how significant are rbe variations in proton therapy...how significant are rbe variations in proton...

How significant are RBE variations in proton therapy ?

Harald Paganetti PhD

Definition of RBEM

. Krä

mer

, W. K

. Wey

rath

er, M

. Sch

olz:

Tec

hn. C

ance

r R

es. T

reat

m. 2

, 427

-436

, 200

3

RBE =Dγ

Dion

effect

Proton therapy: RBE = 1.1

DOSE

bio-effective dose

physical dose

DEPTH

M. Goitein

Clinical RBE

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

Endpoint: Cell Survival

Paga

netti

et a

l.: In

t. J.

Rad

iat.

Onc

ol. B

iol.

Phys

.200

2; 5

3, 4

07

1.21 ±

0.20

RBE from experimental dataClinical RBE

RB

E

Mice data: Lung tolerance, Crypt regeneration, Acute skin

reactions, Fibrosarcoma NFSa

Paga

netti

et a

l.: In

t. J.

Rad

iat.

Onc

ol. B

iol.

Phys

.200

2; 5

3, 4

07RBE values in vivo (center of SOBP; relative to 60Co)

1.07 ±

0.12

RBE from experimental dataClinical RBE

RB

E

•

tumors approached very closely, abutted, or displaced the brain stem

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

•

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

RBE from clinical dataClinical RBE

RBE = 1.1 for brain stem damage appears to be reasonable

Outcome: brain stem toxicity free survival at 10 years = ~88%

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

Clinical RBERBE from clinical data

Problems in estimating RBE values based on clinical data:•

photons generally deliver a more uniform dose to

critical structures•

the probability of radiation damage for a specified

dose is sensitive to the volume of normal tissues irradiated

Experimental data in vivo are supporting theuse of a clinical RBE of 1.1 in proton therapy

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

RBE depends on• energy/LET• dose• tissue

Linear Energy Transfer (LET)

Energy transferred to tissueper path length per particle

LET ↔ Energy

LET

Lesion complexity

Lesions can be repairable or non- repairable

High-LET radiation produces more non-repairable lesions

Hypoxic cells are more radio- resistant than well oxygenated

cells for low-LET radiation

Oxygen Enhancement RatioRBE as a function of particle energy / LET

Paganetti H:

Med Phys 2005: 32, 2548-2556

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

ρ

[g/cm3]

RBE as a function of particle energy / LET

M. K

räm

er e

t al.:

Tech

n. C

ance

r Res

. Tre

atm

. 2, 4

27-4

36, 2

003

Photons Low-LET 12C

Medium-LET 12C High-LET 12C

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

RBE as a function of particle energy / LET

Track halo

protons create lower energy δ-rays (smaller track halo) compared to heavy ions at a given LET⇒ higher local dose

⇒ proton RBE > ion RBE at a given LET

Krämer, Scholz et al

LET ↔ RBE

Increasing effectiveness with decreasing energyNumber of complex lesions increases with LETTransition from shouldered to straight survival curvesSaturation effects at very low energies

Weyrather et al., IJRB 1999

RBE as a function of particle energy / LET

Paga

nett

i: Ph

ys. M

ed. B

iol.

1998

; 43,

214

7-21

57Implication of RBE(LET) for RBE(depth)

Dose = Fluence [1/cm2]

×

LET [keV/cm]

/

ρ

[g/cm3]

RBE as a function of particle energy / LET

1

1

2

2

3

3

Wilk

ens a

nd O

elfk

e: P

hys M

ed B

iol2

004

49; 2

811–

2825

RBE as a function of particle energy / LET

Dose ×

RBEDoseRBE

LET

Wou

ters

et a

l. Ra

diat

Res

1996

; 146

, 159

-170

RBE as a function of particle energy / LET

Fit of all available RBE values: RBE increased by 5% at 4 mm from the distal edge

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

RBE (depth)

RBE as a function of particle energy / LET

depth in water [cm]1.5 2.0 2.5 3.0 3.5

0

20

40

60

80

100

120

physical dose

biological dose

depth in water [cm]

1.5 2.0 2.5 3.0 3.5

0

20

40

60

80

100

120

physical dose

biological dose

2 Gy

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

Paga

nett

i, G

oite

in: M

ed. P

hys.

