Download Accelerators and Principles for Hadron Therapy Eal Lee 2012

Accelerators and Principles
for Hadron Therapy
Eal Lee
2012
KAERI REVIEW
Major Application Areas of Ion Beam
•Nuclear physics
•Radiotherapy
•Medical radioisotopes production
•Radionuclide (medical imaging)
•Biomedical research
•Other applications (~50%)
The main objective of this presentation is to describe
the particle accelerators for medical applications,
namely for proton therapy.
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Contents
•Accelerators and Facilities
•Physics of Hadron Therapy
The goal of any cancer therapy is to destroy the malignant
cells in the body while doing minimal damage to the healthy
tissue. Modern cancer therapies, no matter if they are
chemotherapy, targeted medications, surgery, X-ray therapy,
or particle beam therapy, are all about collateral damage:
destroy the cancer but not the patient.
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Why Use Protons?
•Same tumor killing properties as X-rays
•Decreased dose to normal tissues by 50-70%
•Decreased side-effects and complications
•Ability to treat tumors close to critical organs like the
spinal cord
•With X-rays, 20% of cancers come back because
treatment dose was too low to be effective
•Possibility to increase the safe dose delivered to tumors
•Possibility of increased cure rates
•The ability to re-treat tumors after recurrences
•The added ability to treat benign conditions
Source: Penn Medicine, Perelman Center for Advanced Medicine
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Benefits and Experience
Benefits
• Proton therapy is widely recognized as the most
effective external beam method in the selective
destruction of cancer cells.
• Non-invasive
• Minimal side affects
• Most precise treatment, targeting only the tumor
• Healthy tissue around the tumor is spared
Treatment Experience
• Treatments are completely painless.
• The actual radiation time is a matter of seconds.
• Patients receive outpatient treatment, with each
appointment time being 15-30 minutes per day for five
to eight weeks
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Typical Accelerators Used for Hadron Therapy
Linac: push particles (timed alternating voltage)
Cyclotron: repetitive use of linac (constant B field
and constant rf frequency of E-field)
Synchrocyclotron: Overcome relativistic effects
by synchronized rf E-field (only one dee is used,
E-field frequency is decreased as particles get heavier)
Synchrotron: Overcome relativistic effects by
pulsed magnet and synchronized rf (both B
and E field are varied)
FFAG: fixed magnet with strong focusing
(combine the cyclotron’s advantage of continuous
operation with the synchrotron’s relatively inexpensive
small magnet ring, of narrow bore)
FFAG: Fixed-Field Alternating Gradient
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Linear Particle Accelerator (linac)
Particles pass through a line of hollow metal tubes enclosed in an evacuated cylinder. An
alternating voltage is timed so that a particle is pushed forward each time it goes through a
gap between two of the metal tubes. The length of tubes determined by the frequency and
power of the driving power source and the nature of the particle to be accelerated, with
shorter segments near the source and longer segments near the target.
Note that the increased electron energy is exhibited by relativistic changes in mass.
Picture source: wikipedia, see also p. 69 Patterson in Ch 3, Rad. Chem.
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Cyclotron Principle
RF Oscillator
D1
D2
N
So
C
D1
So
D2
S
Target
Deflector
The elements of a cyclotron, showing the particle source ‘So’ and the dees.
A uniform magnetic field is directed perpendicular to the dees. Circulating protons
spiral outward within the hollow dees, gaining energy every time they cross the gap
between the dees, which bias is changing alternately by the RF oscillator.
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Inside of Cyclotron
The interior of a 235MeV proton cyclotron used for proton therapy
The interior of a cyclotron with three spiralled pole sectors with improved
vertical focusing properties and more room for the extraction system. -IBA
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250 MeV Synchrotron
CIS: Circumference = 1/5 C_cooler = 17.364 m
Dipole length = 2 m, 90 degree bend, edge angle = 12 deg.
Inj KE= 7 MeV, extraction: 250 MeV
A synchrotron is a particular type of cyclic particle accelerator in which the magnetic field (to turn the
particles so they circulate) and the electric field (to accelerate the particles) are carefully synchronized
with the travelling particle beam. However, since the particle momentum increases during acceleration,
it is necessary to turn up the magnetic field B in proportion to maintain constant curvature of the orbit.
In consequence synchrotrons cannot accelerate particles continuously, as cyclotrons can, but must
operate cyclically (cyclic pulse mode), supplying particles in bunches, which are delivered to a target
or an external beam in beam "spills" typically every few seconds. - Wikipedia
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Lattice Structure of Compact Synchrotron
K. Endo, Z. Fang and S. Ninomiya
High Energy Accelerator Research Organization (KEK)
1-1 Oho, Tsukuba-shi, Ibaraki-ken 305-0801, Japan
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FFAG Accelerator
8 triplet cells
A Fixed-Field Alternating Gradient accelerator (FFAG) is a type of circular particle accelerator that
has features of cyclotrons and synchrotrons.
FFAG accelerators combine the cyclotron's advantage of continuous, unpulsed operation, with the
synchrotron's relatively inexpensive small magnet ring, of narrow bore.
