HADRON THERAPY FOR CANCER USING

HEAVY IONS

by

Khalid Mohammed S Yamani

A dissertation submitted to the Department of Physics,
University of Surrey, in partial fulfilment of the degree of
Master of Radiation & Environment Protection


Bepaitment of Physics
Faculty of Electionics & Physical Sciences
0niveisity of Suiiey

September 2009

Khaliu Nohammeu S Yamani 2uu9

HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 2
"#$%& '( )'*"&*"+

ABSTRACT 4
AKCKN0WLEBuENENT S
GLOSSARY 6
1. Beam intensity
6
2. Beam Range in an Absoibing Neuium
6
S. Biagg Peak
7
4. Range Aujustment
8
S. Rauiation Fielu
8
6. Fielu Bomogeneity on A Tiansveise Section
8
7. Bomogeneity iegion in a plan oithogonal to the beam uiiection
9
8. Fielu homogeneity along the beam axis
9
9. Field symmetry
1u
10. Lateral penumbra
1u
11. Distal dose fall-off
1u
Chaptei 1: INTR0B0CTI0N 0F RABI0TBERAPY

1.1 Cancei anu iauiation theiapy
11
1.2 Bistoiical uevelopment of iauiation theiapy
11
Chaptei 2: PHHYSICAL AND RADIOBIOLOGICAL PROPERTIES OF
HADRONS
14
2.1 Physical characteristic of the beam
1S
2.1.1 Depth-dose distribution and Bragg-peak
1S
2.1.2 Defined range:
16
2.1.3 Lateral scattering:
16
2.1.4 Non-elastic nuclear reaction:
17
2.1.5 Positron emission tomography technique (PET)
17
2.2 Biological effect
18
2.2.1 The Relative Biological Effectiveness (REB) and Linear Energy
Transfer (LET):
19
2.2.2 Oxygen Enhancement Ratio (OER)
2u
Chaptei S:Hadrons Therapy equipments 22
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page S
3.1 Conventional Accelerator Radiotherapy

22
3.2 Accelerator for heavy ions and proton
2S
3.2.1 Fixed Field Alternation Gradient accelerator (FFAG)
2S
3.2.2. The dielectric-wall accelerator (DWA)
2S
3.4 Beam delivery systems and techniques
2S
3.4.1 Passive beam shaping
26
3.4.2 Active beam shaping:
27
3.5 Gantry design for proton and carbon hadrontherapy facilities
28
3.6 Cost-effectiveness of hadron therapy in cancer
S2
Chaptei 4: TREATMENT PLANNING SS
4.1 Imaging protocol
S4
4.2 Organs contouring
S4
4.3 Dose calculation algorithms
S4
4.4 Choice of the ports
S4
4.5 Positioning and treatments
S4
Chaptei 4: COCULUSION
S6
Refeiences S7
Appendix A S9
Appendix B 4u
Appendix C 42
Appendix D 4S
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 4

#,-./01.
The application of hadron accelerators (proton and light ions) in cancer treatment is
relatively new. They are far from standardized, but the use of hadron therapy as an alternative
to conventional radiation has led to important developments and refinements in conventional
treatment technique. Hadron beams allow highly conformal treatment of deep-seated tumours
with great accuracy, while delivering minimal doses to normal surrounding tissue.
This overview of hadron therapy covers the following topics: an introduction of
radiotherapy represents the relationship between cancer and radiotherapy, and the historical
development of radiation therapy, physical and radiobiological properties of hadrons, hadrons
therapy equipments with the cost of hadron facilities.

















HADRON THERAPY FOR CANCER USING HEAVY IONS
Page S
#1234567897:73.
I would like to thank Pro. Paddy Regan for his supervision, and guidance throughout this
project, I did appreciate his help and advice.
I would like to thank my wife for support I was provided with during the completion of
dissertation masters.





























HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 6
Glossary
*
:
;< $70: =3.73-=.>
The meuical anu acceleiatoi physicists to mean quite uiffeient things use the
teim beam intensity. The accuiate uefinitions of teims ielating the numbei of
acceleiateu paiticles aie as follows:
Numbei of paiticles, N
Fluence, !: paiticles unit aiea, ! " #$%#&
Flux, F : paiticles unit time, ' " #$%#(
Intensity) *: eneigy unite aiea unit time
* " +#
,
%#(#& " +#!%#( " +#'%#& -./.0
Wheie + is the eneigy of paiticles
Foi oui puipose of uesciibing mono-eneigetic paiticles, it is suitable to uefine:
Intensity, *: paiticles\ unit aiea unite time
* " #
,
%#(#& " #!%#( " #'%#& -./,0
Bowevei, acceleiatoi physicist use the teim beam intensity to mean the numbei
of paiticles pei unite time, i.e., as the flux uefineu above.
Intensity, *: paiticles\ unite time
* " #$%#( " ' -./10
anu 23 / * " 23#$%#( " 43&5 678839( -./:0
The beam intensity with this uefinition uoes not vaiy when the beam cioss-
section changes. Anu the beam intensity mouulation means the beam flux
mouulation.
?< $70: @0397 =3 03 #,-4/,=39 A78=B:
The iange of beam is uefineu as the iepiesent uepth of penetiation measuieu
along stiaight line paiallel to the oiiginal uiiection of motion of the piotons oi
caibon ions fiom the point wheie they penetiate the meuium to the point at which
auuitional uisplacement is no longei uetectable.
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 7

(=9B/7 ;C $70: /039 =3 :78=B:
If a uepth uose cuive is consiueieu, the iange ielates to the uistance between the
entiance suifaces of the beam anu the uistal point of 8u% uose (Fig.1). In the clinical
application, the iange is expiesseu in gcm
2
, in oiuei to be inuepenuent of specific
cases wheie inhomogeneities can be piesent. If it is piesent on the beam tiack (foi
example lung oi bone), the iange will be somewhat uiffeient fiom the value ielative
to watei.
D< $/099 E702
This is uefineu on a uepth uose cuive as the uistance between the pioximal anu
the uistal points ielateu to the 9u% of the peak height. The 1uu% is associateu to
the maximum point of the S0BP (Fig. 2)

(=9B/7 ?C F7G=3=.=43 4G .H7 +I/708 'B. $/099 E702 J+'$EK
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 8
L< @0397 #8MB-.:73.
This expiession iefeis to the possibility of tianslating the S0BP in uepth.
N< @08=0.=43 (=768
The iauiation fielu is uefineu as the locus of the point s wheie the absoibeu uose
exceeus Su% of the uose absoibeu at point wheie the beam axis inteicepts the
suiface (Fig. S)

Figure 3: Definition of the Spread Out Bragg Peak (SOBP)
O< (=768 P4:49737=.> 43 # "/03-Q7/-7 +71.=43C
The homogeneity is uefineu as the following:
;( "-<5&= %<5>90" .??@ -./A0
BC383 <5&= is the maximum absoibeu uose, at any point in the iiiauiation fielu,
aveiage ovei a suiface not laigei than 1 cm
2
foi a beam spieau by passive system
anu not laigei than u.2S cm
2
foi a pencil beam useu foi magnetic scanning;
<5>9 is the minimum ubiquitous absoibeu uose in the homogeneity iegion, aveiage
ovei a suiface not laigei than 1 cm
2
foi a beam spieau by passive system anu not
laigei than u.2S cm
2
foi a pencil beam useu foi magnetic scanning.
The measuiement shoulu be peifoimeu at the suiface of a watei equivalent
phantom. This suiface, it shoulu be at the isocentiic anu peipenuiculai to the beam
axis foi iotating gantiy. Bowevei, the phantom must extenu to the least S cm
beyonu the geometiical euge of the iauiation fielu; thickness of phantom must be at
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 9
least S cm gieatei than the uepth of the Biagg peak. In auuition, the phantom
suiface shoulu be at the noimal tieatment uistance foi fixeu beam.
R< P4:49737=.> /79=43 =3 0 I603 4/.H494306 .4 .H7 ,70: 8=/71.=43
The homogeneity iegion is uefineu by the lines connecting the points on the
piinciple axes anu on the uiagonals of a squaie fielu. The uimensions um anu ue aie
uefining the homogeneity iegion as shown in Fig.4.

