August 7, 2008 at Kyushu University

2008 KNS-AESJ Joint Summer School for Students & Young Scientists/ The Sixth Korea Accelerator Summer School

Compact Linac and Medical Physics

Mitsuru Uesaka Nuclear Professional School, University of Tokyo

CONTENTS 1. Medical Linear Accelerator and Theory 2. Advanced Compact Linacs and RF Sources 3. IMRT(Intensity Modulated Radiation Therapy) 4. DDS(Drug Delivery System) 5. Biological Guided Radiation Therapy

Annual change of morality rate for cause of death in Japan

Mortality rate per population of 100,000

cancer heart disease brain vessel disease pneumonia liver disease tuberculosis

year

Direct/indirect radiation-bio-effects
All informations DNA of living are memorized by the array of four SA T S P bases of T S C PS T (thiamine), C P S G (cytosine), A (adenine), and G (guanine).
e
+ O + particle + OH + + H +
H

P GS P A SS P CS

Indirect effect
Decomposing the living body water and active radical (OH) is made and it breaks DNA

e
+ + particle + + + + + +

Direct effect
Destroy the DNA directly.

10 -7 cm

2 10 7 cm

Profiles of the energy deposition of various radiations

140MeV
proton

X-ray10MeV
Ionization

Eloss is linear to E-3

Electron8MeV
10kV
X-ray

10MV X-ray

60Co -ray

8MeV
Electron

14MeV
electron

X-ray10keV

Depth

Energy Amount of Human Radiation Exposure

Whole body exposure X-ray

Energy amount of LD50/60 of 4 Gy Gy: J/kg

LD50/60Lethal Dose

Weight70kg LD50/60=4Gy Absorbed energy704 280J 2804.1867cal

Drink a hot coffee Temperature difference60-3723 LD50/60 volume of coffee6723 3ml

50% of people die within 60 days

Weight lifting Weight70kg Equvalent human work 280700.0981

0.4m

APPLICATION OF LINEAR ACCELERATOR AND OTHERS RADIATION MACHINES FOR MEDICAL TREATMENT

Linear Accelerator
Single modality
Single photon energy 6 MV

Dual modality
Two photon energies
6 MV 10 MV or 15 MV or 18 MV typically

Five to six electron energies

4 to 18 MeV typically

Types of linac

Alvarez linac

Widere type linac Disc-loaded waveguide

Disc loaded cylindrical waveguide and cavity

Magnetic field

g 0

vp c

A particle cant be accelerated

1 cavity

Electric field

I L
g g 0 A particle can be accelerated 1 cell is resonant cavity

vp c

An equivalent circuit

N coupled cavities
Lt L I2 C L I3 C C Lt IN C

An equivalent circuit
Ct

I1

Ct

k 2 k 2 2 1 + 2 t I1 2 0 I 2 = I1 k 2 k 2 2 2 0 I1 + (1 + k ) 0 I 2 0 I 3 = I 2 2 2 M k 2 k 2 0 I N 1 + 1 + t I N = 2 I N 2 2

The m-th eigenvalue is given by

m = 1 2k cos 2 2N
m 1 k cos 2 2N

(m = 1, 2, L N )

where

0 t

1 2C ,k = C' LC 2C 1 , kt = t C' Lt Ct

If there are N coupled cavities, there are N modes. Acceleration cavity has a several modes.

Dispersion curves

vp =vg
Cut-off frequency 1/(k) 1/g

The dispersion curve of free space

0 mode /2 mode vg : max mode vg = 0

The dispersion curve of waveguide Standing Wave (SW): vg=0 Traveling Wave (TW): vg=0

Ncell
Slope of the curve is group velocity - 2/3 mode

infinite

vp =vg The dispersion curve of infinite periodic structure

An N coupled cavity has N resonance-frequencies on the dispersion curve. (5 cells case)

General comparison of TW and SW accelerators

TW accelerator Shunt impedance Isolator or circulator Maximum accelerating beam current Tuning sensitivity Input coupler design Buncher design Spectrum sensitivity on accelerating field Coupler Coupler position Low High ~2A High Complicated Rather complicated Low Dual First and last SW accelerator High Low ~0.5A Low Simple Simple High Single Any Not needed = E2/Shunt-impedance Needed RF power

Since shunt impedance is higher, in other words field gradient is higher, the /2 mode is used for medical accelerators.

Standing-wave accelerators
/2 mode is used for SW accelerators as the sum of forward and backward TWs because its shunt impedance is high.
A coupling cavity A accelerating cavity A coupling cavity A accelerating cavity

Alternating periodic structure (APS)

Side coupled structure

Since coupling cavities not accelerate electrons, APS has wide accelerating cavities and small coupling cavities. The shunt impedance is lower, but the structure is simple to be fabricated

The side coupled structure has only accelerating cavity on axis so that the shunt impedance is higher. But this is not symmetry. So it is difficult to make this structure.

