The Use of High-Energy Protons in Cancer Therapy Reinhard W. Schulte Loma Linda University Medical...
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Transcript of The Use of High-Energy Protons in Cancer Therapy Reinhard W. Schulte Loma Linda University Medical...
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 R. Wilson suggests use of protons• 1954 First treatment of pituitary tumors• 1958 First use of protons as a neurosurgical tool• 1967 First large-field proton treatments in Sweden• 1974 Large-field fractionated proton treatments
program begins at HCL, Cambridge, MA• 1990 First hospital-based proton treatment center
opens at Loma Linda University MedicalCenter
World Wide Proton Treatments*
LLUMC (1990)6174
LLUMC (1990)6174
HCL (1961)6174
HCL (1961)6174
Uppsala (1957): 309 PSI (1984): 3935Clatterbridge(1989): 1033Nice (1991): 1590Orsay (1991): 1894Berlin (1998): 166
Uppsala (1957): 309 PSI (1984): 3935Clatterbridge(1989): 1033Nice (1991): 1590Orsay (1991): 1894Berlin (1998): 166
Chiba (1979) 133Tsukuba (1983) 700Kashiwa (1998) 75
Chiba (1979) 133Tsukuba (1983) 700Kashiwa (1998) 75
NAC (1993)398
NAC (1993)398
Dubna (1967) 172Moscow (1969) 3414St. Petersburg (1969) 1029
Dubna (1967) 172Moscow (1969) 3414St. Petersburg (1969) 1029
*from: Particles, Newsletter (Ed J. Sisterson), No. 28. July 2001
LLUMC Proton Treatment Center
Hospital-based facility
Fixed beam line
40-250 MeV Synchrotron
Gantry beam line
Main Interactions of Protons
• Electronic (a)– ionization
– excitation
• Nuclear (b-d)– Multiple Coulomb scattering (b),
small – Elastic nuclear collision (c),
large – Nonelastic nuclear interaction (d)
e
pp
p’
p
p
p’
nucleus
n
p’
p
e
nucleus
(b)
(c)
(d)
(a)
Why Protons are advantageous
• Relatively low entrance dose (plateau)
• Maximum dose at depth (Bragg peak)
• Rapid distal dose fall-off
• Energy modulation (Spread-out Bragg peak)
• RBE close to unityDepth in Tissue
Rel
ativ
e D
ose
10 MeV X-raysModulated
Proton Beam
Unmodulated Proton Beam
Uncertainties in Proton Therapy
• Patient setup• Patient movements• Organ motion• Body contour• Target definition
• Relative biological effectiveness (RBE)
• Device tolerances• Beam energy° Biology related:
° Patient related: ° Physics related:
• CT number conversion• Dose calculation
° Machine related:
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)
X-ray tube
Detector array
• 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
Processing of Imaging Data
CT Hounsfield values (H)
CT Hounsfield values (H)
Isodose distribution
Isodose distribution
Calibration curve
H = 1000 tissue /water
Relative proton
stopping power (SP)
Relative proton
stopping power (SP)
SP = dE/dxtissue /dE/dxwater
H
SP
Dose calculation
• 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
CT Calibration Curve Stoichiometric Method*
• Step 1: Parameterization of H– Choose tissue substitutes
– Obtain best-fitting parameters A, B, C
800
1000
1200
1400
1600
1800
2000
800 1000 1200 1400 1600 1800 2000
Hounsfield value (expected)
Hou
nsf
ield
va
lue
(ob
serv
ed
H = Nerel {A (ZPE)3.6 + B (Zcoh)1.9 + C}
Klein-Nishina cross section
Rel. electron density
Photo electric effect
Coherent scattering
*Schneider U. (1996), “The calibraion of CT Hounsfield units for radiotherapy treatment planning,” Phys. Med. Biol. 47, 487.
CT Calibration Curve Stoichiometric Method
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
0 500 1000 1500 2000 2500
H valueS
P
• Step 2: Define Calibration Curve– 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
Fat
CT Range Uncertainties
• Two types of uncertainties– inaccurate model parameters
– beam hardening artifacts
• Expected range errors
Soft tissue Bone TotalH2O range abs. error H2O range abs. Error abs. error
(cm) (mm) (cm) (mm) (mm) Brain 10.3 1.1 1.8 0.3 1.4Pelvis 15.5 1.7 9 1.6 3.3
1 mm 4 mm
Proton Transmission Radiography - PTR
• 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 2MWPC 1
SC
p
En
ergy
det
ecto
r
Comparison of CT Calibration Methods
• 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) SPcalc - Spmeas [%]
No
of P
TR
pix
els
[%]
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
DAQ
Trigger logic
Si MS 2 EDSi MS 1 Si MS 3 SC
x
p cone beam
Proton Beam Design
Modulator wheel
Aperture
BolusInhomogeneity
Proton Beam Shaping Devices
Cerrobend apertureWax bolus 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
W = 10 mmW = 4 mm
W = 2 mm
W = 1 mmW = 1 mm
No heterogeneity
BoneWater
Protons
W
Central axis
Depth [cm]155 10
Cen
t ra l
ax i
s d
o se
Alderson Head Phantom
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.