This is achieved by using magnets with strong focusing alternating-gradient quadrupole fields to
confine the beam, accompanied by a dipole bending magnetic field which bends the beam to close
the orbital ring. By the use of a strong radial magnetic field gradient in the dipole component, yet with
a time-constant "fixed field" as the particles are accelerated, particles with larger energies move
successively to slightly larger orbits, where the bending field is larger. The beam thus remains
confined to a narrow ring, as in a synchrotron, yet without the synchrotron's requirement that the
machine be operated in pulsed acceleration cycles.
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Proton Therapy Facilities
Typical facility components:
(i) accelerator
(ii) beam-transport system
(iii) treatment-delivery system
gantry
beam nozzle
snout
volume-tracking
beam-gating device
patient-positioning
immobilization system
(iv) shielded enclosure from radiation
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Schematic Representation of Proton Gantry
• A rotating beam port, a rotating beam line
• For treating the patient in supine position
• With maximal flexibility to apply the beam from any desired direction
E. Pedroni Center for Proton Radiation Therapy - Paul Scherrer Institute - WE Chiba 01-05-2010
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Energy Selection System (ESS)
At 180,000 km/sec, protons penetrate the body to a depth of approximately 38 cm.
If a radiation target, i.e., the tumor, is closer to the surface, the protons have to
be degraded (slowed down). This occurs immediately after the protons leave the
cyclotron in the Energy Selection System (ESS), which places graphite wedges in
the path of the beam to achieve the precise speed required.
Rinecker Proton Therapy Center, http://www.rptc.de/en/
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Schematic Representation of Nozzle
Schematic, not to scale, of the IBA universal nozzle in double-scattering mode. Components are a binary fixed scatterer
system (FS: fine-tune the flatness of the lateral dose profile), a range modulator track (RM: flatness of the SOBP in the depth
direction), magnets (not used for double scattering), a contoured second scatterer (SS), collimator jaws, monitor unit
chamber (IC), and snout, which is the part of the nozzle closest to the patient. The snout supports the aperture/collimator
and compensator. -Med Phys. 2009 June; 36(6): 2172–2180.
The nozzle also contains beam detectors which control the radiation intensity, the beam energy and thus the penetration
depth, and the deflection of the X and Y dimensions. The detectors also match up the desired data for the patient with
beam targeting independently of other control functions. The beam then passes through a Kapton plastic window that acts
as a vacuum seal and emitted into the open. – Rinecker Proton Therapy Center, http://www.rptc.de/en/
The functions of the nozzles include the 3-D beam shaping to irradiate the target volume at a constant dose, the beam
monitoring and dosimetry, to help for patient positioning and field alignment verification, and the support of patient specific
devices. The spreading techniques provided by the IBA nozzle are the double scattering for small to moderate fields, and the
wobbling technique for the largest and deepest fields. The nozzle is compatible with a future upgrade to pencil beam
scanning. – Jongen et al., IBA
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Shaping the Beam to the Shape of the Tumor
Passive scattering is one possibility to confirm the beam shape to the tumor. By widening the beam
and sending it through special collimators the cross section of the beam is shaped to conform
exactly to the shape of the tumor in radial direction. Using range modulators (materials with varying
thicknesses) together with a compensator bolus (a block of material which is a negative imprint of
the far edge of the tumor) the Bragg peak can be adjusted to optimum overlap with the axial
dimension of the tumor.
Source:
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Modulator, Collimator, Compensator
A modulator (or range shifter wheel) and scatter
foil are used to take the thin beam line and widen it
to fit the tumor.
A collimator and compensator can be used to
further shape the beam. A collimator is used to
shape the beam coming out of the nozzle and is
usually made of brass.
A compensator, made of wax or acrylic, shapes
the far edge or end of the beam, making some
areas more or less deep to contour to the tumor.
These pieces are made specifically for each
patient's tumor treatment plan.
Some cons to passive scatter include the creation of custom
pieces for each patient, the disposal of these pieces (as they
become radioactive after use and the shifting of dose towards
the front end of the beam, towards the skin, which can result in
unwanted dose to the patient
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Nozzle Operational Modes
Single Scattering: Delivers a uniform proton dose in small fields with
only one scatterer.
Double Scattering: Accepts any energy at nozzle entrance within the
70-235 MeV range. Reduces the distal falloff. Reduces the lateral
penumbra and the radiation level.
Uniform Scanning: The beam spot is moved by magnetic scanning and
allows several mini-irradiations. Full modulation, field uniformity, very
safe treatment.
Pencil Beam Scanning: Slice-by-slice irradiation of the target with
millimeter precision. Primary advantages include: multiple fast repainting,
no use of aperture, no compensator devices, dose uniformity, intensity
modulation (IMPT), and gating.
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Proton Pencil Beam
As protons are elementary particles which carry a positive charge they can be deflected and
focused in magnetic fields, and the beam can be shaped as desired. The most modern facilities
today use a proton beam as thin as a pencil. By varying the energy the depth where the dose is
delivered can be varied. By deflecting the beam sideways using magnetic fields one can ‘paint’ a
complex picture at a given depth in the body – similar to generating a TV image with a single
electron beam scanning across the screen line by line. Combining these two methods (rapidly
varying the energy of the beam and painting the tumor cross section slice by slice) any complex
shape of a tumor can be covered.
