1. The Use of High-Energy Protons in Cancer Therapy
Reinhard W. Schulte
Loma Linda University Medical Center

2. A Man - A Vision
In 1946 Harvard physicist Robert Wilson ( ) 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.

3. 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 Medical
Center

4. World Wide Proton Treatments*
Dubna (1967) 172
Moscow (1969)
St. Petersburg (1969) 1029
Uppsala (1957): 309
PSI (1984):
Clatterbridge(1989): 1033
Nice (1991):
Orsay (1991):
Berlin (1998): 166
HCL (1961)
6174
LLUMC (1990)
6174
Chiba (1979) 133
Tsukuba (1983) 700
Kashiwa (1998) 75
NAC (1993)
398
*from: Particles, Newsletter (Ed J. Sisterson), No. 28. July 2001

5. LLUMC Proton Treatment Center
Hospital-based facility
Fixed beam line
MeV Synchrotron
Gantry beam line

6. Main Interactions of Protons
Electronic (a)
ionization
excitation
Nuclear (b-d)
Multiple Coulomb scattering (b), small q
Elastic nuclear collision (c), large q
Nonelastic nuclear interaction (d) p’ p
nucleus
g, n e
(b)
(c)
(d)
(a) q
This slide needs to be remade!

7. Why Protons are advantageous
Depth in Tissue
Relative Dose
10 MeV X-rays
Modulated Proton Beam
Unmodulated Proton Beam
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 unity

8. Uncertainties in Proton Therapy
Patient related:
Physics related:
Patient setup
Patient movements
Organ motion
Body contour
Target definition
Relative biological effectiveness (RBE)
CT number conversion
Dose calculation
Machine related:
Device tolerances
Beam energy
Biology related:

9. 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

10. Treatment Delivery Fabrication of apertures and boluses
Beam calibration
Alignment of patient using DRRs
Computer-controlled dose delivery

11. 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

12. Processing of Imaging Data
SP = dE/dxtissue /dE/dxwater
H = 1000 mtissue /mwater
Relative proton stopping power (SP)
CT Hounsfield values (H)
Calibration curve H SP
Dose calculation
Isodose distribution

13. 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

14. CT Calibration Curve Stoichiometric Method*
Step 1: Parameterization of H
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
Klein-Nishina cross section
*Schneider U. (1996), “The calibraion of CT Hounsfield units for radiotherapy treatment planning,” Phys. Med. Biol. 47, 487.

15. CT Calibration Curve Stoichiometric Method
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

16. CT Range Uncertainties
1 mm
4 mm
Two types of uncertainties
inaccurate model parameters
beam hardening artifacts
Expected range errors
Soft tissue Bone Total
H2O range abs. error H2O range abs. Error abs. error
(cm) (mm) (cm) (mm) (mm)
Brain
Pelvis

17. Proton Transmission Radiography - PTR
MWPC 2
MWPC 1 SC 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

18. 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 PTR pixels [%]

19. 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

20. Proton Beam Computed Tomography
DAQ
Trigger logic
Si MS 2 ED
Si MS 1
Si MS 3 SC x
p cone beam
Conceptual design
single particle resolution
3D track reconstruction
Si microstrip technology
cone beam geometry
rejection of scattered protons & neutrons

21. Proton Beam Design
Modulator wheel
Aperture
Bolus
Inhomogeneity

22. Proton Beam Shaping Devices
Wax bolus
Cerrobend aperture
Modulating wheels

23. 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

24. Effect of Heterogeneities
W = 10 mm
W = 4 mm
W = 2 mm
W = 1 mm
No heterogeneity
Bone
Water
Protons W
Central axis
Depth [cm] 15 5 10
Central axis dose

25. Effect of Heterogeneities
Alderson Head Phantom
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.

26. Pencil Beam Dose Algorithm
WED S P
Cylindrical coordinates
Measured or calculated pencil kernel
Water-equivalent depth
Accounts for multiple Coloumb scattering
more time consuming

27. 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

28. Comparison of Dose Algorithms
Protons
Bone
Water
Monte Carlo
Ray-tracing
Pencil beam
Petti P. (1991), “Differential-pencil-beam dose calculations for charged particles,” Med Phys. 19, 137.

29. 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.

30. 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
Patch field 1
Critical structure

31. Lateral Penumbra Penumbra factors: Upstream devices Air gap
100 80 60 40 20 25 15 10 5
Distance [mm]
% Dose B A
A - no air gap
B - 40 cm air gap
80%-20%
Penumbra factors:
Upstream devices
scattering foils
range shifter
modulator wheel
bolus
Air gap
Patient scatter
Air gap

32. Lateral Penumbra Thickness of bolus , width of air gap 10 8 6 4 2 16 12
no bolus
Measurement
5 cm bolus
20-80% penumbra
Air gap [cm]
Pencil beam
Ray tracing
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.

33. Nuclear Data for Treatment Planning (TP)
Experiment
Theory
Evaluation
† e.g., ICRU Report 63
‡ e.g., Peregrine
Integral tests,
benchmarks
Validation
Quality Assurance
Radiation Transport
Codes for TP‡
Recommended Data†

34. 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

35. 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

36. 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

37. Nonelastic Nuclear Reactions
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) 40 10 15 20 25 30 35 5
250 MeV
Depth [cm]
Energy Deposition (dE/dx)
All interactions
Electronic interactions
Nuclear interactions

38. Nonelastic Nuclear Reactions
Total Nonelastic Cross Sections
p + 16O
p + 14N
p + 12C
Source: ICRU Report 63, 1999

39. Proton Beam Activation Products
Activation Product Application / Significance
Short-lived b+ emitters in-vivo dosimetry
(e.g., 11C, 13N, 18F) beam localization
7Be none
Medium mass products none
(e.g., 22Na, 42K, 48V, 51Cr)
Long-lived products in radiation protection
collimators, shielding

40. Positron Emission Tomography (PET) of Proton Beams
Reaction Half-life Threshold Energy (MeV) e
16O(p,pn)15O min 16.6
16O(p,2p2n)13N 10.0 min
16O(p,3p3n)13C 20.3 min 14.3
14N(p,pn)13N min 11.3
14N(p,2p2n)11C 20.3 min
12C(p,pn)17N min 20.3

41. PET Dosimetry and Localization2 4 6 8 10
Depth [cm]
Activity
dE/dx
PET experiment
calculated activity
calculated energy
deposition
110 MeV p on Lucite, 24 min after irradiation
Experiment vs. simulation
activity plateau (experiment)
maximum activity (simulation)
cross sections may be inaccurate
activity fall-off 4-5 mm before Bragg peak
Del Guerra A., et al. (1997) “PET Dosimetry in proton radiotherapy: a Monte Carlo Study,” Appl. Radiat. Isot , 1617.

42. 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

43. 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)

44. Linear Energy Transfer (LET) vs. Depth
100 MeV
250 MeV
40 MeV
Depth

45. Source: S.M. Seltzer, NISTIIR 5221
RBE vs. LET
100
102
103
104
101
0.0
2.0
3.0
4.0
5.0
6.0
LET [keV/mm]
RBE
1.0
high
low
Source: S.M. Seltzer, NISTIIR 5221

46. RBE of a Modulated Proton Beam
1.7 4 6 8 12 14 16 18 20 10 2
0.8
0.6
0.2
0.4
0.9
0.0
1.1
1.2
1.3
1.4
1.5
1.6
1.0
Modulated beam
160 MeV
Depth [cm]
RBE
low
high
Relative dose
Clinical RBE
Source: S.M. Seltzer, NISTIIR 5221

47. 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

48. 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