Pencil Beam Dose Algorithm
• Cylindrical coordinates• Measured or calculated
pencil kernel• Water-equivalent depth• Accounts for multiple
Coloumb scattering• more time consuming
WED
SP
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
Monte CarloRay-tracing Pencil beam
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
Patch field 2
Patc
h fie
ld 1
Critical structure
Lateral Penumbra
• Penumbra factors:• Upstream devices
– scattering foils
– range shifter
– modulator wheel
– bolus
• Air gap• Patient scatter
Air gap
100
80
0
60
40
20
25 0 20 15 10 5
Distance [mm]
% D
ose BA
A - no air gapB - 40 cm air gap
80%-20%80%-20%
Lateral Penumbra
• Thickness of bolus , width of air gap lateral penumbra
• Dose algorithms can be inaccurate in predicting penumbra
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.
10
8
0
6
4
2
16 0 12 8 4
no bolus
Measurement
5 cm bolus
20-8
0% p
enu
mb
ra
Air gap [cm]
Pencil beam
Ray tracing
Nuclear Data for Treatment Planning (TP)
Experiment Theory
Evaluation
Radiation TransportCodes for TP‡
Validation
Quality Assurance
Recommended Data†
† e.g., ICRU Report 63‡ e.g., Peregrine
Integral tests,
benchmarks
Nuclear Data for Proton Therapy
Application Quantities needed
Loss of primary protons Total nonelastic cross sections
Dose calculation, radiation Diff. and doublediff. cross sectionstransport for neutron, charged particles, and
emission
Estimation of RBE average energies for light ejectilesproduct 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
Nonelastic Nuclear Reactions
• Remove primary protons• Contribute to absorbed dose:
– 100 MeV, ~5%– 150 MeV, ~10%– 250 MeV, ~20%
• Generate secondary particles– neutral (n, )– charged (p, d, t, 3He, ,
recoils)
400 10 15 20 25 30 355
250 MeV
Depth [cm]
En
ergy
Dep
osit
ion
(d
E/d
x) All interactions Electronic interactionsNuclear interactions
Nonelastic Nuclear Reactions
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0 50 100 150 200 250 300
Energy [MeV]
s [
bar
n]
p + 16O
p + 14N
p + 12C
Source: ICRU Report 63, 1999
Total Nonelastic Cross Sections
Proton Beam Activation Products
Activation Product Application / Significance
Short-lived + emitters in-vivo dosimetry(e.g., 11C, 13N, 18F) beam localization7Be none
Medium mass products none(e.g., 22Na, 42K, 48V, 51Cr)
Long-lived products in radiation protectioncollimators, shielding
Positron Emission Tomography (PET) of Proton Beams
Reaction Half-life Threshold Energy (MeV) e
16O(p,pn)15O 2.0 min 16.6 16O(p,2p2n)13N 10.0 min 5.516O(p,3p3n)13C 20.3 min 14.314N(p,pn)13N 10.0 min 11.314N(p,2p2n)11C 20.3 min 3.112C(p,pn)17N 20.3 min 20.3
PET Dosimetry and Localization
• Experiment vs. simulation– activity plateau (experiment)
– maximum activity (simulation)
– cross sections may be inaccurate
– activity fall-off 4-5 mm before Bragg peak
2 4 6 8 100
Depth [cm]
Act
ivit
y dE
/dx
PET experiment
calculated activity
calculated energydeposition
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.
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 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
100 MeV 250 MeV40 MeV
Depth
RBE vs. LET
100 102 103 1041010.0
2.0
3.0
4.0
5.0
6.0
LET [keV/m]
RB
E
1.0
high
low
Source: S.M. Seltzer, NISTIIR 5221
RBE of a Modulated Proton Beam
1.7
4 6 8 12 14 16 18 200 102
0.8
0.6
0.20.4
0.9
0.0
1.11.21.31.41.51.6
1.0Modulated beam
160 MeV
Depth [cm]
RB
E
low
high
Rel
ativ
e d
ose
1.0
Clinical RBE
Source: S.M. Seltzer, NISTIIR 5221
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