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Applications of Silicon Detectors in Proton Radiobiology and Radiation Therapy
Reinhard W. Schulte
Loma Linda University Medical Center
Outline
• Introduction to proton beam therapy
• Applications of silicon detectors– Proton radiography and computed tomography– Particle tracking silicon microscope– Nanodosimetry
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.
Short History of Proton Beam Therapy
• 1946 R. Wilson suggests use of protons• 1954 First treatment of pituitary glands in Berkeley, USA• 1956 Treatment of pituitary tumors in Berkeley, USA• 1958 First use of protons as a neurosurgical tool in Sweden• 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 Treatment Centers
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 unity
Why Silicon Detectors
• Combined measurement of position, angle and energy or LET of single particles
• High spatial resolution (microns)• Wide dynamic energy range• radiation hardness• compatibility with physiological
conditions of cells
Applications of Silicon Detectors
• Proton Treatment planning– Proton radiography– Proton computed tomography (CT)
• Proton Radiobiology– Particle microscope– Nanodosimetry
Proton 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
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
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)
Ho
un
sfie
ld v
alu
e (o
bse
rved
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
Problems with the Current Method
• Proton interaction Photon interaction
• Multi-segmental calibration curve required
• No unique SP values for soft tissue Hounsfield range
• Tissue substitutes real tissues
• Uncertainty requires larger range to cover tumor
• Risk for sensitive structures
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
Alderson Head Phantom
Proton Range Uncertainties
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.
Proton Beam Computed Tomography
• Proton CT for diagnosis– first studied for diagnostic use during the 1970s– dose advantage over x rays for similar resolution– not further developed after development of x-ray CT
• Proton CT for treatment planning and delivery– renewed interest during the 1990s (2 Ph.D. theses)– fast data acquisition and proton gantries available– further R&D needed
Proton Beam Computed Tomography
• Applications– Precise calculation of dose distributions– 3D verification of dose patient treatment position– tumor delineation without need of contrast media
Proton Beam Computed Tomography
• Conceptual design– single particle resolution
– 3D track reconstruction
– Si microstrip detectors
– p cone beam geometry
– multiple beam directions
– energy loss measurement
– analysis of scattering and nuclear interactions
DAQ
Trigger logic
SSD 1 EDSSD 3 SSD 2 SSD 4
p cone beam
Development of Proton Beam Computed Tomography
• Experimental Study– two detector planes– water phantom on
turntable
• Theoretical Study– GEANT MC simulation– influence of MCS and
range straggling– importance of angular
measurements
Protonbeam
Simodule 2
Simodule 1
Water phantom
Turntable
Scatteringfoil
Applications of Silicon Detectors
• Proton Treatment Planning– Proton radiography– Proton computed tomography (CT)
• Proton Radiobiology– Particle microscope– Nanodosimetry
Proton Radiobiology in Perspective
D = 1 Gy
10 m
n = 112
10 MeV protons
n = 54
4 MeV protons
n = 416
50 MeV protons
dE/dx per m
4.7 keV
134 ionizations
10 keV
276 ionizations
1.3 keV
36 ionizations
RBE*
1.4
2.0
1.1
* rel to 60 Co rays
in vitro (in glass ware):• single cell suspension seeded in culture flasks or Petri dishes
• immortalized cell lines
• exponential or stationary phase
in vivo (in a living organism):• tumor growth in animals
• normal tissue response in animals (e.g., crypt cells)
• response of microscopic animals (e.g., nematodes)
Study of Cellular Radiation Responses
Study of Cell Survival in vitro
Study of cell survival in vitro• seeded cells are incubated for 3 - 14 days
• ‘surviving cells’ form large colonies (> 50 cells)
• surviving fraction is defined as
• plating efficiency (PE) is defined as the fraction (%) of cells in an unirradiated culture that form colonies
)(PE(%)/100seeded cells #
counted colonies#)(Fraction Surviving
S
Dose
S 0.1 -
0.01 -
1 -
Applications of Silicon Detectors
• Proton Treatment Planning– Proton radiography– Proton computed tomography (CT)
• Proton Radiobiology– Particle microscope– Nanodosimetry
Particle Tracking Silicon Microscope• Conventional radiobiological
experiment– random traversal of cells by a broad
particle beam
– only average number of hits per cell is known
• Particle-tracking radiobiological experiment– number of particles per cell is exactly
known
– broad beam or microbeam setup
SSD
n = 2 1 3 0
= 1.5 P(n) = n/n! e-
SSD