2000

: 27,

111

9-11

26

RBE as a function of particle energy / LET

Increased effectiveness as a function of depth

Extended beam range(causes range uncertainty; to be considered whenpointing a field towards a critical structure)

RBE might be higher close to the target (but mainly in OAR)

RBE as a function of particle energy / LET

Dose [Gy]

Surv

ivin

g Fr

actio

n

M. Belli et al. 1993

X-rays

p (3.2 MeV)

p (1.4 MeV)

RBE=2/1=2 RBE=5/3=1.7

RBE as a function of dose

in vitro in vivo

RBE as a function of dose

RB

E

RB

E

RB

E

RB

E

RB

E

Dose [Gy] Dose [Gy] Dose [Gy]

Hall et al.: Int. J. Radiat. Oncol. Biol. Phys. 1978: 4, 1009-1013

RBE as a function of dose

RBE decreases with increasing doseThe lower the LET, the smaller the effect

Weyrather et al., IJRB 1999

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

0

1

2

3

4

5

6

0 0.5 1 1.5 2dose (Gy)

RB

E

RBE protonRBE carbon

Wilkins and Oelfke, IJROBP 2008

RBE as a function of dose

0

0.5

1

1.5

2

2.5

3

3.5

0 50 100 150 200 250depth (mm)

eff.

dose

(GyE

)

p (RBE=1.1)

C12

Wilk

ins a

nd O

elfk

e:In

t. J.

Rad

iat.

Onc

ol. B

iol.

Phys

. 200

8

Higher RBE for OAR (lower doses)

RBE as a function of dose

RBE increases with decreasing dose;effect seems to be very small for protons in vivo

Indicates higher RBE for OAR

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

Paganetti et al.: Int. J. Radiat. Oncol. Biol. Phys.

2002; 53, 407-421

RBE as a function of tissue

V79 cells onlyR

BE

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

Mice data: Lung tolerance,Crypt regeneration,Acute skin reactions,Fibrosarcoma NFSaPaganetti et al.: Int. J. Radiat. Oncol. Biol. Phys.

2002; 53, 407-421

RBE as a function of tissue

In vitro; non-V79 cells onlyR

BE

human cells

Proton beams of < 10 MeV; RBE in vitro

Belli et al. 2000Bettega et al. 1979

RBE as a function of tissue

Do cells with higher repair capacity show higher RBE?

Carbon ions Photons

S(D) = e-(αD+βD2)

RBE as a function of repair capacity (α/β)

high (α/β)x

(> 5 Gy)early responding

tumor tissue

low (α/β)x

(≤

5 Gy)late respondinghealthy tissue

RBE as a function of repair capacity (α/β)

Paga

netti

,Ger

wec

k,G

oite

inIn

t. J.

Rad

iat.

Biol

.200

0:

76, 9

85-9

98

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

DNA damage of thyroid follicular cells (Green et al. 2001):no significant difference compared to the cell survival RBE

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

(human, hamster cells)

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

(up to 17%)

dicentrics,rings in peripheral lymphocytes (Matsubara et al. 1990):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))

RBE for non-lethal injurygene mutation, chromosomal abnormalities, carcinogenesis

RBE as a function of tissue

RBE as a function of tissue & LET

Heavy Ions may overcome radioresistance of hypoxic tumors

Oxygen Enhancement Ratio

V79 survival in vitro

0

0.2

0.4

0.6

0.8

0 20 40 60dose averaged LET [keV/µm]

alph

a [1

/Gy]

)β(LET),α,β,α,RBE(D ppXXp

Wilkens and OelfkePhys Med Biol 2004 49; 2811–2825

RBE as a function of tissue & LET

Dose LET

©U

. Oel

fke,

DK

FZ H

eide

lber

gRBE as a function of tissue & LET

©U

. Oel

fke,

DK

FZ H

eide

lber

g

RBE ·

Dose(V79)

Dose

RBE as a function of tissue

We have to be careful when using V79 cell datato estimate RBE effects in clinical scenarios

RBE seems to be higher for tissues with a lowα/β

ratio (organs at risk, prostate)

RBE seems to be higher for non-lethal injuries

RBE as a function of tissue

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

RBE variations are typically small in proton therapy

Our current data are not sufficient to change the clinical use of a generic RBE of 1.1

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 area(consider LET, dose, and tissue dependency)

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

CONCLUSIONS