Biological Uncertainties in Proton (Ion) Therapy Harald Paganetti PhD

Biological Uncertainties in Proton (Ion) Therapy

Harald Paganetti PhD

Definition of RBEhn

. Can

cer

Scho

lz: T

ech

yrat

her,

M. S

36, 2

003

er, W

. K. W

eytm

. 2, 4

27-4

3

D

M. K

räm

eR

es. T

reat

IsoeffectIonD

DRBE

Clinical RBE

Proton therapy: RBE = 1.1bio-effective dose

DOSE

ff

physical dose

tons

Pro

DEPTH

M. Goitein

DEPTH

RBE from experimental dataClinical RBE

2.5

RBE values in vitro (center of SOBP; relative to 60Co)

2; 5

3, 4

07

RBE from experimental data

2.0

Phys

.200

2

tons

RB

E

1.5

Onc

ol. B

iol.

1 21 0 20

Pro

1.0

J. R

adia

t. O1.21 0.20

Dose per fraction [Gy]1 10

0.5

Endpoint: Cell Survival et a

l.: In

t. J.

Endpoint: Cell Survival

Paga

netti

e

RBE from experimental dataClinical RBE

2.5RBE values in vivo (center of SOBP; relative to 60Co)

2; 5

3, 4

07

RBE from experimental data

2.0

Phys

.200

2

tons

RB

E

1.5

Onc

ol. B

iol.

Pro

1.0

J. R

adia

t. O1.07 0.12


0.5

Mice data: Lung tolerance, Crypt regeneration, Acute skin reactions, et a

l.: In

t. J

g , yp g , ,Fibrosarcoma NFSa

Paga

netti

e

RBE from clinical dataClinical RBE

Example: Debus et al. IJROBP 1997; 39: 967-975

RBE from clinical data

• Evaluation of brain stem morbidity following 348 proton patients with skull-base sarcomasto

ns

• tumors approached very closely, abutted, or displaced the brain stemPr

o

• total dose to the brain stem from the end of range of a field was limited to <10 GyRBEyRBE

• if the dose increment is 10%, the increase in dose in that volume would have been 1.0 GyRBEyRBE

Clinical RBERBE from clinical data

RBE value of 1 10 for brain stem damage in patients free of

Outcome: brain stem toxicity free survival at 10 years = ~88%RBE from clinical data

RBE value of 1.10 for brain stem damage in patients free of known risk factors appears to be reasonable

This does not prove that the RBE of 1.1 is correct !tons

p

Problems in estimating RBE values based on clinical data:• heterogeneity of dose

Pro

heterogeneity of dosephotons generally deliver a more uniform dose to critical structures

• proton and photon treatment volumes are different and the• proton and photon treatment volumes are different and the probability of radiation damage for a specified doseis sensitive to the volume of normal tissues irradiated

Experimental data in vivo are supporting thef RBE f 1 1i huse of an RBE of 1.1in proton therapy

O li i l i d i di htons

Our clinical experience does not indicate thatthe RBE of 1.1 for proton therapy is incorrectPr

o

Damage as a function of LETLesion complexity Oxygen Enhancement Ratio

Lesions can be repairable or non-repairableHigh-LET radiation produces g pmore non-repairable lesionsCurtis: Radiat Res 1986; 106 252-270Paganetti H: Medical Physics 2005: 32 2548-2556

Hypoxic cells are more radio-resistant than well oxygenated

ll f l LET di tiPaganetti H: Medical Physics 2005: 32, 2548-2556 cells for low-LET radiation

Damage as a function of LET & fluence

r Gy

m2 )

500

600 Med P

n tr

acks

pe

(Anu

cl =

50

200

300

400 PaganetPhys 2005:

0 10 20 30 40 50

Prot

onpe

r cel

l

0

100

200 tti H:

32, 2548-2

Proton Energy [MeV]0 10 20 30 40 50 556

Photons Low-LET 12C

Dose = Fluence [1/cm2] × LET [keV/cm] / [g/cm3]

6, 2

003

m. 2

, 427

-436

al.: Res

. Tre

atm

Medium-LET 12C High-LET 12C

. Krä

mer

et a

chn.

Can

cer

M.

Tec

Radiation is more effective when energy depositions are more concentrated in spaceRadiation is more effective when energy depositions are more concentrated in space

Protonsvs

Carbon ions

protons create lower energyKrämer, Scholz et al

(M. Krämer)

protons create lower energy -rays (smaller track halo) compared to heavy ions at a i p igiven LET higher local dose proton RBE > ion RBE

p ions

pat a given LET

RBE d dRBE depends on• energy/LETgy• dose• tissue• tissue

RBE as a function of particle energy / LET

Increasing effectiveness with decreasing energyWeyrather et al., IJRB 1999

Increasing effectiveness with decreasing energy Number of complex lesions increases with LET Transition from shouldered to straight survival curves Saturation effects at very low energies Saturation effects at very low energies


Carbon ion RBE at 2Gy for various endpoints

nson

Ion

Car

bo

Implication of RBE(LET) for RBE(depth)

RBE as a function of particle energy / LET47

-215

7Implication of RBE(LET) for RBE(depth)

1 2 3

998;

43,

21

ed. B

iol.