n = 0 0 3 0
collimator
Particle Tracking Silicon Microscope
• Conceptual design– biological targets located
on detector surface– single-particle tracking– energy or LET
measurement– ASIC and controller design
adapted to application– dedicated data acquisition
system
DSSD ASIC RO Control Cables DAQ
MCM
Low-Dose Cell Survival
• Low-dose studies with a proton microbeam– precise low-dose/fluence
cell survival curves
– hypersensitive region at low doses
– more pronounced at higher proton energies (3.2 MeV vs. 1 MeV)
Dose (Gy)
3.2 MeV protons
Schettino et al. Radiation Res. 156, 526-534, 2001
Adaptive Response & Bystander Effect
• Low-dose studies with an alpha particle microbeam– only 10% of cells exposed
– more cells inactivated than traversed (bystander effect)
– previous exposure to low level of DNA damage increases resistance (adaptive response)
--- expected
-o- 6 hrs after priming dose
-- 6 hrs after priming � dose
Sawant et al. Radiation Res. 156, 177-180, 2001
Goals of the LLU/SCIPP Particle Tracking Microscope Project
• Develop a versatile and inexpensive broad-beam and microbeam particle tracking system for– protons and alpha particles – wide range of energies (1 MeV - 70 MeV protons)– in vitro and in vivo radiobiological studies– research studies for radiation therapy and protection– support of DOE and NASA low-dose research
programs
Applications of Silicon Detectors
• Proton Treatment Planning– Proton radiography– Proton computed tomography (CT)
• Proton Radiobiology– Particle microscope– Nanodosimetry
Nanodosimetry Collaboration
Loma Linda University Medical Center (1997)
UCSC (2000) SCIPP
Weizmann Institute of Science (1997) UCSD (1998)
Nanodosimetry Concepts
• DNA is the principle target in radiobiology
• Radiation interaction with DNA is a stochastic event
• Single damages (break or base oxidation) are easily repaired
• Clustered damages are difficult or impossible to repair
Clustereddamageirreparable
Single damagereparable charged
particle
~2nm
electron 50 base pair DNA segment
Conceptual Approaches
Track Structure Imaging Single-Volume Sampling
Mean Free Path versus Gas Pressure
• Mean free path:
– n, targets per unit volume
– , interaction cross section
• Assumptions:– same atomic composition
– is independent of density
• Density Scaling:
gas = (ref / gas) ref
= 1 / (n
1 mm in 1 Torr propane 2.4 nm in unit density material
1 Torr Propane (C3H8)
projectile
target
Ion Counting Nanodosimetry
• Ionization volume filled with low-pressure gas
• single particle detection• ion drift through aperture• wall-less sensitive
volume• evacuated ion detection
volume
trigger
E1
Ion counter
SV ions
gas
E2aperture
DAQ
vacuum
28 29 30 31 32 33-0.3
-0.2
-0.1
0.0
0.1
Sig
nal
[V
]
Ion drift time [sec]
particle
SSDSSD
The Ion Counting Nanodosimeter
• Pulsed drift field
• differential pumping system
• electron multiplier
• internal alpha source
Anode
50m
m
Cathode
E1
E2
e-
ion
1 Torr
Intermediatevacuum
particle
EM to pump 2
to pump 1
High vacuum
Single Charge Counting
• Ionization volume filled with low-pressure gas
• single particle detection• ion drift through aperture• wall-less sensitive
volume• evacuated ion detection
volume
trigger
E1
Ion counter
SV ions
gas
E2aperture
Particle detector
DAQ
vacuum
28 29 30 31 32 33-0.3
-0.2
-0.1
0.0
0.1
Sig
nal
[V
]
Ion drift time [sec]
The Ion Counting Nanodosimeter
• Pulsed drift field
• differential pumping system
• electron multiplier
• four SS detector planes for particle tracking and energy reconstruction
Anode
50m
m
Cathode
E1
E2
e-
ion
1 Torr
Intermediatevacuum
particle
EM to pump 2
to pump 1
High vacuum
SSD2SSD1
Nanodosimetric Spectra
• ND spectra change with particle type and energy
• average cluster size increases with increasing LET
1.E-02
1.E-01
1.E+00
1.E+01
1.E+02
0 20 40 60 80Cluster size
Ab
s. F
req
ue
nc
y (
%) protons
alpha carbon
Applications
• New Standard of Radiation Quality in Mixed Fields
• Radiation Treatment Planning: biological weighting factor
• Radiation Protection: risk-related weighting factors
• Manned Space Flight: Risk prediction (cancer & inherited diseases)
Acknowledgements
• LLUMCVladimir BashkirovGeorge CoutrakonPete Koss
• WISAmos BreskinRachel ChechikSergei ShchemelininGuy GartyItzik OrionBernd Grosswendt - PTB
• UCSD - Radiobiology– John Ward– Jamie Milligan– Joe Aguilera
• UCSC - SCIPP– Abe Seiden– Hartmut Sadrozinsky– Brian Keeney– Wilko Kroeger– Patrick Spradlin
The nanodosimetry project has been funded by the National Medical Technology Testbed (NMTB) and the US Army under the U.S. Department of the Army Medical Research Acquisition Activity, Cooperative Agreement # DAMD17-97-2-7016. The views and conclusions contained in this presentation are those of the presenter and do not necessarily reflect the position or the policy of the U.S. Army or NMTB.