(=9B/7 LC Homogeneity region in a plan orthogonal to the beam direction
S< (=768 H4:49737=.> 06439 .H7 ,70: 0T=-
It is necessary to define the homogeneity along the beam direction in correspondence
to the SOBP region for example with proton beams. The region of homogeneity is defined
as the region between two distal fall-off widths (below) inside the 50% dose point distally
and one distal fall-off width inside 90% dose point proximately. It is assumed that 100%
corresponds to the point of maximum dose in the SOBP as shown in Fig. 2 .
The homogeneity is uefineu as the iatio:
;( "-<5&= %<5>90" .??@ -./D0
BC383 <5&= is the maximum uose absoibeu eveiywheie in the iiiauiation fielu,
aveiage on a suiface not laigei than 1 cm
2
;
<5>9 is the minimum ubiquitous absoibeu uose in the homogeneity iegion, aveiage
ovei a suiface not laigei than 1 cm
2
.
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 1u

U< Field symmetry
The symmetry, on a plane transverse to the beam axis is defined as the maximum
value S of the ratio between the highest and the lowest absorbed dose, average on a
surface not larger then 1 cm
2
, for every pair of symmetrical positions with respect to the
beam axis inside the homogeneity region. It should be expressed as a percentage. The
measurement should be performed in the same conditions as for the determination of the
homogeneity.
10. Lateral penumbra
Is defined as the distance between the points 80% and 20% absorbed dose. It is
assumed that 100% corresponds to the beam axis (Fig.5)

Figure 5: Definition of the lateral penumbra.
11. Distal dose fall-off
Is defined as the distance between the points 80% and 20% absorbed dose along beam
axis beyond the Bragg peak. It is assumed that 100% corresponds to the maximum in the
SOBP (Fig.2)




V W. =- .0273 G/4: .H=- ,442 X E/4.43 @08=0.=43 #11767/0.4/-Y
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 11
)H0I.7/ ;C W3./48B1.=43 4G @08=4.H7/0I>C
;<; )0317/ 038 /08=0.=43 .H7/0I>
Cancer can be defined as the uncontrolled growth and proliferation of groups of cells.
It is reported that is affecting the industrial countries in Europe, 26% of deaths are in relation
with cancer. The average survival of a 5 years-cancer is 40%. Many factors are involved in
cancer development: food, medicines, genetics, infections, and professional. The
radiotherapy, chemotherapy and surgery are the main therapist against cancer.

Figure 1.1:Present situations of the different treatments against solid tumors by EC (Haberer,
2002)
Figure1.1 present situation in cancer treatment, as we can see that of 45% of all patient
are cured, among various cancer treatments; surgical removal of the tumor tissue,
radiotherapy, and chemotherapy. Surgery and radiotherapy are today of crucial important and
successful in 22% and 12% of cases respectively. Moreover, radiotherapy is involved in
almost half of the curative treatment of the localized cancer when combined the 12% for
another 6% of the cases. For 18% of all cancer patients the local control of the primary
tumour without metastasis fails. And these patients could be cured successfully if improved
treatment modalities as the application of proton and ion beams in radiation therapy (haberer,
2002)

;<? P=-.4/=106 87Q764I:73. 4G /08=0.=43 .H7/0I>
Radiation therapy is the one of the treatment cancer with ionizing radiation that can be
use electromagnetic (X-rays, gamma rays) or corpuscular (protons, neutrons, electrons, heavy
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 12
ions, alpha particles, mesons, etc) to target cancerous tissue by; external beam therapy, sealed
source therapy (Brachytherapy) and unsealed source therapy. External beam therapy is the
most common form of radiation therapy. It is performed with electron or photon beams; these
are produced by a linear accelerator
Charged particles beams have been used for radiotherapy such as protons and heavier
ions. E. Rutherford who is discovered the protons at the end of the second decade of the 19
th