Source:
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Irradiation of Moving Target (e.g., lung tumors)
RF-Knock-out (KO) extraction [Moritz et al. 2005]: Allows pausing and
resuming within a pulse, Experimental at GSI, standard at HIT
Parameters: 2 mm grid spacing; ~18 mm spot size; 1-9 mm gating window
Long term: tracking adaptation of beam position to follow target motion
Short term: gating restrict irradiation to phases with little motion
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Real Time Tumor Tracking Proton Beam Therapy
By combining the real-time tumor-tracking radiation therapy and a small system of spot-scanning
proton beam technology, it is possible to treat large tumors in moving organs including intractable
ones such as lung, liver, and pancreatic cancers, and maximize the effect of proton beam treatment,
while greatly reducing the radiation delivered to the surrounding normal tissues.
Source: Under development at Hokkaido University Graduate School of Medicine (2011)
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Immobilization for Proton Therapy
Various patient immobilization devices are used for:
• High accuracy and high reproducibility
• Patient comfort
• Minimization of inter-fraction setup errors
• Minimization of residual intra-fraction patient and/or organ motion
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Overview of State of The Art
Principles of different machine types are used for varying scanning techniques at treatment facilities round the world:
NPTC = North East Proton Therapy Centre (USA), PSI = Paul Scherrer Institute (CH), LLUMC = Loma Linda University
Medical Centre (USA), HIMAC = Heavy Ion Medical Accelerator (J), GSI = Gesellschaft für Schwerionenforschung (D).
M Sholz in M. Regler, M. Benedikt, K. Poljanc, CERN Accelerator School,
Hephy-PUB-757/02
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Current Locations of Proton Therapy Centers
Ilsan, Korea
(2007)
Fewer than 30 proton therapy centers exist worldwide (red), but a growing number
are either planned or already under construction (yellow). (Image courtesy of Jay Flanz,
Massachusetts General Hospital.)
American Institute of Physics
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Ion Beam Therapy in Europe
At present, seven facilities in Europe treat deep-seated tumors with particle beams, six with proton
beams and one with carbon ions. Three of these facilities are in Moscow, St. Petersburg and
Dubna, Russia. Other facilities include the TSL Uppsala, Sweden, CPO Orsay, France, and PSI
Villigen, Switzerland, all for proton therapy, and GSI, Darmstadt, Germany, which utilizes carbon
ions only. But only two of these facilities irradiate with scanned ion beams: the Paul Scherer
Institute (PSI), Villigen (protons) and the Gesellschaft für Schwerionenforschung (GSI),
Darmstadt. These two facilities are experimental units within physics laboratories and have
developed the technique of intensity-modulated beam scanning in order to produce irradiation
conforming to a 3-D target. There are three proton centers presently under construction in Munich,
Essen and Orsay, and the proton facility at PSI has added a superconducting accelerator
connected to an isocentric gantry in order to become independent of the accelerator shared with
the physics research program. The excellent clinical results using carbon ions at National Institute
of Radiological Science (NIRS) in Chiba and GSI have triggered the construction of four new
heavy-ion therapy projects (carbon ions and protons), located in Heidelberg, Pavia, Marburg and
Kiel. The projects in Heidelberg and Pavia will begin patient treatment in 2009, and the Marburg
and Kiel projects will begin in 2010 and 2011, respectively. These centers use different accelerator
designs but have the same kind of treatment planning system and use the same approach for the
calculation of the biological effectiveness of the carbon ions as developed at GSI [1]. There are
many other planned projects in the works. Do not replace the word “abstract,” but do replace the
rest of this text. If you must insert a hard line break, please use Shift+Enter rather than just tapping
your “Enter” key. You may want to print this page and refer to it as a style sample before you begin
working on your paper. ©2009 American Institute of Physics
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Schematics of Accelerator and Treatment Facilities
The proton beam treatment facility at National Cancer Center (NCC), Ilsan Korea, is
operational since 2007, which is an IBA 235 MeV cyclotron with energy selection system
(ESS), two gantry rooms, one fixed-beam room, expandable by one gantry room.
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Construction of Gantry and Treatment Facilities
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Cross-Section of Gantry / Treatment Room
Curtsey of IBA
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Cyclotron
A cyclotron accelerates protons to an extremely high speed, then generates a controlled beam that is directed by
magnetic fields through a nozzle to the targeted tumor, releasing a dose of protons inside the tumor that kills cancer
cells with minimal impact on surrounding healthy tissues. The proton beam can be contoured to the shape of the
tumor, further decreasing radiation exposure to healthy cells and limiting side effects.
Courtesy
of IBA, Belgium
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Beam Transport System
The beam transport system distributes a beam of proton energy to each of
the treatment rooms quickly and efficiently. The beam transport line can be
as long as a football field and links the cyclotron to each treatment room.
