A MechanismA Mechanism--Based Approach to …...A MechanismA Mechanism--Based Approach to Predict...

A MechanismA Mechanism--Based Approach to Predict Relative Based Approach to Predict Relative i i ff i ff fi i ff i ff fBiological Effectiveness and the Effects of Tumor Biological Effectiveness and the Effects of Tumor

Hypoxia in Charged Particle RadiotherapyHypoxia in Charged Particle Radiotherapy

David J. Carlson, Ph.D.David J. Carlson, Ph.D.Assistant ProfessorDepartment of Therapeutic Radiologyp p gyYale University School of [email protected]://radonc.yale.edu

Presented at the2011 Joint AAPM/COMP Meeting in 2011 Joint AAPM/COMP Meeting in VancouverVancouver

Therapy Symposium:Therapy Symposium:P di ti d E l iti th Eff t f R di ti Q lit i I ThPredicting and Exploiting the Effects of Radiation Quality in Ion Therapy

Date and Time: Date and Time: August 2, 2011 from 4:30-6:00 PMLocation: Location: Ballroom A

Yale University School of Medicine, Department of Therapeutic RadiologyYale University School of Medicine, Department of Therapeutic Radiology

DisclosuresDisclosuresDisclosuresDisclosures

Conflict of interestConflict of interest:: None


OverviewOverview

Monte Carlo Damage Simulation (MCDS)Monte Carlo Damage Simulation (MCDS)

OverviewOverview

• Simple and fast Monte Carlo scheme used to estimate overall yield of DSB, SSB, and clustered base damage produced in cells by low- and high-LET radiation

• Nucleotide-level maps of spatial configuration of lesions within a DNA segment

RepairRepair--MisrepairMisrepair--Fixation (RMF) ModelFixation (RMF) Model• Kinetic reaction-rate model relates DSB induction and processing to cell death• Provides formulas linking LQ radiosensitivity parameters to DSB induction andProvides formulas linking LQ radiosensitivity parameters to DSB induction and

repair that explicitly account for unrejoinable DSB, misrepaired DSB, and exchanges formed through intra- and inter-track DSB interactions

RMF d MCDS d l d i bi ti tRMF d MCDS d l d i bi ti t RMF and MCDS models used in combination to:RMF and MCDS models used in combination to:• Predict trends in intrinsic radiosensitivity with particle LET• Investigate putative mechanisms of cell death for low- and high-LET radiation

D i ti l ti t f th RBE d HRF f DSB d ll killi f• Derive practical estimates of the RBE and HRF for DSB and cell killing for clinically-relevant charged particle therapy (e.g., protons and carbon ions)

• Investigate the interplay between RBE and oxygen effects


RadiationRadiation induced DNA damageinduced DNA damage

Many experiments for all types of clustered DNA damage, including DSB, show that damage formation is proportional to dose up to hundreds of Gy

RadiationRadiation--induced DNA damageinduced DNA damage

show that damage formation is proportional to dose up to hundreds of Gy

(n = 2 lesions)

DSBs are formed through DSBs are formed through ggoneone--tracktrack mechanismsmechanisms

DSB induction in human fibroblastsDSB induction in human fibroblasts (MRC-5) irradiated by 90 kVp x-rays (Rothkamm and Lobrich 2003)


OneOne and twoand two track radiation damagetrack radiation damageOneOne-- and twoand two--track radiation damagetrack radiation damage

Lethal lesions are created by the actions of one or two radiation tracks

1 track damage1 track damage(( DD))

Lethal DSB misrepair, Lethal DSB misrepair, Pairwise interaction Pairwise interaction ppunrepairable damageunrepairable damage

2 track damage2 track damage

of two DSBsof two DSBs

Pairwise interaction Pairwise interaction of two DSBsof two DSBs

2 track damage2 track damage(( DD22))


DSB Processing PathwaysDSB Processing PathwaysDSB Processing PathwaysDSB Processing PathwaysOneOne--track action:track action:

