Biological Uncertainties in Proton (Ion)
Therapy
Harald Paganetti PhD
M. Krämer, W. K. Weyrather, M. Scholz: Techn. Cancer
Res. Treatm. 2, 427-436, 2003
Definition of RBE
Dγ
RBE =
effect
Dion
RBE from experimental data
RBE
Protons
RBE values in vitro (center of SOBP; relative to 60Co)
1.21 ± 0.20
Endpoint: Cell Survival
Paganetti et al.: Int. J. Radiat. Oncol. Biol. Phys. 2002; 53, 407
Clinical RBE
RBE from experimental data
RBE
Protons
RBE values in vivo (center of SOBP; relative to 60Co)
1.07 ± 0.12
Mice data: Lung tolerance, Crypt regeneration, Acute skin reactions,
Fibrosarcoma NFSa
Paganetti et al.: Int. J. Radiat. Oncol. Biol. Phys. 2002; 53, 407
Clinical RBE
Protons
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
RBE as a function of particle energy / LET
Lesion complexity
Oxygen Enhancement Ratio
Lesions can be repairable or nonrepairable
High-LET radiation produces
more non-repairable lesions
Hypoxic cells are more radioresistant than well oxygenated
cells for low-LET radiation
RBE as a function of particle energy / LET
Dose = Fluence [1/cm2] ×
LET [keV/cm] / ρ [g/cm3]
Paganetti H:
Med Phys 2005: 32, 2548-2556
Carbon Ions
RBE as a function of particle energy / LET
Carbon ion RBE at 2Gy for various endpoints
RBE as a function of particle energy / LET
Implication of RBE(LET) for RBE(depth)
1 2 3
3
2
1
Dose = Fluence [1/cm ] × LET [keV/cm] / ρ [g/cm ]
2
3
Wouters et al. Radiat Res 1996; 146, 159-170
Protons
RBE as a function of particle energy / LET
RBE as a function of particle energy / LET
Protons
RBE (depth)
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
120
biological dose
100
80
60
physical dose
40
20
0
1.5
2.0
2.5
3.0
depth in water [cm]
3.5
Carbon Ions
RBE(depth)
as a function
of particle
energy / LET
RBE
for Carbon
beams
Protons
An increasing RBE with depth cause an
extended biologically effective range (1-2 mm)
biological dose
120
100
80
physical dose
60
40
20
2 Gy
0
1.5
2.0
2.5
depth in water [cm]
3.0
3.5
Paganetti, Goitein: Med. Phys. 2000: 27, 1119-1126
RBE as a function of particle energy / LET
RBE as a function of particle energy / LET
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*
Surviving Fraction
RBE as a function of dose
RBE=2/1=2
X-rays
p (3.2 MeV)
p (1.4 MeV)
Dose [Gy]
RBE=5/3=1.7
M. Belli et al. 1993
RBE as a function of dose
in vivo
RBE
RBE
Dose [Gy]
RBE
RBE
RBE
Protons
in vitro
Dose [Gy]
Dose [Gy]
RBE as a function
dosefor Carbon
Dose dependency
of RBEof
values
Carbon Ions
Carbon ion beams; RBE in vitro
RBE as a function
dosefor Carbon
Dose dependency
of RBEof
values
Weyrather et al., IJRB 1999
Wilkins and Oelfke, IJROBP 2008
  RBE decreases with increasing dose
  The lower the LET, the smaller the effect
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 as a function of tissue
RBE values in vitro (center of SOBP; relative to 60Co)
RBE
Protons
V79 cells only
Paganetti et al.: Int. J. Radiat. Oncol. Biol. Phys. 2002; 53, 407-421
RBE as a function of tissue
RBE values in vivo (center of SOBP; relative to 60Co)
RBE
Protons
In vitro; non-V79 cells only
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
Protons
Proton beams of < 10 MeV; RBE in vitro
human cells
Belli et al. 2000
Bettega et al. 1979
RBE as a function of repair capacity (α/β)
2
Carbon Ions
S(D) = e-(αD+βD )
  Do cells with higher repair capacity show higher RBE?
Carbon ions
Photons
RBE as a function of repair capacity (α/β)
Protons
low (α/β)x (≤ 5 Gy)
late responding
healthy tissue
high (α/β)x (> 5 Gy)
early responding
tumor tissue
RBE as a function of tissue
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
CONCLUSIONS
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