Some treatment rooms are built without a gantry.
Courtesy of IBA, Belgium (Installed at Particle Therapy and UFPTI Jacksonville)
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Gantry
The gantry is a large, sphere shaped structure that houses the equipment used to
actually give the protons to the patient. The gantry is three stories tall and built into a
large concrete casing. The patient enters the treatment area on the second floor. The
gantry allows the beam to spin 360 degrees around the patient. - IBA
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Gantry Treatment Room
Gantry is a device for rotating the radiation delivery apparatus around the patient
during radiation therapy. The gantry rotates around the patient to deliver treatment
from different angles, allowing the physician to precisely target the tumor site.
Courtesy
of IBA, Belgium
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Patient Positioning System
Courtesy of IBA, Belgium
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Nozzle
Nozzle is a device through which protons are delivered to the patient. The IBA Universal Nozzle
allows the flexibility to select the preferred beam delivery mode automatically within a single
treatment room, without manual intervention. One can switch between all four modes (Single
Scattering, Double Scattering, Uniform Scanning, Pencil Beam Scanning) from outside the room.
Courtesy
of IBA
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Trend of Technology
Currently, only five U.S. health care facilities have large-scale proton beam radiation therapy systems weighing more
than 440,000 pounds that require almost 100,000 square feet of space, with a price tag upward of $150 million for the
equipment and building. A group of physicists and other scientists from MIT and other academic proton research
facilities have spent years developing a smaller, more economical cyclotron that can produce and deliver protons for
radiation therapy. This new technology still comes with a hefty price tag. To date, less than ten centers have
committed to purchasing this new technology - among them are MD Anderson - Orlando, Barnes-Jewish Hospital,
Oklahoma University's Cancer Institute, Tufts New England Medical Center, and Oncologics.
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Table-size Superconducting Cyclotron
Table-sized
superconducting
cyclotrons are being
developed by Still
River Systems for
single-room protonradiation treatment.
(Image courtesy of
Still River Systems.)
Accelerators shrink to meet growing demand for proton therapy.
http://ptonline.aip.org/journals/doc/PHTOAD-ft/vol_62/iss_3/22_1.shtml, Matthews 2009
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Clinical Considerations on Facility Design
• The most important elements defining the system
performance are the Nozzle, the Patient Positioning
System and the Beam Delivery System!
• The Accelerator and the Beam Transport System have
much less impact on the system performance!
• ELISA (Energy, LET, Intensity, Safety, Availability)
• The simplest accelerator meeting the clinical
specifications in a cost-effective way should be
selected! The Accelerator should be transparent at
treatment level.
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Hadron Therapy
u
quark
matter
d
u
up quark
d
down quark
u
proton
u
d
d
neutron
Hadron: Any of a class of subatomic particles that are composed
of quarks and take part in the strong interaction.
Particle therapy works by aiming energetic ionizing particles at
the target tumor. These particles damage the DNA of tissue
cells, ultimately causing their death. Because of their reduced
ability to repair damaged DNA, cancerous cells are particularly
vulnerable to attack.
Source: Wikipedia
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Medical Specifications for P- and C-Therapy
•Field Size (typical): 20x20 cm2, up to 40x40 cm2 for fixed beam
•Range in tissue: up to 30 cm
•Energy:
Proton:
Carbon Ions:
70 – 250 MeV
120 – 400 MeV/n
•Spread-out Bragg-peak over whole tumor depth
•Treatment duration:
∼2 min
•Typical dose:
∼2 Gy, Vol ∼2l
These figures are somewhat arbitrary, rather traditional.
Have to be redefined if Hypo-fractionation becomes standard in Ion Therapy
Up to now, only Cyclotrons, Synchrotrons have been used for
Hadron therapy. After its discovery, the FFAG becomes fashionable.
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SI ‘Dose’ Unit
1 Becquerei (Bq) = 1 nuclear transformation per sec (s-1)
= 2.7x10-11 curie (Ci)
1 Curie (Ci) =3.7×
×1010 decays/s ~ the activity of 1g of 226Ra.
(1 g Co-60 (ττ ~5.27y) contains about 50 Ci)
1 Roentgen (R) = 2 58×
×10−4 Coulomb/kg of dry air
1 Rad (radiation absorbed dose) = 1 erg/g = 0.01 J/kg
A typical therapy dose for the destruction
1 Gray (Gy) (absorbed dose)
of a tumor amounts to approximately 60
= 1 J/kg = 6.24x1018 eV/kg = 104 erg/g
to 70 Gy. It is transferred in individual
= 100 rad (radiation absorbed dose)
fractions in several successive days
1 DE (dose effective) = absorbed dose x RBE (QF)
(approx. 30 fractions in total).
1 rem (rad equivalent in man) = absorbed dose in rad x RBE (QF)
Sievert (Sv) (effective dose, radiation effect in human )
= 1 Joule per kilogram (J/kg)
=100 rem (roentgen equivalent man)
=Gy*RBE
=100 rad*rbe
1 Roentgen (R)= 2.58x10-4 coulombs per kilogram
1 Roentgen=1 rad
In radiology one arbitrarily defines the relative biological
Relative biological effectiveness (RBE) (Q factor)
effectiveness (RBE) of a radiation type as the ratio of energy (dose)
RBE=1
for x-, β-, γ- rays
needed for an X-ray treatment using a Cobalt-60 source to inflict the
D
same
damage as when using this new type of radiation under study.