Century. In 1955, the Lawrence Berkeley Laboratory (LBL) was the first organisation in the
world that is performed the first clinical application for a proton beams in California. During
this period 1919-1955, there are two significant on proton therapy occurred; in 1930, E. O.
Lawrence was built the first cyclotron with high energy for application of cancer treatment,
and in 1946, Robert Wilson was used the proton beams for deep-seated tumour treatment.
Moreover, Wilson referred to the physical aspects of the dose distribution of the proton
beams, such as an advantage for proton compared to X-ray therapies. (Subramania,
1996;Aferd.2009)
There is an on going level of interest in using charge particles as beams of hadrons in
radiation therapy such as protons, neutrons and heavy ions. Particles therapy act to damage
the DNA of cancerous tissues that they cannot multiply and grow, and minimizing damage to
the surrounding healthy cells. At the present, there are now about 25 developed facilities
around the world using protons and light ions (carbon) for cancer treatment; they have been
treated more than 55,000 patients with proton therapy and 5000 patients with carbon ions
(Aferd.2009).
According to Dale et al. project that the Royal College of Radiologists (2003) in the
European study was found 11% tumours that are treated by chemotherapy, 40% by
radiotherapy and 49% are cured by surgery. As a result, the 40% is very respectable and
provides a strong indication of why the research is continuing and investment in this modality
is justified (Dale et al, 2009).

In general proton therapy and light ions therapy is more expensive than photon therapy.
The ratio of the cost was found about 2.4 relating to Goitein et al. project in 2002, and they
expected that the cost will be reduced to 1.7 or less in the next few years. Also Alfred pointed
out on his project that the refund rate is currently somehow sufficient to develop hadrons
facilities with the progress of technologies and a reasonable incoming margin. In the future,
the cost of these modalities will decrease more and will be spread more than before among
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 1S
more patient.


.
Fig 1.2:Development of radiation therapy linear accelerator (a)-4MeV AEI linac with an in line
treatment head, mfd. in 1955;(b)- the SL75 Philips linac with a horizontal accelerating structure
and 90 bending magnet, suitable for full rotation therapy, mfd. in 1964;(c)- the Dynaray 4 linac
with 270 achromatic magnet, mfd. in 1971; (d)- a present-day system with an in- line treatment
head, without beam binding, e.g. 4MeV LMR-4 Toshiba Linac with 35 cm along accelerating
structure.











HADRON THERAPY FOR CANCER USING HEAVY IONS
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)H0I.7/ ?C Physical and Radiobiological Properties of Hadrons
Hadrons are compound subatomic particles made of quark and antiquarks, bound
either in doublets or in triplets by strong force. The hadrons that are employed for
radiotherapeutic purpose are protons, neutrons and light ions (such as carbon, helium, neon
and oxygen). Among the use hadrons, protons show approximately the same LET as
conventional photons and electron beams when they going into treated body, but have an
increasing LET at the end of their track in tissues. However, neutrons and light ions are high-
LET particles (table 2.1)
Table 2.1: LET (L!) of ionizing particles and radiations of radiations of interest in
radiotherapy and radiobiology, after (Wioletta & Waldemer, 2001)

The ability to change the radiative properties is due to the fact that the biological
affects are correlated with the distribution of energy deposited. This distribution is influenced
by the atomic number Z (for carbon=8, for proton=1) and the energy of the impinging
hadrons. The basic physical and radiobiological properties of photons and ions are compared
in table 2.2
Hadron therapy is using of charge particle beams of protons or carbon ions for
treatment of cancer. Ion beam therapies have a major of important advantages over
conventional radiation therapy for deep-seated cancerous cells, also for tumors closed to a
critical tissue of organ. The development of the physical characteristic of particles beams
from proton to carbon and of ion accelerator, they hold promise due to its capability to deliver
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 1S
high dose to target volume. The heavy charge particles have rather reduced depth-dose
outline, but enhanced responses biological effectiveness (Wioletta & Waldemer, 2001)
Table 2.2: Differences between photons and ions, after (Wioletta & Waldemer, 2001)



