notation and conventions:
E(D): probability of effect (any effect!)
S(D)=1-E(D): probability of the absence of effect (aka survival probability, although nothing needs to actually survive…)
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Dose response curves are important because they help us
understand, for instance, whether:
• the effect is a result of single or multiple radiation-induced lesions
• the temporal pattern of dose delivery matters
• the outcome depends of the position of the cell in the cell cycle
• the radiation-induced damage is repairable
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An exponential dose response curve indicates a single-hit mechanism of radiation action
( ) , 0DS D e α α−= >
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A concave downward dose effect curve shows an accumulation of sublesions and represents a multi-hit mode of radiation action.
2
( ) ,, 0
D DS D e α β
α β
− −=>
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Interpretation:
• Exponential response: Surviving cells have no memory of previous exposure to radiation (single-hit effect)
• Concave response: cells carry residual damage (sublesions), several of which produce lesions (multi-hit effect)
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Hits: what are they?
The dots indicate the locations of energy deposition (ionizations or excitations) by a hypothetical charged-particle track in tissue. Also shown are two cells – one traversed by the main track and the other by a secondary electron (delta ray). The ensemble of energy deposition sites within the radiosensitive volume which are associated with one track defines a (microdosimetric) event.
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Different patterns of dose delivery:Single (acute) exposure
Protracted irradiation
Fractionation
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Treatment with an exponentiallyTreatment with an exponentially--decaying decaying dose rate (this is typical of brachytherapy):dose rate (this is typical of brachytherapy):
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Temporal aspects:
As the dose rate decreases the quadratic term (βD2) becomes increasingly smaller. At very low dose rates only the linear term, αD, remains (dashed curve). Lower solid curve: acute exposure; upper dashed curve: protracted exposure.
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Terminology:• Event (physical hit): the traversal of a cell by
an ionizing particle. Events are instantaneous, and occur randomly in space and in time.
• Lesion (biological hit): cellular damage that results in the observed effect
• Sublesion: damage not sufficient to produce the effect but enough to enhance its induction probability at subsequent exposures.
• Low dose: dose where the effect is proportional to dose and independent of dose rate
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Definition of Relative Biological Effectiveness (RBE)
A comparison of two ionizing radiations for producing the same biological effect.
effectthegivetoradiationofDose
effectbiologicalsomegivetoradiationofDose
sametest
reference
RBE =
(all other experimental condition being equal)
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Relative Biological Effectiveness (RBE)
A
B
DRBED
=
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Oxygen enhancement ratio (OER)Oxygen enhancement ratio (OER)
anoxic
oxic
DOERD
=
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RBE and OER as a function of LETRBE and OER as a function of LET
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Cellular proliferation
• The cell cycle of actively dividing cells is conventionally divided in four stages: G1, S, G2 and M.
• Cells are most radiosensitive in M phase and most radioresistant in the latter part of S
• Exposure to radiation results in a lengthening of the G2 phase (this is known as the G2 block)
• Exposure to radiation decreases the division probability
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αα and and β (β (and thusand thus RBERBE) ) depend on celldepend on cell--cycle agecycle age
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Cell proliferation in Cell proliferation in tumorstumors
• Proliferating cells (P)• Quiescent cells (Q) in G0
• Differentiated cells (sterile)• Necrotic cells
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Transfer of cells between Transfer of cells between compartmentscompartments
• Q to P (recruitment)• P to Q•• Cell lossCell loss: failure to divide,
differentiation, leaving the tumor volume (metastasis), death
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Tumor growth rateTumor growth rate•• TTdd = tumor volume doubling time•• TTcc = cell cycle time (clonogen doubling
time)•• TTpotpot = potential doubling time (no cell
loss)• Cell loss factor: φ = 1-Tpot/Td
• GF=growth factor (fraction of cells actively proliferating)
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Kinetic parameters of a Kinetic parameters of a typical human tumortypical human tumor
• Cell cycle time (Tc): ~ 2 days• Growth fraction: ~ 40%• Potential doubling time (Tpot): ~ 5 days• Cell loss: ~ 90%• Volume doubling time (Td): ~ 60 days
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The kinetics of cell growth:1 ln 2
1 ln(1 )d cT TGFϕ
=− +
ln 2ln(1 )pot cT T
GF=
+
1 pot
d
TT
ϕ = −
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MicrodosimetryMicrodosimetry is the systematic study and quantification of the spatial and temporal distribution of absorbed energy in irradiated matter. It deals with the stochasticsof energy deposition.
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Ionizing radiation is uniquely efficient in its action on matter (including living matter) because:
• it transfers energy in a highly concentrated form,
• ionizations are produced in spatially correlated patterns in the tracks of charged particles.
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Definitions (I):Definitions (I):•• Ionizing particlesIonizing particles: charged or uncharged
particles capable of ionization in primary or secondary interactions.
•• Energy depositEnergy deposit:•• Transfer pointTransfer point: the point of interaction•• Energy impartedEnergy imparted in a volume (site):•• Specific energySpecific energy:
i in outε =T -T +Q
∑ ii
ε= ε
ez =m
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Definitions (II):
• Absorbed dose:
• Frequency distributions: f(z), f1(z), f(y)• Dose distributions:
→V 0D = zlim
zf(z)d(z) =D
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Definitions (III):• Frequency averages:
• Dose averages:
• Event frequency:
∞
∫F 10z = z f (z)dz
∞
∫ 2D 10
F
1z = z f (z)dzz
F
Dn=
z
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A microdosimetric account of the LQ formalism
2
2 2
2
( )
( ) ( )
( )
D
D
E z z
E D z z D D
z
D D D
β
β βαβ
ε α β
=
= = +
=
= +
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Dα
2Dβ
IntraIntra--track event (single track)track event (single track)
InterInter--track event (two tracks)track event (two tracks)
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Temporal aspects (II):
2( ) ( )D D q t Dε α β= +
0( ) ( )q t h t dtτ
∞= ∫
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q(t/τ)
( )rerr
rq
tr
−−⎟⎠⎞
⎜⎝⎛−=
=
122)( 2
τ
For irradiation at a constant dose rate (t=irradiation time, τ= mean repair time)
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To find equivalent treatments use:
1,
1211111
2
potpot TtDqD
TtqDD −+=−+ βαβα
t= total treatment time
Tpot= mean potential doubling time
τ= mean repair time of sublesions
For f fractions: q=1/f
For t >> τ : q=2τ/t (τ~1 hour)
Other relations: t=D/R (R=dose rate)
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( )( )
hGyD
hGyDPd
hGyDI
Gy
Gytimerepairh
HDR
LDR
LDR
respondinglate
respondingearly
/90
/20.0)(
/07.0)(
3/
10/)(5.0
103
125
=
=
=
=
==
•
•
•
−
−
βα
βατ
Some typical numerical valuesSome typical numerical values
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Radiation quality
Radionuclide zD/zD(Co)
Pd-103 2.3
I-125 2.1
Am-241 2.1
Ir-192 1.3
Co-60 1.0