1) Non-lethal damageCorrectrepair

OneOne--track action:track action:1) Non-lethal damage

Correctrepair

1 DSB1 DSB Incorrectrepair

3) Non-lethal damage

2) Lethal damageIncorrect

repair

Intrinsically 4) L th l d

1 DSB1 DSB Incorrectrepair

3) Non-lethal damage

2) Lethal damageIncorrect

repair

Intrinsically 4) L th l d

Lethal binary 6) L th l d

Intrinsicallyunrejoinable

4) Lethal damage

Damage fixation(unrejoined DSB)

5) Lethal damage

Lethal binary 6) L th l d

Intrinsicallyunrejoinable

4) Lethal damage

Damage fixation(unrejoined DSB)

5) Lethal damage

Lethal binarymisrepair

2 DSB2 DSB

6) Lethal damage

7) Non-lethal damageStable binaryi i

Lethal binarymisrepair

2 DSB2 DSB

6) Lethal damage

7) Non-lethal damageStable binaryi imisrepair

TwoTwo--track action:track action:8) Lethal damageLethal binary

misrepair

misrepair

TwoTwo--track action:track action:8) Lethal damageLethal binary

misrepair

2 DSB2 DSB

9) Non-lethal damageStable binarymisrepair

2 DSB2 DSB

9) Non-lethal damageStable binarymisrepair


RMF interpretation of LQ parametersRMF interpretation of LQ parametersRMF interpretation of LQ parametersRMF interpretation of LQ parameters

Surviving fraction is related to yield of fatal lesionsSurviving fraction is related to yield of fatal lesions

2( ) exp ( ) expS D F D GD

1 Unrejoinable and lethal damage 3. Intra-track DSB interactions

(1 ) [ / ][ ]R R Rf f f

1. Unrejoinable and lethal damage 3. Intra track DSB interactions

2[ /(2 )][ ]( )Rf

2. Lethal misrepairand fixation

4. Inter-track DSB interactions

[ ( )][ ]( )Rf

fR ≡ fraction of potentially rejoinable DSB ≡ rate of DSB repair (~10-1100 h-1) ≡ rate of binary misrepair ( 10-5 10-4 h-1)

≡ expected # of DSB (Gy-1 cell-1) ≡ prob. DSB lethally misrepaired/fixed ≡ prob exchange type aberration lethal ≡ rate of binary misrepair (~10 510 4 h 1)

≡ zFfR ≡ # of DSB per track per cell ≡ prob. exchange-type aberration lethal

Carlson DJ, Stewart RD, Semenenko VA, Sandison GA. Combined use of Monte Carlo DNA damage simulations and deterministic repair models to examine putative mechanisms of cell killing. Radiat. Res. 2008; 169: 447459.


Predicting trends in radiosensitivityPredicting trends in radiosensitivityPredicting trends in radiosensitivityPredicting trends in radiosensitivity

Cell-specific model constants calculated based on

21x Fz

2

2 x

1 50

1.75 0.25

2/ 2 2Fz

low-LET reference parameters for 200 kVp X-rays: /x x

2x

(G

y-1)

0 75

1.00

1.25

1.50

(G

y-2)

0 10

0.15

0.20 F

0.00

0.25

0.50

0.75 0.00

0.05

0.10

LET (keV/m)1 10 100 1000

LET (keV/m)1 10 100 1000

Radiosensitivity parameters for V79 cells irradiated in vitro. Symbols: estimates of α and β reported by y p y β p yFurusawa et al. (2000) for He-3 (blue circles), C-12 (green triangles) and Ne-20 (red squares). Lines: RMF-predicted parameters.

Frese MC, Yu VK, Stewart RD, Carlson DJ. A mechanism-based approach to predict the relative biological effectiveness (RBE) of protons and carbon ions in radiation therapy. Accepted. Int. J. Radiat. Oncol. Biol. Phys. (2011)


Method to determine RBE for cell killingMethod to determine RBE for cell killingMethod to determine RBE for cell killingMethod to determine RBE for cell killing

RMF-derived predictions of and are used to estimate the RBE f ll killi i li i ll l i h iRBE for cell killing in clinically-relevant ion therapies