2.1 Physical characteristic of the beam
The physical properties of charge particles interaction with critical organs introduce an
eminent benefit of hadron therapy compared to conventional radiation therapy, it allows a
delivery adequate high dose to stop a tumors growth, destroy it, and prevent damage to the
normal cell that is surrounding tumors as much as possible. According to Weyrather and
Debus project that they have reviewed the physical properties of particle beams interaction
with tissue, and summarized it as the following (2003):
2.1.1 Depth-dose distribution and Bragg-peak
HADRON THERAPY FOR CANCER USING HEAVY IONS
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The dose decreases exponentially for penetrating depths beyond the build-up depth for
photon conventional radiation therapy. At the same time as a charge particle beam loses just a
small quantity of its energy at the access until the maximum penetration depth where the
remaining energy lost over a short distance consequences in a high dose presented as Bragg-
peak (Fig.1.3)

Figure 2.1: Comparison of Depth-dose curves for photons, proton, and carbon beams
(Weyyrather&Debus, 2003|)
As we know that the target volume of tumours is much larger than the unmodified
Bragg peak width. In clinical applications a relatively consistent dose distribution be able to
deliver to tumours by spreading out the Bragg peak (SOBP) through a Range Modulated
Wheel (RMW) or through modulating the energy from pulse to pulse as can achieved with a
synchrotron.
2.1.2 Defined range
The particles beam prevents damage to healthy tissue beyond the tumour by the
defined range, and after the Bragg peak drops almost to zero. It is determined the density of
the target tissue and the energy of particles. A rang straggling in Bragg peak due to multiple
scattering of the particles which depend on the atomic number of the particles, and this
straggling for protons is highest and it decreases quadratically with atomic number of the
projectile ion.
2.1.3 Lateral scattering:
Heavy ions such as carbon have the advantage of the small scattering angle as they
penetrate the target. The expansion of carbon beam is less than 1mm at 10 cm depth, while for
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 17
proton it goes more than 2mm. this advantage give more accuracy for irradiating of deep-
seated tumour close to a critical tissue (Fig.3.2)

Figure 2.2: Comparison of the lateral scattering of photon, proton and carbon beams as
function of the penetration depth (Weyyrather&Debus, 2003|)

2.1.4 Non-elastic nuclear reaction:
The interactions depend on the type of the charge particles and the cross-sectional of
the target volumes, as we know the particle beams undergoes nuclear interaction with target
materials. In the proton case, the non-elastic nuclear interaction results in attenuation of the
primary beam and emission of secondary proton and other particle with relatively lower
energy. However, for carbon, a small amount of the primary beam transferred to lighter
nuclear fragments causing a long dose tail beyond the Bragg peak, but it continues within the
acceptable limits.
2.1.5 Positron emission tomography technique (PET)
The PET technique allows 3D retrospective analysis for the dose distribution inside
the body of patients. There is a small percentage of the passage particle beam that going to
body tissue can be transferred to nuclear fragments with the same atomic number of the
projectile due to the only one or two neutrons are lost. As unstable carbon isotopes (
10
C,
11
C,
and
15
O) are produced. The decay of these isotopes with 19 second, 20 minutes, and 2 minutes
respectively of its half-life are under emission of a positron and neutrino. In carbon therapy, a
10
C and
11
C ranges differ only slightly from the range of stable
12
C and the stopping point
can be screened by measuring the coincident emission of tow annihilation quanta of the
positron decay, by using PET-camera outside the body without extra dose to the patient.
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 18
However, the range of positron emitters is few mm in proton therapy shorter than the range of
primary proton due to the threshold of energy of nuclear reaction and fragmentation. On the
other hand, the positron emitter stopping point is somehow correlated with the Bragg peak.
This is an advantage for proton therapy to using PET; also the activity of positron emitters is
higher then for carbon approximately three times at the same depth. This is help to increase
the sensitivity of PET imaging in proton therapy over carbon therapy.
2.2 Biological effect:
The biological effects of ionizing radiation result generally from ionization and
excitation of atoms and molecules in the matter via radiation. These primary processes initiate
a complex chain of events in a living cell, which lead to chemical changes in some
biomolecules (DNA that is the most important target) and to bio functional changes such as
cell death, transformation and mutation (Paganetti 3( &E),??,0.

