Applications of Silicon Detectors in Proton Radiobiology and Radiation Therapy Reinhard W. Schulte...

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


• Applications– Precise calculation of dose distributions– 3D verification of dose patient treatment position– tumor delineation without need of contrast media


• 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


• Proton Treatment Planning– Proton radiography– Proton computed tomography (CT)


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 -

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

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.

Applications of Silicon Detectors in Proton Radiobiology and Radiation Therapy Reinhard W. Schulte...

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