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