Figure 2.3: Comparison of tracks of sparsely and densely ionizing radiation with the relevant
biological targets (Amaldi & Siliari,1996)
2.2.1 The Relative Biological Effectiveness (REB) and Linear Energy Transfer (LET):
The different biological effect depending on the energy atomic number of the ion and
can occur from the same dose in high-LET as a hadron beams, while the low-LET radiation
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 19
such as "-rays, X-ray and electrons that is used in conventional therapy, exhibit the same
biological effect when applied the same dose.
The Relative Biological Effectiveness (REB) can be calculated from measured data as
we can show that in Fig 3.3. For example, the ratio between the dose of X-ray and the ion
particle dose necessary to produce the same biological effect.(Weyrather&Debus, 2003|)

Figure 2.4: Definition of the relative biological electiveness, RBE, illustrated for cell
survival curves with carbon ions of different energy (Weyrather&Debus, 2003|)

As we can see at Fig.2.4, the shoulder in heavy ions (carbon ions) dose-effect curve is
much smaller, while in the proton represents repair capacity of the cell at low doses. This
represents a high ionization density is reduced the repair capacity of cell at the same dose.
And the most interesting conclusion is that protons in plateau are as the lethal as "-rays, while
protons in the Bragg peak show a higher effectiveness.






HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 2u


Table 2.3: RBE for inactivation of cultured mammalian cells irradiated with proton
beams of high initial energies (Amaldi & Siliari, 1996)


The RBE in hadron therapy is dependent on several biological and physical factors.
As the Weyrather and Kraft mentioned to Experiments revealed a dramatic dependence of
RBE on the dose level, atomic number and the repair capacity of the biological system. It also
showed that carbon ion are the optimal choice for high-LET therapy; later scattering and its
range are small producing an optimum precision in dose delivery system(2004). The
efficiency of ions to induce biological damage changes along their path. Local ionisation
density increases at the end of the range, and causing difficulty repairing for high DNA
damage and RBE increases up to maximum, while the high energies and light ions at the
entrance channel are easily repaired for the induced damage, and RBE is close to those
induced by low-LET radiation (Weyrather&Debus, 2003). At Fig. 3.3 that clears the RBE is
inversely dependent on the dose, its large for low doses and small for high dose. And high
RBE is related with lower dependence on Oxygen to have an effect on the cancerous tissues.
Therefore, heavier ions and carbon can effective to slow or stop growth of radio-resistance
and poorly oxygenated tumours (Dale et al, 2009).
2.2.2 Oxygen Enhancement Ratio (OER)
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 21
The Oxygen enhancement ratio is an additional indicator for realising the therapeutic
effects giving by a certain type of radiation. The OER is the ratio of doses with or without
oxygen to produce the same biological effect. Therefore, the OER has a strong dependence on
the LET; it decreases as LET exceeds approximately 10 and approaches unity at very high
LET, as a result, the better oxygen enhancement ratio when its lower value.

Figure 3.1 is shown the comparison of the relative biological effectiveness (RBE) and
oxygen enhancement ratio (OER) values for different radiation particles and ions. It is clear
that to obtain the optimum curative effect; the RBE value should be high while the OER
should be low.













(=9B/7 D<;C The RBE and the OER of various radiations from "-ray to Ar particle
(Takashi N. & Lawrence H., 2006)
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 22




)H0I.7/ DCHadrons Therapy equipments

Nowadays, the main source of radiation therapy carried with types of accelerators for
electron, and X-ray radiotherapy such as Linear accelerator, betatrons and microtrons. All
these accelerate electrons to high velocities that have varying energy, also as we mention
before the electrons are accelerated, the tissue penetration depth, the tissue at that greatest
dose of radiation is absorbed. (Bertil J, Alan M, 2006).

Hadron therapy is the one of the therapeutic technique that used to treatment cancer, and
its varied application of treatment that uses the widespread range of particle accelerators from
the use of small electron linear accelerators for radiotherapy, to the use of proton cyclotron for
radionuclide production is 10-20 MeV, and to the application of 50-60 MeV proton
accelerator for proton therapy or neutron treatment of eye melanomas to the hadron
accelerators that it is installed in radiation treatment centres for cancer therapy with ion beam
or proton (Amaldi U, et all, 1996).