γ
RBE=3
for thermal n
RBE =
RBE is a complex concept and the exact number depends on many
Dion details of the study, including cell type, definition of damage to be
RBE=10 for fast n, α, p
studied, and many other things, and one must be careful when
RBE=20 for recoil nuclei
making quantitative statements on this issue.
Low dose:
Medium low dose:
Medium high dosage exposure:
High dosage exposure:
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less than 1Sv (100 rem)
1-2 Sv (100 – 200 rem)
2-5 Sv (200 – 500 rem)
more than 5 Sv (500 rem and more)
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Cross-section, Stopping Power, LET
Cross-section:
affected area
(nm2)
Stopping Power:
energy deposit x cross-section
(eV-nm2)
LET:
atomic density x stopping power (eV/nm)
LET: Linear Energy Transfer or energy absorbed in a target per unit length (-dE/dx)
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Two Important Factors in Radiotherapy
• Ballistic effect - i.e. the improved physical selectivity
for charged particles, which means the delivery of a
homogeneous dose to the tumor volume while
minimizing the dose to surrounding healthy tissues.
(Here, the ballistic effect means the straightness of particle trajectory,
not nuclear displacement)
• Radiobiological effect - i.e. the improved
biological effectiveness (RBE) of hadrons due to dense
ionizing tracks produced by these particles.
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100 keV vs. 200 MeV
Energy
100 keV
200 MeV
Longitudinal Range
Longitudinal Straggle
Lateral Projection
Lateral Straggle
1.19 µm
876 A
857 A
1136 A
237 mm
3.31 mm
3.16 mm
4.54 mm
Dominant effect is the ionization (≥99%)
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235 MeV Proton on Human Cell
When the velocity of a particle is high, the particle-medium interaction
time is short and thus the energy deposition is small, thereby highest
energy deposition occurs near the end of ion track.
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Coulomb Force between Two Charged Ions
Coulomb Force assuming no screening effect:
Fc =
εo = 8.85x10-12 C2/Nm2
q = 1.6x10-19 C
1 eV = 1.6x10-19 Joule (Nm)
q 1q 2
9 q1q 2
=
(
9
x
10
) 2 N or Joule/m
4πε o r 2
r
1
Energy gained by displaced ions :
r2
Ec =
∫
r1
Bond
type
1 1
q 1q 2
9
dr
=
(
x
)
q
q
9
10
− 
1 2
4πε o r 2
 r1 r2 
1
Bond
length
nm
Nm or Joule
F c for q 2 at
Bond length Bond energy
used for calc
bond distance
nm
eV
eV/nm
E c for 50%
displ of bond
length
eV
E c for r 2 =oo
(Fc x bond
length)
eV
C - H
0.1050 0.115
0.1
4.302
144
4.8
14.4
C - C
0.154 0.1203
0.15
3.606
64
2.74
9.6
Coulomb Force between Two Charged Ions Exerts Sufficient Energy to Cause Scission.
Coulomb explosion, a dominant mechanism in insulator.
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Spurs, Blobs, Short-Tracks (energy deposition entities)
Theory: continuous slowing-down approximation (c.s.d.a)
In reality: energy deposition occurs discretely as an entity of ‘spur’ (6-100 eV)
Spurs begin to make a choppy overlap with increasing LET,
such entities are called ‘blob’ (100-500eV)
Spurs overlap for high LET creating ‘short track’ (500-5000 eV)
Theoretical Example:
20-keV electron consumes its energy: 38% for spurs, 12% for blobs, and 50% for short tracks.
1-MeV electron consumes its energy: 65% for spurs, 15% for blobs, and 20% for short tracks.
10-MeV electron consumes its energy: 76% for spurs, 8% for blobs, and 16% for short tracks.
Certain threshold energy is required to free the bound electrons from atoms for ionization or displace
atoms. Thus ion tracks can be taken as made up of isolated ionization, for example. The average
energy loss per event lies between 30 - 40 eV. The energy loss entities are called ‘spurs’
Spur energy is associated with chemical bond energy or the energy levels of the valance electrons
(ionization energy) which are significantly altered in molecules or in polymers.
The track of any low-LET radiation is a collection of isolated spurs.
Zeiss, G. D.; W. J. et al., J. Radiat. Res. 1975, 63, 64; see p. 23 Chapter by Chartterjee,
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X-Ray vs. High LET Particles
Heavy ion therapy makes use of
the high LET, 12C6+ ions for
example.
The relative radiation damage
(relative biological effect or RBE)
of fast neutrons is 4 times that of
X-rays because of the high LET,
meaning 1 rad of fast neutrons is
equal to 4 rads of X-rays.
The RBE of neutrons is also
energy dependent, so neutron
beams produced with different
energy spectra at different
facilities will have different RBE
values.