1. Estimate cell-specific model constants:

21/

x F

x x

z

2

2 x

x

2. Calculated radiosensitivity parameters for ion of given energy Ei:

C l l d d l f d f i f

2ii i F iz 2/ 2i i

x x x

3. Calculate dose-averaged mean values of and as a function of penetration depth for a mixed field of ions of different energy

1 N

D i iDD

1 N

D i iDD

4. Calculate RBE for cell killing relative to a reference treatment (simply an isoeffect calculation using Dx=RBE×D):

1D i i

iD

1D i i

iD

2 24 ( )

, , , ,2

x x D D xx x

x

D DRBE D

D


ClinicallyClinically relevant pristine Bragg peaksrelevant pristine Bragg peaksClinicallyClinically--relevant pristine Bragg peaksrelevant pristine Bragg peaks

Physical and biological properties of proton and carbon ion pristine Bragg peaks. Dose and LET calculated using analytical approximations (Bortfeld 1997 and Wilkens and Oelfke 2003). DSB yields simulated using MCDS. and calc lated ass ming chordoma reference parameters All calc lations incl de Ga ssian particle spectr m and calculated assuming chordoma reference parameters. All calculations include Gaussian particle spectrum.


ClinicallyClinically relevant spreadrelevant spread out Bragg peaksout Bragg peaksClinicallyClinically--relevant spreadrelevant spread--out Bragg peaksout Bragg peaks

Physical and biological properties of a proton and carbon ion SOBP. Fluence of the contributing Bragg peaks optimized to deposit total absorbed dose of 1 Gy. SOBP consists of 17 pristine Bragg peaks with 3 mm spacing.p p y p gg p p g


RBE for cell killing in Proton SOBPRBE for cell killing in Proton SOBPRBE for cell killing in Proton SOBPRBE for cell killing in Proton SOBP

Conditions:Conditions:1. Normoxic chordoma cells: x= 0.1 Gy-1, (/)x=2.0 Gy

Dose, energy, and LET calculated Dose, energy, and LET calculated using analytical approximation using analytical approximation

] 1 4 14

. No o c c o do a ce s: x 0. Gy , (/)x .0 Gy2. Proximal edge of SOBP: 10 cm3. Distal edge of SOBP: 15 cm4. Distance between Bragg peaks: 0.3 cm5. # of Bragg peaks: 17

g y ppg y ppproposed by Bortfeld (1997) and proposed by Bortfeld (1997) and Wilkens and Oelfke (2003)Wilkens and Oelfke (2003)

dose

[Gy

(RB

E)]

1.0

1.2

1.4

10

12

14Physical doseRBE-weighted doseLET

gg p

Results:Results:1. Entrance RBE ~1.0

RB

E-w

eigh

ted

d

0.6

0.8

ETd [

keV

/ m

]

6

8

2. RBE ranges from 1.03 to 1.34 from proximal to distal edge of the SOBP

sica

l dos

e [G

y] /

0.2

0.4

LE

2

43. Mean RBE across

SOBP is ~1.11

Potential for biological Potential for biological

Depth [cm]

0 2 4 6 8 10 12 14 16 18

Phys

0.0 0hot and cold spots hot and cold spots within proton SOBPwithin proton SOBP


RBE for cell killing in Carbon ion SOBPRBE for cell killing in Carbon ion SOBPRBE for cell killing in Carbon ion SOBPRBE for cell killing in Carbon ion SOBP

Conditions:Conditions:1. Normoxic chordoma cells: x= 0.1 Gy-1, (/)x=2.0 Gy

Dose, energy, and LET calculated Dose, energy, and LET calculated using analytical approximation using analytical approximation

] 6 300

. No o c c o do a ce s: x 0. Gy , (/)x .0 Gy2. Proximal edge of SOBP: 10 cm3. Distal edge of SOBP: 15 cm4. Distance between Bragg peaks: 0.3 cm5. # of Bragg peaks: 17

g y ppg y ppproposed by Bortfeld (1997) and proposed by Bortfeld (1997) and Wilkens and Oelfke (2003)Wilkens and Oelfke (2003)

dose

[Gy

(RB

E)]

5

6

250

300Physical doseRBE-weighted doseLETResults:Results:

