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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

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the use of high energy protons in cancer therapy

The Use of High-Energy Protons in Cancer Therapy

Reinhard W. Schulte

Loma Linda University Medical Center

a man a vision
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
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

world wide proton treatments
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

llumc proton treatment center
Gantry beam line

Hospital-based facility

Fixed beam line

40-250 MeV Synchrotron

LLUMC Proton Treatment Center
main interactions of protons
p

p

(a)

p’

q

e

p

(b)

p’

p

nucleus

(c)

p’

e

g, n

p

nucleus

(d)

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)
why protons are advantageous
Modulated Proton Beam

10 MeV X-rays

Relative Dose

Unmodulated Proton Beam

Depth in Tissue

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
uncertainties in proton therapy
Patient setup

Patient movements

Organ motion

Body contour

Target definition

Relative biological effectiveness (RBE)

Device tolerances

Beam energy

Uncertainties in Proton Therapy
  • Patient related:
  • Physics related:
  • CT number conversion
  • Dose calculation
  • Machine related:
  • Biology related:
treatment planning
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
Treatment Delivery
  • Fabrication of apertures and boluses
  • Beam calibration
  • Alignment of patient using DRRs
  • Computer-controlled dose delivery
computed tomography ct
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
SP

H

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

ct calibration curve
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
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.

ct calibration curve stoichiometric method15
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

ct range uncertainties
1 mm

4 mm

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

proton transmission radiography ptr
MWPC 1

MWPC 2

p

Energy detector

SC

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
comparison of ct calibration methods
No of PTR pixels [%]

SPcalc - Spmeas [%]

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)
proton beam computed tomography
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 tomography20
Si MS 1

Si MS 2

Si MS 3

SC

ED

x

p cone beam

Trigger logic

DAQ

Proton Beam Computed Tomography
  • Conceptual design
    • single particle resolution
    • 3D track reconstruction
    • Si microstrip technology
    • cone beam geometry
    • rejection of scattered protons & neutrons
proton beam design
Aperture

Inhomogeneity

Modulator wheel

Bolus

Proton Beam Design
proton beam shaping devices
Proton Beam Shaping Devices

Wax bolus

Cerrobend aperture

Modulating wheels

ray tracing dose algorithm
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

effect of heterogeneities
Protons

No heterogeneity

Bone

Water

W = 1 mm

W = 1 mm

Central axis dose

W

W = 2 mm

W = 4 mm

Central axis

W = 10 mm

5

10

15

Depth [cm]

Effect of Heterogeneities
effect of heterogeneities25
Alderson Head PhantomEffect 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
WED

S

P

Pencil Beam Dose Algorithm
  • Cylindrical coordinates
  • Measured or calculated pencil kernel
  • Water-equivalent depth
  • Accounts for multiple Coloumb scattering
  • more time consuming
monte carlo dose algorithm
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
Bone

Water

Ray-tracing

Pencil beam

Monte Carlo

Comparison of Dose Algorithms

Protons

Petti P. (1991), “Differential-pencil-beam dose calculations for charged particles,” Med Phys. 19, 137.

combination of proton beams
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 beams30
Lateral field

Patch field 2

Patch field 1

Critical structure

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 penumbra
100

A - no air gap

B - 40 cm air gap

80

A

B

60

% Dose

40

20

80%-20%

80%-20%

0

0

5

10

15

20

25

Distance [mm]

Air gap

Lateral Penumbra
  • Penumbra factors:
  • Upstream devices
    • scattering foils
    • range shifter
    • modulator wheel
    • bolus
  • Air gap
  • Patient scatter
lateral penumbra32
10

Pencil beam

5 cm bolus

8

Ray tracing

Measurement

6

20-80% penumbra

4

no bolus

2

0

0

4

8

12

16

Air gap [cm]

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.

nuclear data for treatment planning tp
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†

nuclear data for proton therapy
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
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 therapy36
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
All interactions

Electronic interactions

Nuclear interactions

250 MeV

Energy Deposition (dE/dx)

0

5

10

15

20

25

30

35

40

Depth [cm]

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)
nonelastic nuclear reactions38
p + 16O

p + 14N

p + 12C

Nonelastic Nuclear Reactions

Total Nonelastic Cross Sections

Source: ICRU Report 63, 1999

proton beam activation products
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

positron emission tomography pet of proton beams
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

pet dosimetry and localization
110 MeV p on Lucite, 24 min after irradiation

Activity

PET experiment

calculated activity

calculated energy

deposition

dE/dx

0

2

4

6

8

10

Depth [cm]

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.

pet localization for functional proton radiosurgery
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
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)
rbe vs let
6.0

high

5.0

4.0

RBE

3.0

2.0

low

1.0

0.0

100

101

102

103

104

LET [keV/mm]

RBE vs. LET

Source: S.M. Seltzer, NISTIIR 5221

rbe of a modulated proton beam
1.7

high

1.6

160 MeV

1.5

1.4

RBE

1.3

Clinical RBE

1.2

1.1

low

1.0

0.9

1.0

Modulated beam

0.8

0.6

Relative dose

0.4

0.2

0.0

0

2

4

6

8

10

12

14

16

18

20

Depth [cm]

RBE of a Modulated Proton Beam

Source: S.M. Seltzer, NISTIIR 5221

open rbe issues
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
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
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