The%20Use%20of%20High-Energy%20Protons%20in%20Cancer%20Therapy

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
  (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.
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) 3414 St.
Petersburg (1969) 1029
Uppsala (1957) 309 PSI (1984)
3935 Clatterbridge(1989) 1033 Nice (1991)
1590 Orsay (1991) 1894 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
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)

7
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 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 patients 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
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

• 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
10.3 1.1 1.8 0.3 1.4 Pelvis
15.5 1.7 9 1.6 3.3
17
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

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)

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 RD needed

20
Proton Beam Computed Tomography

• Conceptual design
• single particle resolution
• 3D track reconstruction
• Si microstrip technology
• cone beam geometry
• rejection of scattered protons neutrons

21
Proton Beam Design
22
Proton Beam Shaping Devices
Cerrobend aperture
Wax bolus
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

P
S
24
Effect of Heterogeneities
25
Effect of Heterogeneities

• Range Uncertainties
• (measured with PTR)
• gt 5 mm
• gt 10 mm
• gt 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

• 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
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

31
Lateral Penumbra

• Penumbra factors
• Upstream devices
• scattering foils
• range shifter
• modulator wheel
• bolus
• Air gap
• Patient scatter

32
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.
33
Nuclear Data for Treatment Planning (TP)
Experiment
Theory
Evaluation
e.g., ICRU Report 63 e.g., Peregrine
Validation
Integral tests, benchmarks
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)

38
Nonelastic Nuclear Reactions
Total Nonelastic Cross Sections
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 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

41
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

Del Guerra A., et al. (1997) PET Dosimetry in
proton radiotherapy a Monte Carlo Study, Appl.
Radiat. Isot. 10-12, 1617.
42
PET Localization for Functional Proton
Radiosurgery

• Treatment of Parkinsons disease
• Multiple narrow p beams of high energy (250 MeV)
• Focused shoot-through technique
• Very high local dose (gt 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
45
RBE vs. LET
Source S.M. Seltzer, NISTIIR 5221
46
RBE of a Modulated Proton Beam
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