The Use of High-Energy Protons in
Cancer Therapy
Reinhard W. Schulte
Loma Linda University Medical Center
A Man - A Vision
• In 1946 Harvard physicist Robert
Wilson (1914-2000) suggested*:
– Protons can be used clinically
– Accelerators are available
– Maximum radiation dose can be
placed into the tumor
– Proton therapy provides sparing
of normal tissues
– Modulator wheels can spread
narrow Bragg peak
*Wilson, R.R. (1946), “Radiological use of fast protons,” Radiology 47, 487.
History of Proton Beam Therapy
•
•
•
•
•
1946
1954
1958
1967
1974
• 1990
R. Wilson suggests use of protons
First treatment of pituitary tumors
First use of protons as a neurosurgical tool
First large-field proton treatments in Sweden
Large-field fractionated proton treatments
program begins at HCL, Cambridge, MA
First hospital-based proton treatment center
opens at Loma Linda University Medical
Center
World Wide Proton Treatments*
Dubna (1967)
172
Moscow (1969)
3414
St. Petersburg (1969) 1029
LLUMC (1990)
6174
HCL (1961)
6174
Uppsala (1957):
309
PSI (1984):
3935
Clatterbridge(1989): 1033
Nice (1991):
1590
Orsay (1991):
1894
Berlin (1998):
166
NAC (1993)
398
*from: Particles, Newsletter (Ed J. Sisterson), No. 28. July 2001
Chiba (1979)
Tsukuba (1983)
Kashiwa (1998)
133
700
75
LLUMC Proton Treatment Center
Hospital-based facility
40-250 MeV Synchrotron
Gantry beam line
Fixed beam line
Main Interactions of Protons
p
p
• Electronic (a)
– ionization
– excitation
• Nuclear (b-d)
e
(a)
p
(b)
– Multiple Coulomb scattering (b),
small q
p
– Elastic nuclear collision (c),
(c) p’
large q
– Nonelastic nuclear interaction (d)
p
(d)
p’
q
p’
nucleus
e
g, n
nucleus
Why Protons are advantageous
• Relatively low entrance dose
(plateau)
• Rapid distal dose fall-off
• Energy modulation
(Spread-out Bragg peak)
Relative Dose
• Maximum dose at depth
(Bragg peak)
10 MeV X-rays
Modulated
Proton Beam
Unmodulated
Proton Beam
• RBE close to unity
Depth in Tissue
Uncertainties in Proton Therapy
° Patient related:
•
•
•
•
•
Patient setup
Patient movements
Organ motion
Body contour
Target definition
° Biology related:
• Relative biological
effectiveness (RBE)
° Physics related:
• CT number conversion
• Dose calculation
° Machine related:
• Device tolerances
• Beam energy
Treatment Planning
•
•
•
•
•
•
Acquisition of imaging data (CT, MRI)
Conversion of CT values into stopping power
Delineation of regions of interest
Selection of proton beam directions
Design of each beam
Optimization of the plan
Treatment Delivery
•
•
•
•
Fabrication of apertures and boluses
Beam calibration
Alignment of patient using DRRs
Computer-controlled dose delivery
Computed Tomography (CT)
• Faithful reconstruction of
patient’s anatomy
• Stacked 2D maps of linear
X-ray attenuation
• Electron density relative to
water can be derived
• Calibration curve relates
CT numbers to relative
proton stopping power
X-ray tube
Detector array
Processing of Imaging Data
H = 1000
mtissue /mwater
SP = dE/dxtissue /dE/dxwater
CT
Hounsfield
values (H)
Calibration
curve
Relative
proton
stopping
power (SP)
SP
Dose
calculation
H
Isodose
distribution
CT Calibration Curve
• Proton interaction  Photon interaction
• Bi- or tri- or multisegmental curves are in use
• No unique SP values for soft tissue Hounsfield
range
• Tissue substitutes  real tissues
• Fat anomaly
CT Calibration Curve
Stoichiometric Method*
– Choose tissue substitutes
– Obtain best-fitting parameters A,
B, C
H = Nerel {A (ZPE)3.6 + B (Zcoh)1.9 + C}
Rel.
electron
density
Photo
electric
effect
Coherent
scattering
KleinNishina
cross section
Hounsfield value (observed
• Step 1: Parameterization of H
2000
1800
1600
1400
1200
1000
800
800
1000 1200 1400 1600 1800 2000
Hounsfield value (expected)
*Schneider U. (1996), “The calibraion of CT
Hounsfield units for radiotherapy treatment planning,”
Phys. Med. Biol. 47, 487.