Comparison of Low LET electron and High LET neutron effect
Source: Wikipedia
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Fractionation Effect
1. A typical therapy dose for the destruction of a tumor amounts to
approximately 60 to 70 Gy. It is transferred in individual fractions in several
successive days (approx. 30 fractions in total).
2. Repair of sublethal DNA damage by normal cells. Radiation damage to cancer
cells is the result of DNA strand breaks. Normal cells have better DNA repair
machinery. Fractionated treatment preferentially allows normal cells to repair
sublethal DNA damage.
3. Repopulation of normal healthy cells. The time interval between radiation
fractions allows normal cells to grow, divide, and therefore continue normal
function at the level of tissues and organs.
4. Reassortment of tumor cells into more radiosensitive phases of the cell
cycle. Cancer cells have varying sensitivity to radiation depending on their current
phase of the cell cycle. In between treatments, some proportion of cells will cycle
into a more sensitive phase, rendering them more susceptible to radiation damage.
5. Reoxygenation of tumor cells. The majority of radiation damage to the DNA of
cancer cells occurs through a free radical mechanism that is enhanced by oxygen.
The time interval between fractions allows additional perfusion of oxygen into areas
of the tumor that tend to have low levels of oxygen (that is, hypoxic regions),
leading to an enhanced effect of radiation in the tumor.
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Fractionating Dose Extends Survival
Surviving crypt cells
per circumference
102
101
1
2
3
5
20 (fractions)
100
10-1
200
300
Dose in Rad
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Chronology of Radiation Effects
• Initial Physical Interaction Excitation, Ionization 10-24 - 10-14 s
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• Physiochemical Free Radical Formation
10-12 - 10-8 s
• Chemical Damage: Radical Attack
10-7s - hours
• Biomolecular Damage: DNA, Proteins, etc.
ms - hours
• Early Biological Effects: Toxicity, Mutation
hours - weeks
• Late Biological Effects: Cancer, Genetic
years - centuries
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Radiation Effects
Somatic effects - those which occur in the
person exposed
Genetic effects - those which occur in the
offspring of exposed persons (genetic, DNA)
Stochastic effects - likelihood of effect is
random, but increases with increasing dose
Non-stochastic effects - likelihood of effect is
based solely on dose exceeding some threshold
Somatic effects and genetic effects show
no immediate symptoms.
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Physical Dose Distribution for Various Radiation
The dose from protons to
tissue is maximum just
over the last few
millimeters of the particle’s
range, quite different from
that of electrons or x rays.
The figure shows how beams of electrons, X-rays or protons of different energies (expressed in MeV) penetrate human tissue.
Electrons have a short range and are therefore only of interest close to the skin (e.g., electron therapy). Bremsstrahlung X-rays
penetrate more deeply, but the dose absorbed by the tissue then shows the typical exponential decay with increasing thickness.
For protons and heavier ions, on the other hand, the dose increases while the particle penetrates the tissue and loses energy
continuously. Hence the dose increases with increasing thickness up to the Bragg peak that occurs near the end of the particle's
range. Beyond the Bragg peak, the dose drops to zero (for protons) or almost zero (for heavier ions).
Source: Wikipedia
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X-Ray vs. Particle Therapy
Comparison of dose distribution for X-rays and particle beam therapies.
The pink box depicts the tumor located some distance in the body, the red
curve shows the dose distribution using heavy charged particles, and the
black curve shows the effect of X-rays. The yellow area shows the
unnecessary irradiation of healthy tissue in front and behind the tumor.
Source: ACT Foundation, llc.
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Bragg Peak and Spread Out Bragg Peak
• Doctors can safely
escalate the dose within
a confined target area.
• The probability of side
effects are drastically
reduced.
• Healthy tissue is left
unharmed
This graph shows the relative contribution of the (a.) Spread Out Bragg peak (SOBP)
for protons and (b.) a photon x-ray. The SOBP, which is the therapeutic radiation
distribution, shows that photon treatments give a higher amount of radiation to the
skin when compared with proton treatments. This effect is called "skin sparing".
Source: Wikipedia
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Heavy Ion Therapy
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Why Heavy Ion Therapy?
Heavier Ions show:
• Distinct Bragg peak like protons
• Less radial spreading by collision due to
heavier mass on the way to the tumor
• Thus better confined beam in radial
direction
• Sharper Bragg peak than for protons
• Higher precision in treating tumors in
sensitive areas of the body
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Choice of Particle Species
LET for proton, carbon and neon ions along their path. While for carbon ions the
maximum RBE is in the tumor region, neon ions produce an “overkill-effect” inside
the target volume where the Bragg maximum is situated. The density of the red
color indicates the increased RBE for carbon (schematic).
Although the LET of carbon is higher than that of proton, carbon requires much
higher energy accelerators than proton!
M Sholz in M. Regler, M. Benedikt, K. Poljanc, CERN Accelerator School, Hephy-PUB-757/02
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Carbon Ions – The Magic Bullet
Mother Nature really has meant Carbon ions to be the magic bullet.