Traveling wave Type Linear Accelerator

Animation of Electric Field Lines in 2/3 mode Traveling-wave mode

Computed by axial 2-dimensional code of SUPERFISH to solve electromagnetic field in RF(Resonant Frequency) structure

Traveling-wave 2/3 Mode

Standing-wave /2 mode

Animation of Electron Acceleration

How to get the distribution of unknown index? - ComputedX-ray Tomography y

p(r , )

Ii

I0

X-ray detector alley

,

Helical scannings

distribution of attenuation coefficient : f ( x , y ) (unknown) Intensity of X-ray reaches detector: I 0 = I i exp{ s f (x, y )ds},
s f ( x, y )ds = ln

Ii . I0

(detectable)

Projection data follows r(distance) (angular): p(r , ) = f (x, y )ds Radon transformation
=

f ( x, y ) ( x cos + y sin r )dxdy,

(detectable)

Relation of Fourier transformation F ( , ) and p ( r , ) : F ( , ) =

f (x, y)exp{ j 2 (x +y )}dxdy,

from p ( r , )
Ii I0

= p(r, ) exp( j 2r )dr. = cos , = sin .

F ( , ) from s f (x, y )ds = ln

and Inverse Fourier transformation

f ( x, y ) =

F ( , ) exp{ j 2 (x + y )}dd ,

Can tell us distribution of absorbance index,thus composition of substance

L:Brain CT R:StomachCT CT figure

IMRT(Intensity Modulated Radiation Therapy)

CT image
Inverse solution

Inverse Plan

Iteration (thousands times) on computer High accuracy dose distribution optimized

Affected area

Area needs to avoid exposure

IMRT by 60arm
Gantry angle =315

Gantry angle =0 Gantry angle =45

Gantry angle =270

Gantry angle =90

Market (Numbers) of Medical Accelerators in the world Market (Numbers) of Medical Accelerators in the world
Application Electron Linac Cyclotron/Synchrotron Cancer therapy Cancer therapy Number Number sales year billion yen

Cyclotron/Linac Isotope Electrostatic accelerator/ Electron Linac Roadtron Electrostatic accelerator Total

sterility

Fast CT

Advanced Compact Accelerators and Radiation Therapy

Past 60s
S-band(2.856GHz) 6MW Klystron

Present

Future

Beam sources are matured

X-band(9.3GHz) 1MW Magnetron

Advanced and novel accelerator development -Higher RF(C,X,Ku,Ka,W-bands) -Laser plasma acceleration -Compton scattering hard X-ray source

Variety of new systems for radiation therapy

Band

Frequency(GHz)

W band

20cm

Klystron
Klystron : velocity modulation Density modulation Input cavity RF input Interaction cavity RF output Solenoid coil

Output cavity Electron flow corrector Heater eCooling water Anode Accelerated thermal electron velocity modulation of the electron by input RF The electrons propagates in the drift space gathering each other

Cathode

Excited RF

Magnetron
cathode Electron orbit for different magnetic field Electronic Oven / Microwave

(a)

anode

(b) B-type oscillation

(c)

(d)
Magnetic field : B Electron cloud

Anode current

(a)

(b)

(c) 0
critical field

(d) Magnetic field : B

N = 2 n
(N=2n:mode)

N: number of partitions : phase difference n: oscillation mode number

Schematic layout of compact accelerator using multi-beam klystron (Type 1)

RF power is linear to nI x V

Drift tube

Top view
corrector

10 MeV triode thermionic gun 50 kV power supply

RF output

Drift tube

cavity RF input Pole piece

cathode

Side view

Structure of standing wave acc. tube

Linacgraphy and CT simulation image (Beams eye view)

CT simulation image Check film by LG (MeV X-ray imaging)

MEVATRON TOTAL SYSTEM

Image-Guided Stereotactic Radiosurgery(SRS) Radiation Therapy with CyberKnife

TOMOTHERAPY

X ray CT simultaneous electron irradiation cancer therapy system

X-ray tube X-ray

e-beam (5 - 21 MeV) or X-ray (4 - 10 MV)

Bed

X-band RF gun (3.5cells)

X-ray Detector for CT

Image Guided Radiation Therapy System by inserting small Gold marker (Prof.Hiroki Shirato, Hokkaido University)
X-ray Imaging System

2mm Gold marker

Beam on just only at the original position Breathing motion

Threemaintherapiesagainstcancer
Surgery Drug Radiation

Invassive Less side effect high QOL

Our Task

Chemoradiationtherapy

To minimize radiation dose on normal tissue To minimize side effects by drugs To improve the effectiveness

XrayDrugDeliverySystem

Drug
Anticancerdrug Contrastagent Radiationenhancer

Carrier
Highcirculation rate Undetectable

Pilotmolecule
Targetingspecificcells

FunctionsofDDSdrug

What is DDS(Drug Delivery System) ?