1. Entrance RBE ~1.3

gg pR

BE-

wei

ghte

d d

3

4

ETd [

keV

/ m

]

150

2002. RBE ranges from 1.8 to 5.4 from proximal to distal edge of the SOBP

sica

l dos

e [G

y] /

1

2 LE

50

1003. Mean RBE across SOBP is ~2.8

Depth [cm]

0 2 4 6 8 10 12 14 16 18

Phys

0 0


Dependence on tissue radiosensitivityDependence on tissue radiosensitivityDependence on tissue radiosensitivityDependence on tissue radiosensitivity

Physical (solid line) and RBE-weighted (RWD) dose for a representative clinical spread-out Bragg peaks in proton and carbon ion radiotherapy. Dashed, dash dotted and dotted lines represent RWD for chordoma prostate and headdash-dotted, and dotted lines represent RWD for chordoma, prostate, and head and neck cancer, respectively.


RBE dependence on dose and RBE dependence on dose and //RBE dependence on dose and RBE dependence on dose and //RBE values of cell killing for protons and carbon ions for a range of tissue radiosensitivities and physical doses. Estimates are shown for the proximal edge (d =10 cm), distal edge (d =15 cm ),

RBE ( / =2 Gy)Dose RBE ( / =10 Gy)Protons

p y p g ( ), g ( ),and target average for a clinical SOBP of 5 cm.

Promixmal Distal Avg. Promixmal Distal Avg.

0.1 1.06 1.44 1.13 1.04 1.28 1.090.5 1.06 1.38 1.12 1.04 1.28 1.091 1.03 1.34 1.11 1.03 1.27 1.092 1 03 1 30 1 10 1 03 1 27 1 09

(Gy)

2 1.03 1.30 1.10 1.03 1.27 1.095 1.02 1.27 1.09 1.02 1.26 1.08

10 1.02 1.26 1.08 1.02 1.25 1.08

Carbon ions

Promixmal Distal Avg. Promixmal Distal Avg.0.1 2.69 10.85 4.48 1.81 5.11 2.490.5 2.26 6.74 3.32 1.77 4.59 2.391 1 83 5 38 2 82 1 62 4 21 2 29

RBE ( / =10 Gy)Dose (Gy)

RBE ( / =2 Gy)

1 1.83 5.38 2.82 1.62 4.21 2.292 1.60 4.35 2.43 1.53 3.79 2.175 1.52 3.44 2.10 1.50 3.28 2.02

10 1.49 3.04 1.96 1.48 2.99 1.93


Physical dose optimizationPhysical dose optimizationPhysical dose optimizationPhysical dose optimization

Clinical objective in radiotherapy is to deliver a uniform biological effect (RWD)Clinical objective in radiotherapy is to deliver a uniform biological effect (RWD)

RBE 1 1

j py g ( )j py g ( )

RBE=1.1

Spread out Bragg peaks consisting of pristine Bragg peaks whose fluences were optimized to yield a constant RBE-weighted absorbed dose of 3 Gy (RBE) using the method presented by Wilkens and Oelfke (2006)


Modification of MCDS to SimulateModification of MCDS to SimulateChemical Repair and Oxygen FixationChemical Repair and Oxygen FixationChemical Repair and Oxygen FixationChemical Repair and Oxygen Fixation

HRFHRF ratio of dose at a specific level of hypoxia to the dose under fully aerobic conditions to achieve equal biological effect quantifies reduction in radiosensitivity as pO decreasesto achieve equal biological effect, quantifies reduction in radiosensitivity as pO2 decreases

Th HRF b d

22

ND OHRF O

D O

The HRF can be expressed as a ratio of doses or damage yields, i.e.,

22ND O

DDNN dose required to produce NNindividual or clustered DNA lesions (G 1 Gb 1) i ll d i(Gy-1 Gbp-1) in cells under normoxic conditionsDD((OO22) ) dose required to produce ((OO22))individual or clustered DNA lesions in

ll d Ocells under O2


HRF HRF in proton and carbon ion SOBPin proton and carbon ion SOBPHRF HRF in proton and carbon ion SOBPin proton and carbon ion SOBP