Why is that?
The RBE increases with penetration into the body and also the dose
deposition increases with depth, but only in the case of carbon ions
these two increases go hand in hand.
If we look at heavier ions the RBE is already high before we reach the
Bragg peak, causing an undue amount of biological damage in the
healthy tissue; if we use lighter ions (like helium) the RBE is still
around 1 when we reach the Bragg peak and only increases
significantly at the distal edge of the peak, where the dose has already
dropped sharply.
However, compared to protons, carbon ions have some disadvantage
that beyond the Bragg peak, the dose does not decrease to zero, since
nuclear reactions between the carbon ions and the atoms of the tissue
lead to production of lighter ions which have a higher range. Therefore,
some damage occurs also beyond the Bragg peak.
Source: ACT Foundation, llc.
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Epilog
• Clinical experiences show that the Hadron therapy has advantage over
the photon therapy on cancer control. The number of hadron facilities is
expanding rapidly worldwide.
• Two most common accelerator designs are synchrotron and cyclotron.
- Both systems work! Technical experts are eager to work!
- Physicists & engineers can interact and work with medical doctors!
- Medical physicists are well paid and in high demand.
- Dose verifiability, Beam Stability, Reliability and Reproducibility are
utmost important in a radiation therapy facility.
• Applications of accelerator: Nuclear and High Energy Physics (HEP)
- Better resolution and faster detectors
- Fast and compact electronics
- Better and reliable beam control systems
- Online controls, monitoring and fast Data Acquisition
- New “in situ” imaging and dose verification technologies (in beam PET..)
- Simulation & modeling for treatment planning
• Accelerator Design: beamline design, better uniformity of extracted beams,
Control system reliability and flexibility, etc.
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Extras
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Mathematics of Cyclotron and Synchrotron
Non-relativistic
The centripetal force is provided by the transverse magnetic field B, and the force
on a particle travelling in a magnetic field (which causes it to be angularly
displaced, i.e. spiral) is equal to Bqv. So,
m: mass of the particle
q: charge
B: magnetic field strength
v: velocity
Since ω=2π
πf
Since ω=v/r
r: radius of the path
ω: (=2π
πf) angular frequency
Bq
Bq
Bq
fc =
=
f =
fc: classical frequency
2πm
m
2πm
E: energy
p: momentum
This shows that for a particle of constant mass, the frequency does not depend upon the radius of the particle's
orbit. As the beam spirals out, its frequency does not decrease, and it must continue to accelerate, as it is
travelling more distance in the same time. As particles approach the speed of light, they acquire additional mass,
requiring modifications to the frequency, or the magnetic field during the acceleration. This is accomplished in the
synchrocyclotron.
mv 2
= Bqv
r
v Bq
=
r m
2Vq
v=
m
ω
Relativistic
The radius of curvature for a particle moving relativistically in a static magnetic field is
r=
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γmv
qB
γ=
1
v
1−  
c
2
E
=v
p
f = fc
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v
1−  
c
2
62
Projected Range, Longitudinal and Lateral Straggle
Surface
R
Incident ion
Rp
Projected Range, Rp
R( E ) =
∫
E
0
∆Rr
±∆Rp
dE
( dE / dx ) total
Actual range (R) of an implanted ion and the projected range (Rp) normal to the surface
Most of the ions are within a standard deviation (±∆Rp) or lateral straggle of the projected range,
which is the range at 0.606 Cp (the peak concentration). ∆Rr : vertical straggle
Can be calculated by PRAL (Projected Range Algorithm) in TRIM
“The Stopping and Range of Ions in Solids”, Vol. 1, Ziegler, Biersack, and Littmark, Pergamon Press, New York, 1985
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Concentration Distribution and Fluence
Symmetric Gaussian Distribution Formula
 ( x − Rp ) 2 

C ( x ) = C p exp −
2

2∆R p 

Cp: peak concentration
Rp: projected range
∆Rp: straggle
Fluence (total number of ions implanted)
∞
Q = ∫ C ( x)dx = 2π ∆R p C p
Fluence [#/cm2] and peak
concentration [cm-3] relationship
−∞
Fluence by dosimetry (I, t)
Q=
I ⋅t
q⋅ A
I : ion beam current
t : duration of implantation
A : substrate area
q : ion charge
Fluence ‘Q’ is in unit of [#/cm2], the number of charges per unit area. Q per unit
length [#/cm3] is concentration.
Fluence is the number of ions implanted through a surface in unit of [#/cm2],
generally accepted definition. But Plummer calls Q as ‘Dose’.
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SRIM Simulation for 100 keV H
Side View
Longitudinal distribution
 ( x − Rp ) 2 

C ( x ) = C p exp −
2

2∆R p 

Beam Direction (x) View
Lateral straggle

y2 

C ( x, y ) = Cvert ( x) exp −
2 
2
∆
R
⊥ 

∆R ┴: vertical straggle
Low energy ion species give large straggle, relatively.