Development or discovery of a new drug that has high selectivity to the target New drug
Ministry of Health, Labour and Welfare

Development of a new method for delivering drugs to the target Drug Delivery System
Ministry of Economy, Trade and Industry

Administration

Dynamic control in the body absorption stability amount time speed

tumor

Objectives of DDS

Enhanced absorption

High efficiency Few side effects

Controlled release Convenience Targeting Kindness to patients Improvement of QOL (Quality of Life)

Selective accumulation of polymer nano micelle to solid cancer by the EPR( Enhanced Permeability and Retention )(Kataoka et al.(U.Tokyo))

What is New DDS?

Normal cell Discharge from Lymph system Lymph system Enhanced permeability : low-molecular drug : polymer nano micelle

Underdeveloped lymph system Low discharge function

Cancer cell

Encapsulate drug& DNA to inner core

Stable drug& DNA retention Respond to environment Drug release

Hydrophilic
Excel in Biocompatibility

Based on Nano-Bio-Technology molecular Pilot

Advantage
20~100nm Target binding function

Drug delivery by polymer nano micelle can realize that high targeting to the diseased section

Nanoscale control size

Dynamic control function Tissue penetration function

Synergy of DDS and Electromagnetic Energies in Medicine-Engineering Collaboration of U.Tokyo Methodology Nano-devices Physical Energies
>1m 104

Microwave

MRI Inspection
IR

MRI agents(Gd, Fe) and DDS devices

Anticancer effect

10 mins after dosing

Fe Fe

Tumor Upgrade of negative contrast

Infra-red
103

Thermotherapy

Semiconductor Inner shell

Heat

Au nanoshell
Esophagus cancer

Thermal response Control and release of drug from DDS

Volume of tumor

Visible Laser
102

Photo-Dynamic Therapy
Selective therapy of tumor Lung by generating activated oxygen Via photoexposure

(i)

Dose: 1.8 mg/kg Laser: 100 J/cm

2

tumor

Intraveneous injection of contrast agent Stomach cancer

(ii) Photo-exposure Selective therapy by singlet oxygen

Control

UV
10

cancer

Nanomicell 10 15 20 25 30 Days after threrapy

35

X-ray -ray -ray

0.1 nm

Radiation Inspection/ Therapy

Pilot molecular Binding with target

Innershell with drug Drug release by environmental response Hidrophilic outer shell Good biocompatibility

Blocked copolymer

Drug 50100nm DDS by nanomicell

Combination of DDS of Anticancer drug (Cisplatin etc.) and Radiation Therapy

DDS+BNCT ( Boron Neutron Capture Therapy) has already started.

Some of the diagnostic procedures requiring the use of contrast agents

Carotid() arteriography

angiography

arteriography

Brain CT

B:bone, M:muscle, F:fat

Heavy metal-based requirements

It must have a high degree of water solubility (at least 2M per metal atom) It must be stable at physiological pH, at room temperature and under normal storage conditions Its pharmacokinetic profile should be similar to that of the established iodinated agents It must be completely secreted once it has served its diagnostic purpose It need to be extremely safe, causing minimal patient discomfort and no acute or delayed reactions It must be readily and easily injectable

What is Biologically Guided Radiation Therapy?

1. Purpose No surgery, Less drug side-effects, Less exposure dose 2. Deep cancer therapy by X-ray DDS (1)Iodine-type X-ray DDS - Iodine is standard contrast agent for X-rays - Auger cascade therapy is expected (2)Scintillator-type DDS 3. Image-guided pinpoint X-ray source - Exposure dose to normal cells should be suppressed as low as possible.

PDT (Photodynamic Therapy) and X-ray DDS

energy DDS
PDT type

Laser

keV X-ray

MeV X-ray

bladder carcinoma

Higher Photon Energy

Deeper Cancer

Au-colloid PEG Cisplatin Scintillator

pancreatic carcinoma renal cancer(liver) gallbladder carcinoma

Agent candidates for X-ray DDS

I. Radiation enhancement type Au-colloid PEG Cisplatin II. Active oxygen type Scintillator Talaporfin

plan: experiments to reveal physical background,

in vitro experiments to evaluate toxicity of the materials,
X-ray irradiation, etc.

Monochromatic X-rays can be used in cancer THERAPY:

Auger cascade

These soft X-rays do local damage within the cell.

K-shell electron ejected. L-shell electron replaces it and gives off a soft X-ray. M-shell electron replaces L-shell electron giving off an even softer X-ray and so on.