19

3

i: Ph

ys. M

e

12

Paga

nett

i

Dose = Fluence [1/cm2] × LET [keV/cm] / [g/cm3]Dose = Fluence [1/cm2] × LET [keV/cm] / [g/cm3]


59-1

7019

96; 1

46, 1

tons

Radi

at R

es1

Pro

oute

rs e

t al.

RW

o

RBE (d h)


Fit of all available RBE values:

RBE (depth)

RBE increased by 5% at 4 mm from the distal edge RBE increased by 10% at 2 mm from the distal edge

tons

100

120biological dose

Pro

40

60

80

physical dose

depth in water [cm]1.5 2.0 2.5 3.0 3.5

0

20

depth in water [cm]

RBE (depth) for Carbon beamsRBE as a function of particle energy / LETs

on Io

nC

arbo

C

Weyrather et al.,

RBE (depth) for Carbon beamsRBE as a function of particle energy / LETs

on Io

nC

arbo

C


An increasing RBE with depth cause anextended biologically effective range (1-2 mm)

119-

1126

100

120biological dose

2000

:27,

11

tons

60

80

physical dose

Med

.Phy

s.

Pro

20

40

2 G tti,

Goi

tein

:

depth in water [cm]

1.5 2.0 2.5 3.0 3.5

0

2 Gy

Paga

net

depth in water [cm]


Increasing effectiveness as a function of depth(affects the entire Bragg curve for Carbon beams)( gg )

Extended beam rangeg(causes uncertainty when pointing a field towardsa critical structure))

RBE as a function of dose

1

onvi

val 0.1

ng F

ract

ioX-rays

Surv

0.01

Surv

ivin p (3.2 MeV)

p (1.4 MeV)

0 1 2 3 4 5 6 7 80.001

Dose [Gy]RBE=2/1=2 RBE=5/3=1.7DosisDose [Gy]

M. Belli et al. 1993

Dose dependency of RBE values for CarbonRBE as a function of dose

C b i b RBE i itCarbon ion beams; RBE in vitro

son

Ion

Car

boC

2.5 2.5

in vitro in vivo

RBE as a function of doseB

E

1 5

2.0

BE

1 5

2.0

in vitro in vivo

RB

1.0

1.5

RB

1.0

1.5


0.5


0.5

1.5

Tang et a l 19971.8

Ando et al 1985

RB

E

1.2

1 .3

1 .4Tang et a l. 1997

RB

E

1.4

1.6

Ando et al. 1985

70 MeV NFSa in vivo

oton

s

0 2 4 6 8 100.9

1 .0

1 .1

65 M eV C H O

0 2 4 6 8 10 120.8

1.0

1.2

Pro

D oseDose

0 2 4 6 8 10 12

Dose dependency of RBE values for CarbonRBE as a function of dose

5

6

RBE protonRBE carbon

3

4

RB

E

RBE carbon

Weyrather et al IJRB 1999

1

2

Wilkins and Oelfke IJROBP 2008Weyrather et al., IJRB 1999 00 0.5 1 1.5 2

dose (Gy)

Wilkins and Oelfke, IJROBP 2008

RBE decreases with increasing dose The lower the LET, the smaller the effect

RBE as a function of dose3.5 8

3

3.5

hys.

2008Higher RBE for OAR (lower doses)

2

2.5

se (G

yE)

Bio

l. Ph

1

1.5

eff.

dos

Oel

fke:

. Onc

ol.

0

0.5 p (RBE=1.1)

C12

kins

and

OJ.

Rad

iat

0 50 100 150 200 250depth (mm) W

ilkIn

t. J

RBE as a function of dose

RBE increases with decreasing doseg

Indicates higher RBE for OARg

RBE as a function of tissue

Potential in vivo / in vitro difference due todifferent endpoints looked atre-population effectsrepair differencesintracellular contactmono-layer culture vs. spherical cells

E

2 .0

2 .5

E2 .0

2 .5

in vitro in vivo

1 1 0

RB

0 .5

1 .0

1 .5

1 1 0

RB

E

0 .5

1 .0

1 .5

D o s e p e r f ra c t io n [G y ] D o s e p e r f r a c t io n [ G y ]

RBE values in vitro (center of SOBP; relative to 60Co)


2.5

RBE values in vitro (center of SOBP; relative to Co)