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Linear Energy Transfer (LET) vs. Ion Energy
The stopping power (eV/Å) of water has been plotted for six different particles as a function of specific energy
(MeV per nucleon). In region I the LET is low enough that the spurs develop independently; in region II the spurs
in the trajectory core are merged right from the beginning, but the overlap is not excessive; ie. The diffusion of
radicals competes with the process of radical recombination; in region III the spur overlap is excessive, and
recombination of radicals dominate over diffusion.
p. 19, Chapter by Chartterjee,
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A Dose Calculation Example
1. A 5-MeV α particle is absorbed by 1 gram of water, estimate the dosage in
rad and rem.
5MeV 1.6 × 10 −13 J 107 erg 1rad
= 8.0 ×10 −8 rad
1g
1MeV
1J 100erg / g
The RBE (Q factor) is 10 for α particle, and thus the dose is 8x10-7 rem or
8x10-9 Sv. If the a particle is absorbed by a of 10-9 g cell, then the dose is
109 times higher (0.8 Gy, 8Sv), exceed lethal dose for most living beings.
2. Proton at 250 MeV are used for radiation therapy with a treatment volume
of 1 kg. Assuming 70% efficiency in reaching the planted treatment
volume (PTV). What is the number of protons per second needed for the
dosage of 2 Grays in 2 minutes?
250MeV 1.6 ×10 −13 J
N × 120s × 70% = 2 J / kg
1kg
1MeV
N = 6 × 108 particles / s
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Simulation of Photons vs. “Spot Ionization” of C-ions
Left: local dose of photons at 2 Gy is homogeneous on a micrometer scale;
Right: carbon ions generate clusters of lesions, with a substantial decrease of
repair capacity. The dose distribution on a cell scale (nucleus of the cell app.
100 µm2) is still sufficiently homogeneous (-> “Poisson statistics”).
M Sholz in M. Regler, M. Benedikt, K. Poljanc, CERN Accelerator School, Hephy-PUB-757/02
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Immunofluorescence-Stained Visualization of Radiation Damage
Left: photons deposit their energy randomly distributed and thus nearly
homogeneously over the irradiated medium;
Right: C6+ ions (1 MeV/u) transfer their energy to the liberated electrons, which
form a track around the particle trajectory.
In a high LET track the damage is produced in high density and thus with a high
possibility to form "clustered lesions" which are to a large amount irreparable.
B. Jakob et al., Radiation Response after Damage Produced by Heavy-Ion Tracks, Radiat.Res. 154, 398-405 (2000).
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Positron Emitting Radioisotopes
•Carbon-11
•Nitrogen-13
•Oxygen-15
•Fluorine-18
Functional imaging by means of positron emission tomography (PET) or
single photon emission computerized tomography (SPECT) can facilitate
the evaluation of tumor physiology, metabolism and proliferation. These
are parameters determining outcome to radiotherapy treatment. PET can
be used to get also quantitative information about the in-vivo distribution
of positron-emitting radioisotopes such as 11C, 13N, 15O, 18F.
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Typical Isotopes Used in Medical Applications
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Positron Annihilation
e+ + e- = γ + γ
1.
Positron annihilation produces two 511 keV photons leaving in opposite directions.
We are detecting “back-to-back” 511 keV (co-incident) photon pairs resulting from
positron annihilation.
Figure: Timothy G. Turkington, J. Nucl. Med. Technol., V29 (1) 2001, 4-11.
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Detection
Jonathan “Eoin” Carney, Ph.D., University of Pittsburgh
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Basic Principle of PET
In clinical applications, a very small amount of labeled compound (called radiopharmaceutical or radiotracer) is
introduced into the patient usually by intravenous injection and after an appropriate uptake period, the concentration
of tracer in tissue is measured by the scanner. During its decay process, the radionuclide emits a positron which, after
travelling a short distance (3-5 mm), encounters an electron from the surrounding environment. The two particles
combine and "annihilate" each other resulting in the emission in opposite directions of two γ-rays of 511 keV each.
We are detecting “back-to-back” 511 keV (coincident) photon pairs resulting from positron annihilation within 12
nanoseconds between two detectors on opposite sides of the scanner. For accepted coincidences, lines of response
connecting the coincidence detectors are drawn through the object and used in the image reconstruction.
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Proton Therapy Centers
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Need of Proton Therapy Accelerators
• Estimates indicate that proton therapy could help a quarter
of a million patients.
• As of mid-2008, nearly 20,000 patients treated in U.S. First
hospital-based proton center opened in 1990 at Loma Linda
University Medical Center. Operating proton centers can
treat 150-200 patients daily.
• However, doctors face agonizing decisions about whom to
treat — and some patients are lucky if they're in a waiting
room rather than on a waiting list.
Proton therapy is a radiotherapy treatment modality that allows high conformality
of the dose distribution to the target volume. More than 40,000 patients have been
treated worldwide with proton therapy and the number of new institutes is growing
rapidly. The vast majority of proton radiotherapy patients have been treated with
passively scattered proton beams and this will likely remain the dominant
treatment modality for the next few years.
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Useful Web-sites
http://worldwidescience.org/topicpages/p/proton+therapy+nozzle.html
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