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
Dose per fraction [Gy]1 10
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
RBE as a function of particle energy / LET
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]
RBE as a function of particle energy / LET
59-1
7019
96; 1
46, 1
tons
Radi
at R
es1
Pro
oute
rs e
t al.
RW
o
RBE (d h)
RBE as a function of particle energy / LET
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
RBE as a function of particle energy / LET
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]
RBE as a function of particle energy / LET
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
Dose per fraction [Gy]1 10
0.5
Dose per fraction [Gy]1 10
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)
RBE as a function of tissue
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
Dose per fraction [Gy]1 10
0.5
Dose per fraction [Gy]1 10
0.5
Dose per fraction [Gy]1 10
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)
RBE as a function of tissue
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
Dose per fraction [Gy]1 10
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
RBE as a function of tissue
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
RBE as a function of tissue
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 as a function of tissue
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