2.5V79 cells only

2.5non-V79 cells

2.02.02.0

tons

RB

E

1.5

RB

E

1.5

RB

E

1.5Pro

0 5

1.0

0 5

1.0

0 5

1.0


0.5


0.5


0.5

Paganetti et al : Int J Radiat Oncol Biol Phys 2002; 53 407-421Paganetti et al.: Int. J. Radiat. Oncol. Biol. Phys. 2002; 53, 407 421

RBE values in vivo (center of SOBP; relative to 60Co)


2.5

RBE values in vivo (center of SOBP; relative to 60Co)

2.0

in vitro (non V79)tons

RB

E

1.5

( )

Pro

0.5

1.0


Mice data: Lung tolerance,Crypt regeneration,Acute skin reactions,Fibrosarcoma NFSaP tti t l I t J R di t O l Bi l Ph 2002 53 407 421Paganetti et al.: Int. J. Radiat. Oncol. Biol. Phys. 2002; 53, 407-421


55

Proton beams of < 10 MeV; RBE in vitro

4

5

4

5

tons

RB

E 3

RB

E 3 human cellsPro

1

2

1

2

Belli et al. 2000Bettega et al. 1979

Proton Energy [MeV]1 10

Proton Energy [MeV]1 10

RBE as a function of tissue & LET

O E h R iOxygen Enhancement Ratio

Heavy Ions may overcome radioresistance of hypoxic yptumors

RBE as a function of repair capacity ()

Do cells with higher repair capacity show higher RBE?

Carbon ions Photons

son

Ion

Car

boC

linear-quadratic: RBE ( ) ?qS(D) = e-(D+D2) RBE () ?

high () (> 5 Gy)low () ( 5 Gy)

RBE as a function of repair capacity ()

Gy)

1.6

1.8

in 1999

;

high ()x (> 5 Gy)early responding

tumor tissue

low ()x ( 5 Gy)late respondinghealthy tissue

BE e

xp (2

G

1 0

1.2

1.4

1.6

rwec

k, K

ozi

her.

Onc

ol.1

50, 1

35-1

42

tons

1 8 [Gy]

0 2 4 6 8 10 12 14 16 18 20

R 1.0

Ger

Radi

oth 5

in 0:

Pro

lc (2

Gy)

1.82.02.22.4

rwec

k,G

oite

it.

Biol

.200

085

-998

0 2 4 6 8 10 12 14 20 22

RB

E ca

1.01.21.41.6

Paga

netti

,Ger

Int.

J. R

adia

t76

, 98

[Gy] P I

RBE for non-lethal injuryi h l b li i i i


dicentrics,rings in peripheral lymphocytes (Matsubara et al. 1990):SOBP; 70 MeV proton beam

gene mutation, chromosomal abnormalities, carcinogenesis

SOBP; 70 MeV proton beam RBE increased with increasing depth (1.4 ± 0.3 (2 Gy; distal half))RBE increased with decreasing dose (1.0±0.1 (8 Gy) to 2.3±1.2 (0.1 Gy))

tons

mutation induced by heavy ions (Cox et al 1977):

induction at the HPRT locus in V79 cells (Cherubini et al. 1995):RBE values higher for mutation compared to cell survival (up to 17%)Pr

o

DNA damage of thyroid follicular cells (Green et al. 2001):

mutation induced by heavy ions (Cox et al. 1977):RBE overall higher than the RBE for cell survival (human, hamster cells)

micronucleus formation for Chinese hamster cells C1-1 (Sgura et al. 2000):no significant difference compared to the cell survival RBE

g f y f ( )no significant difference compared to the cell survival RBE

no significant difference compared to the cell survival RBE


RBE seems to be higher for low ratioRBE seems to be higher for low ratio(organs at risk, prostate)

RBE seems to be higher for non-lethal injuries

OER does favor heavy ions

CONCLUSIONS

Before we can implement RBE variations in proton therapy we need to understand them in vivotherapy we need to understand them in vivo

We have to consider RBE variations in heavy ionWe have to consider RBE variations in heavy ion radiation therapy, which does lead to considerable uncertainties

We need more in vivo experiments !

“high LET radiation” versus “low LET radiation”

CONCLUSIONS

high-LET radiation versus low-LET radiation

High RBE is not an advantage per se

It is an advantage if it affects mainly the target due to• high RBE confined to the tumor• high-RBE confined to the tumor• ‘targets’ specific tumor cells (OER)

Hypofractionation might be advantageous for high-LET radiation (less tumor repopulation) because it causes aradiation (less tumor repopulation) because it causes a lack of cellular repair, i.e. reduces the advantage of fractionation

Biological Uncertainties in Proton (Ion) Therapy Harald Paganetti PhD

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Transcript of Biological Uncertainties in Proton (Ion) Therapy Harald Paganetti PhD