X-ray DDS
1.Contrast Agent: DDS with high-Z atoms, Au-colloid PEG, Au-Talaporfin
gold

Prof.Aizawa of Waseda U.

2. Radiation Enhancement: Cisplatin, Au-colloid PEG

carrier PEG

3. Scintillator+PDT: CsI, LSO, BC-501A, CdSe

Promising candidates for an X-ray DDS

Au-colloid
as contrast medium staining dye for TEM/SEM tumor marker contrast medium for cancer therapy? as therapy
in USA

in vivo using gold nanoparticles absorption to DNA? as a vector

quite promising results have been recognized

Cisplatin micelle
at clinical trial stage (phase II) enhances curative effect if aided by X-ray, but its physical background is not yet fully studied further studies are necessary

Uptake study of cisplatin micelle by PIXEParticle Induced X-ray Emission

Measurement principle
Kazue Mizuno, The best poster prize, Excellence Research Award(AESJ), Silver medal of the Dean of school of Engineering Award 2008

Innershellionization

EmissionofcharacteristicXray

Accelerator

2~4 MeV

Vacantstate

Beamsizemm (Sub beamisavailable)

Secondaryelectron

Ge detector
CountingthenumberofcharacteristicXray

Elemental analysis

30 nm

1 nm

Experiment 1 The CHO cells were treated with 50ppm of cisplatin and cisplatin micelle for 24 hours. The signals of Pt L (9.4 keV) for both of media and cells were counted.

DNA damage induced by colloidal gold DDS or its combined effect with X-rays graduate thesis H20 EE
Azusa MORI

In vitro analysis of DNA damages

alkaline comet assay

1
70

SSB
0Gy

JSME Young Engineers Award, SAEJ Best Student Research Award

4Gy
70

Frequency (%)

due to drugs and ionizing radiation

2 3 4

60 50 40 30 20 10

control 2nm 20% 20nm 20%

60 50 40 30 20 10 0

control 2nm 20% 20nm 20%

damage levels

0 1 2 3 4 5

Irradiation
(Gy)
single-strand breaks SSBs1000 double-strand breaks DSBs3040 observed by fluorescent microscopy

DSB

gamma-H2AX assay

Education and Training for Medical Physicist

in cooperation of Univ. Tokyo and National Cancer Center
Department of Nuclear Engineering and Management, . Prof.Teiji Nishio(NCC)
Depratmet of Science, Depratmet of Science, Enginnering, Health Enginnering, Health sciences, sciences, Univ. Tokyo, Other Univ. Univ. Tokyo, Other Univ. Bachlors course Bachlors course mathematics, physics, electromagnetism, statistical physics, radiation physics, atomic physics, nucleus physics,
Entrance examination

Graduate Shool of Graduate Shool of Engineering, Univ. Tokyo Engineering, Univ. Tokyo Masters course: 8 students Masters course: 8 students radiation physics, radiation measurement, radiation biology, radiology, imaging anatomy, Basic study of medical physics,
Employment

Entrance examination

Graduate Shool of Graduate Shool of Engineering, Univ. Tokyo Engineering, Univ. Tokyo Doctors course: 2 students Doctors course: 2 students Study of system and device development, Compact accelerator, Graduate Shool of Medicine Graduate Shool of Medicine and Faculty of Medicine, and Faculty of Medicine, Univ. Tokyo Univ. Tokyo

Entrance examination

Doctors course: 2 students Doctors course: 2 students Study of irradiation method, ... IGRT, Proton scanning,

Clinical Medical Physicist R&D based Medical Physicist

Medical Physicsit in Hosipital, University, Institute, Manufacturer,

Employment

New National Project for the Total System Development

Manipulation (Accethera Co., Univ.Tokyo) Treatment Planning (Hokkaido Univ., Cancer Lab.) X

Accuthera, Inc.
Business venture at Silicon Valley, USA. Collaboration with Varian, Inc., the top maker of linac

Accelerator (Accethera Co., Univ.Tokyo)

Pin-point Dynamic Tracking X-ray Cancer Therapy System PinX-

R&D-based Medical Physics

Advanced Laser/Beam Sources

Spatial Control
IMRT Precise Dosimetry PET-CT/micro-PET

Temporal Control
Drug Delivery System Radiation Chemistry in Bio-water Blood flow Bleathing Movement of Organs

150m

Bio-Simulator
Future Inspection/Therapy Planning

150m

Medical Physicist for Safe Inspection/Therapy and R&D

Acknowledgement
School of Engineering, University of Tokyo Kazue Mizuno, Takuya Natsui, Azusa Mori, all other members of Uesakas laboratory Material Engineering Department Nobuhiro Nishiyama, Kazunori Kataoka National Institute for Radiological Science High Energy Accelerator Research Organization Massachusetts Institute of Technology Richard Temkin