CT Calibration Curve
Stoichiometric Method
1.8
• Step 2: Define Calibration Curve
1.4
Fat
1.2
SP
– select different standard tissues
with known composition (e.g.,
ICRP)
– calculate H using parametric
equation for each tissue
– calculate SP using Bethe Bloch
equation
– fit linear segments through data
points
1.6
1
0.8
0.6
0.4
0.2
0
0
500
1000
1500
H value
2000
2500
CT Range Uncertainties
• Two types of uncertainties
– inaccurate model parameters
– beam hardening artifacts
• Expected range errors
Soft tissue
H2O range
abs. error
(cm)
(mm)
Brain
10.3
1.1
Pelvis 15.5
1.7
1 mm
Bone
H2O range abs. Error
(cm)
(mm)
1.8
0.3
9
1.6
4 mm
Total
abs. error
(mm)
1.4
3.3
Proton Transmission Radiography - PTR
MWPC 2
p
Energy detector
• First suggested by Wilson
(1946)
• Images contain residual
energy/range information of
individual protons
• Resolution limited by multiple
Coulomb scattering
• Spatial resolution of 1mm
possible
MWPC 1
SC
• PTR used as a QA tool
• Comparison of measured and
CT-predicted integrated
stopping power
• Sheep head used as model
• Stoichiometric calibration (A)
better than tissue substitute
calibrations (B & C)
No of PTR pixels [%]
Comparison of CT Calibration Methods
SPcalc - Spmeas [%]
Proton Beam Computed Tomography
• Proton CT for diagnosis
– first studied during the 1970s
– dose advantage over x rays
– not further developed after the advent of X-ray CT
• Proton CT for treatment planning and delivery
– renewed interest during the 1990s (2 Ph.D. theses)
– preliminary results are promising
– further R&D needed
Proton Beam Computed Tomography
• Conceptual design
–
–
–
–
–
single particle resolution
3D track reconstruction
Si microstrip technology
cone beam geometry
rejection of scattered
protons & neutrons
Si MS 1 Si MS 2
Si MS 3 SC
x
p cone
beam
Trigger logic
DAQ
ED
Proton Beam Design
Aperture
Modulator wheel
Bolus
Inhomogeneity
Proton Beam Shaping Devices
Wax bolus
Cerrobend aperture
Modulating wheels
Ray-Tracing Dose Algorithm
• One-dimensional dose
calculation
• Water-equivalent depth
(WED) along single ray
SP
• Look-up table
• Reasonably accurate for
simple hetero-geneities
• Simple and fast
WED
S
P
Effect of Heterogeneities
Protons
No heterogeneity
Water
Bone
W = 1 mm
W = 1 mm
W
W = 2 mm
W = 4 mm
Central axis
W = 10 mm
5
10
Depth [cm]
15
Effect of Heterogeneities
Range Uncertainties
(measured with PTR)
> 5 mm
> 10 mm
> 15 mm
Schneider U. (1994), “Proton
radiography as a tool for quality control
in proton therapy,” Med Phys. 22, 353.
Alderson Head Phantom
Pencil Beam Dose Algorithm
• Cylindrical coordinates
• Measured or calculated
S
pencil kernel
• Water-equivalent depth
• Accounts for multiple
Coloumb scattering
• more time consuming
WED
P
Monte Carlo Dose Algorithm
• Considered as “gold
standard”
• Accounts for all relevant
physical interactions
• Follows secondary particles
• Requires accurate cross
section data bases
• Includes source geometry
• Very time consuming
Comparison of Dose Algorithms
Protons
Bone
Water
Ray-tracing
Pencil beam
Monte Carlo
Petti P. (1991), “Differential-pencil-beam dose calculations for charged particles,” Med Phys. 19, 137.
Combination of Proton Beams
• “Patch-field” design
• Targets wrapping around
critical structures
• Each beam treats part of
the target
• Accurate knowledge of
lateral and distal
penumbra is critical
Urie M. M. et al (1986), “Proton beam penumbra: effects of separation
between patient and beam modifying devices,” Med Phys. 13, 734.
Combination of Proton Beams
• Excellent sparing of
critical structures
• No perfect match
between fields
• Dose non-uniformity at
field junction
• “hot” and “cold” regions
are possible
• Clinical judgment
required
Lateral field
Critical structure
Lateral Penumbra
• Penumbra factors:
• Upstream devices
A - no air gap
B - 40 cm air gap
80
% Dose
–
–
–
–
100
scattering foils
range shifter
modulator wheel
bolus
A
60
B
40
20
80%-20%
• Air gap
• Patient scatter
80%-20%
0
0
5
10
15
20
Distance [mm]
Air gap
25
Lateral Penumbra
• Thickness of bolus ,
width of air gap 
 lateral penumbra 
• Dose algorithms can be
inaccurate in predicting
penumbra
20-80% penumbra
10
Pencil beam
8
5 cm bolus
Ray tracing
Measurement
6
4
no bolus
2
0
0
4
8
12
Air gap [cm]
Russel K. P. et al (2000), “Implementation of pencil kernel and depth penetration algorithms for treatment planning
of proton beams,” Phys Med Biol 45, 9.
