Biological Uncertainties in Proton (Ion) Therapy
Harald Paganetti PhD
Definition of RBE M
. 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
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 data Clinical RBE Pr
oton
s
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
07
RBE values in vivo (center of SOBP; relative to 60Co)
1.07 ± 0.12
RBE from experimental data Clinical RBE Pr
oton
s
RB
E
Experimental data in vivo are supporting the use of a clinical RBE of 1.1 in proton therapy
Our clinical experience does not indicate that the RBE of 1.1 for proton therapy is incorrect Pr
oton
s
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 Ratio RBE 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
RBE as a function of particle energy / LET
Carbon ion RBE at 2Gy for various endpoints
Car
bon
Ions
Implication 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
Wou
ters
et a
l. Ra
diat
Res
199
6; 1
46, 1
59-1
70
RBE as a function of particle energy / LET Pr
oton
s
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
Prot
ons
RBE (depth) for Carbon beams RBE as a function of particle energy / LET C
arbo
n Io
ns
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 an extended biologically effective range (1-2 mm)
Paga
netti
, Goi
tein
: Med
. Phy
s. 20
00: 2
7, 1
119-
1126
RBE as a function of particle energy / LET Pr
oton
s
Increased effectiveness as a function of depth (affects the entire Bragg curve for Carbon beams)
Extended beam range (causes range uncertainty; to be considered when pointing a field towards a critical structure)
RBE in the target is significantly higher than in the OAR for heavy ions*
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 Pr
oton
s
RB
E
RB
E
RB
E
RB
E
RB
E
Dose [Gy] Dose [Gy] Dose [Gy]
Dose dependency of RBE values for Carbon RBE as a function of dose
Carbon ion beams; RBE in vitro
Car
bon
Ions
RBE decreases with increasing dose The lower the LET, the smaller the effect
Weyrather et al., IJRB 1999
Dose dependency of RBE values for Carbon RBE as a function of dose
Wilkins and Oelfke, IJROBP 2008
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 Pr
oton
s
V79 cells only R
BE
RBE values in vivo (center of SOBP; relative to 60Co)
Mice data: Lung tolerance,Crypt regeneration,Acute skin reactions,Fibrosarcoma NFSa Paganetti et al.: Int. J. Radiat. Oncol. Biol. Phys. 2002; 53, 407-421
RBE as a function of tissue Pr
oton
s
In vitro; non-V79 cells only R
BE
human cells
Proton beams of < 10 MeV; RBE in vitro
Belli et al. 2000 Bettega et al. 1979
RBE as a function of tissue Pr
oton
s
Do cells with higher repair capacity show higher RBE?
Carbon ions Photons
S(D) = e-(αD+βD2)
Car
bon
Ions
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 responding healthy tissue
RBE as a function of repair capacity (α/β) Pr
oton
s
We have to be careful when using V79 cell data to estimate RBE effects in clinical scenarios
RBE seems to be higher for tissues with a low α/β ratio (organs at risk, prostate)
RBE seems to be higher for non-lethal injuries
Oxygen Enhancement Ratio is an advantage of heavy ions
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
We have to consider RBE variations in heavy ion radiation therapy, which does lead to considerable uncertainties
We need more in vivo experiments !
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