Effects of oxygen concentration on the Effects of oxygen concentration on the HRFHRF for DSB induction found at the for DSB induction found at the proximal (solid) and the distal (dotted) edge of 5 cm proton and carbon ion SOBPproximal (solid) and the distal (dotted) edge of 5 cm proton and carbon ion SOBP


RBERBE weighted dose for hypoxic targetsweighted dose for hypoxic targetsRBERBE--weighted dose for hypoxic targetsweighted dose for hypoxic targets

(RB

E))

1.2

1.4

(RB

E))

5

6ProtonsProtons Carbon ionsCarbon ions

nd R

WD

(Gy

0.6

0.8

1.0

nd R

WD

(Gy

2

3

4

0 2 4 6 8 10 12 14 16

Dos

e (G

y) a

n

0.0

0.2

0.4

0 2 4 6 8 10 12 14 16D

ose

(Gy)

an

0

1

2

Depth (cm)0 2 4 6 8 10 12 14 16

Depth (cm)0 2 4 6 8 10 12 14 16

Physical and RBE-weighted (RWD) dose for a representative clinical spread-out Bragg peaks in y g ( ) p p gg pproton and carbon ion radiotherapy. RWD has been calculated for under various O2 conditions for chordoma cells (x= 0.1 Gy-1, (/)x=2.0 Gy).


Optimization of physical doseOptimization of physical doseOptimization of physical doseOptimization of physical dose

ProtonsProtons Carbon ionsCarbon ions

(Gy

(RB

E))

2.0

2.5

3.0

(Gy

(RB

E))

0.8

1.0

1.2

Gy)

and

RW

D

1.0

1.5

Gy)

and

RW

D

0.4

0.6

Depth (cm)0 2 4 6 8 10 12 14 16

Dos

e (G

0.0

0.5

Depth (cm)0 2 4 6 8 10 12 14 16

Dos

e (G

0.0

0.2

Physical dose required under various O2 conditions required to achieve a constant RBE-weighted dose of 1 Gy (RBE) across a 5 cm SOBP for chordoma cells (x= 0.1 Gy-1, (/)x=2.0 Gy).

Theoretically, given a 3D distribution of particle energy spectrum and tumor Theoretically, given a 3D distribution of particle energy spectrum and tumor oxygenation, we can optimize a 3D dose distribution for isoeffect across a tumoroxygenation, we can optimize a 3D dose distribution for isoeffect across a tumor


ConclusionsConclusionsConclusionsConclusions

Proposed approach using the biologicallyProposed approach using the biologically--motivated RMF motivated RMF p pp g g yp pp g g yand MCDS models results in:and MCDS models results in:

1. Quantitative evaluation of the effect of particle LET on DSB i d ti d ll d th i t d b i di thinduction and cell death in proton and carbon ion radiotherapy

2. Enhanced understanding of the biophysical mechanisms underlying cell killing in x-ray and particle therapy

3. Determination of RBE values for cell killing that can be practically used in proton and carbon ion therapy Protons: entrance RBE ~1.0, RBE ranges from 1.02 to 1.4 from proximal to distal edge of SOBP Carbon : entrance RBE ~1 3 RBE ranges from 1 5 to 10 9 from proximal to distal edge of SOBP Carbon : entrance RBE 1.3, RBE ranges from 1.5 to 10.9 from proximal to distal edge of SOBP RBE values increase as particle energy, dose fraction size, and tissue / decrease

4. A method for quantifying the effects of tumor hypoxia in charged particle radiotherapy For extreme hypoxia, proton and carbon ion doses may need to be increased by factors as high as

2.9 and 1.6, respectively, to compensate for reduced biological effectiveness


AcknowledgementsAcknowledgementsAcknowledgementsAcknowledgements

Malte C. Frese, M.S.,• German Cancer Research Center (DKFZ)• Yale University

Robert D. Stewart, Ph.D.U i it f W hi t

Victor K. Yu, M.S. P d U i it• University of Washington • Purdue University

• Yale University

Work supported by: American Cancer Society Institutional Research Grant (IRGWork supported by: American Cancer Society Institutional Research Grant (IRG--5858--012012--52)52)

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