16
Nuclear Data for Treatment Planning (TP)
Experiment
Theory
Evaluation
Integral tests,
benchmarks
Validation
†
e.g., ICRU Report 63
‡
e.g., Peregrine
Quality Assurance
Recommended
Data†
Radiation Transport
Codes for TP‡
Nuclear Data for Proton Therapy
Application
Quantities needed
Loss of primary protons
Total nonelastic cross sections
Dose calculation, radiation Diff. and doublediff. cross sections
transport
for neutron, charged particles, and
g emission
Estimation of RBE
average energies for light ejectiles
product recoil spectra
PET beam localization
Activation cross sections
Selection of Elements
Element
Mainly present in
H, C, O
Tissue, bolus
N, P
Tissue, bone
Ca
Bone, shielding materials
Si
Detectors, shielding materials
Al, Fe, Cu, W, Pb
Scatterers, apertures, shielding
materials
’
Nuclear Data for Proton Therapy
• Internet sites regarding nuclear data:
–
–
–
–
–
–
–
–
International Atomic Energy Agency (Vienna)
Online telnet access of Nuclear Data Information System
Brookhaven National Laboratory
Online telnet access of National Nuclear Data Center
Los Alamos National Laboratory
T2 Nuclear Information System.
OECD Nuclear Energy Agency
NUKE - Nuclear Information World Wide Web
• Remove primary protons
• Contribute to absorbed
dose:
– 100 MeV, ~5%
– 150 MeV, ~10%
– 250 MeV, ~20%
• Generate secondary
particles
– neutral (n, g)
– charged (p, d, t, 3He, a,
recoils)
Energy Deposition (dE/dx)
Nonelastic Nuclear Reactions
All interactions
Electronic interactions
Nuclear interactions
250 MeV
0
5
10
15
20
25
Depth [cm]
30
35
40
Nonelastic Nuclear Reactions
Total Nonelastic Cross Sections
s [barn]
0.60
p + 16O
0.50
p + 14N
0.40
p + 12C
0.30
0.20
0.10
0.00
0
50
100
150
Energy [MeV]
Source: ICRU Report 63, 1999
200
250
300
Proton Beam Activation Products
Activation Product
Application / Significance
Short-lived b+ emitters
(e.g., 11C, 13N, 18F)
in-vivo dosimetry
beam localization
7Be
none
Medium mass products
(e.g., 22Na, 42K, 48V, 51Cr)
none
Long-lived products in
collimators, shielding
radiation protection
Positron Emission Tomography (PET)
of Proton Beams
Reaction
16O(p,pn)15O
Half-life
Threshold Energy (MeV) e
2.0 min
16.6
16O(p,2p2n)13N
10.0 min
5.5
16O(p,3p3n)13C
20.3 min
14.3
14N(p,pn)13N
10.0 min
11.3
14N(p,2p2n)11C
20.3 min
3.1
12C(p,pn)17N
20.3 min
20.3
PET Dosimetry and Localization
110 MeV p on Lucite,
24 min after irradiation
Del Guerra A., et al. (1997) “PET Dosimetry in
proton radiotherapy: a Monte Carlo Study,” Appl.
Radiat. Isot. 10-12, 1617.
dE/dx
– activity plateau (experiment)
– maximum activity
(simulation)
– cross sections may be
inaccurate
– activity fall-off 4-5 mm
before Bragg peak
Activity
• Experiment vs. simulation
PET experiment
calculated activity
calculated energy
deposition
0
2
4
6
Depth [cm]
8
10
PET Localization for Functional
Proton Radiosurgery
• Treatment of Parkinson’s disease
• Multiple narrow p beams of high
energy (250 MeV)
• Focused shoot-through
technique
• Very high local dose (> 100 Gy)
• PET verification possible after
test dose
Relative Biological Effectiveness
(RBE)
• Clinical RBE: 1 Gy proton dose  1.1 Gy Cobalt g dose
(RBE = 1.1)
• RBE vs. depth is not constant
• RBE also depends on
– dose
– biological system (cell type)
– clinical endpoint (early response, late effect)
Linear Energy Transfer (LET) vs. Depth
40 MeV
100 MeV
Depth
250 MeV
RBE vs. LET
6.0
high
RBE
5.0
4.0
3.0
2.0
low
1.0
0.0
100
101
Source: S.M. Seltzer, NISTIIR 5221
102
LET [keV/mm]
103
104
Source: S.M. Seltzer,
NISTIIR 5221
Relative dose
RBE
RBE of a Modulated Proton Beam
1.7
1.6
1.5
1.4
1.3
1.2
1.1
1.0
0.9
1.0
0.8
0.6
0.4
0.2
0.0
high
160 MeV
Clinical RBE
low
Modulated beam
0
2
4
6
8
10
12
Depth [cm]
14
16
18
20
Open RBE Issues
•
•
•
•
Single RBE value of 1.1 may not be sufficient
Biologically effective dose vs. physical dose
Effect of proton nuclear interactions on RBE
Energy deposition at the nanometer level clustering of DNA damage
Summary
• Areas where (high-energy) physics may
contribute to proton radiation therapy:
–
–
–
–
–
Development of proton computed tomography
Nuclear data evaluation and benchmarking
Radiation transport codes for treatment planning
In vivo localization and dosimetry of proton beams
Influence of nuclear events on RBE