3.1 Conventional Accelerator Radiotherapy
(=9B/7 D<;C Two cyclic accelerators: (a) a betatron and (b) a cyclotron.
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 2S

Hadron accelerators have two types (cyclotron and synchrotron) to produce a charge
particle beam with sufficient energy that passing trough the beam transport system to reach
the target volume with enough intensity, due to achieve a typical medical treatment.

The cyclotrons are made up of the particle beam and a large magnet to moves starting
from machine center with a long spiral path, and it is working at fixed field and fixed
frequency of energy due to continuous beam, also operating reliability and simplicity. In
synchrotrons the radio frequency and magnetic fields are varying that provide a sufficiently
high dose rate for treatment compared to cyclotrons. However, cyclotrons have a capacity to
produce sufficient beam with high intensity (flux). (Chu et al, 1993).

In recent years, the building accelerators have increased throughout the world for
medical treatment, and the development and improvement is providing a new generation of
accelerators, which are more compact, efficient and inexpensive.

3.2 Accelerator for heavy ions and proton
Theoretically, the hadron beams that used in cancer (protons, light ions such as carbon)
has developed considerably since the middle of the last century and the hadron therapy
presents the potential of both physical (protons and ions) and biological (neutrons and ions)
advantages in the therapy of localised tumour (Lodge M, et all, 2007). The use of protons in
the treatment cancer depend on the superior dose distribution which can be achieved with
respect to electrons and photons, as a result, it is due to the low lateral scattering undergone
by protons, their will-defined range and the increasing dose deposition (ionization) with
increasing penetration in cell tissue, that produces the Bragg peak (Fig. 2.1)

The depth at which the Bragg peak occurs depends on the initial energy of the protons
and its width on the energy spread of the beam. Fig. 4.1 shows that, an even enhanced dose
distribution and the additional advantages of an increasing the relative biological
effectiveness (RBE) at the end of range in tissues for protons. The therapy beam which used
in treatment cancer must have enough range to reach the deepest point of volume of the body,
in order to irradiate tumors that the minimum energy required for carbon ions are 400 MeV/u
and for protons are 200 MeV. All the clinical procedures can be requests satisfied among light
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 24
ions range energies between 120-400 MeV/u and 10
9
-10
10
ions/s of beam intensities, which
depends on the ion type. For protons corresponding figure are 60-250 MeV and 5 # 10
10
-10
11

(Fig. 4.3). (Amaldi, et al.1996).






















These requirements stand for hadron accelerator considered for cancer treatment that the
basic specification must be met by ion radiation or proton therapy facility to represent an
Fig. 3.2: Depth-dose curves for photons, electrons, neutrons and 200MeV
protons.
Fig. 3.3: Range-energy curves in tissues for light ions and photons
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 2S
effective and reliable instrument against cancer. The performance standards of the accelerator
and of delivery systems and beam transport must satisfy a number of clinical requirements.
These performance standards are expressed in terms of beam intensity, energy variability and
range, distal dose fall-off, time structure of extracted beam, lateral penumbra, beam abort time
and raster scanning specifications (Goitein M, 2007).
According to Alfred project that is summarized the new accelerator technologies for
proton therapy designed such as:

3.2.1 Fixed Field Alternation Gradient accelerator (FFAG):
In Japan, the Energy Accelerator Research Organization (KEK) was built the first
proton FFAG accelerator in 1999. The energy range of several FFAG accelerators which is
manufactured tell this point are 150-250 MeV, and it is join the fixed magnetic field of
cyclotrons and the energy variability of the synchrotrons. In addition, the easy operation and
compact size of the FFAG accelerators make them more attractive for hadron therapy. In the
UK, the British Accelerator Science and Radiation Oncology Consortium (BASROC) aim to
build non-scaling FFAG accelerators to be used for hadron therapy.

3.2.2 The dielectric-wall accelerator (DWA)
In USA, the Lawrence Livermore National laboratory (LLNL) has developed the
dielectric-wall accelerator. This technology uses to accelerate the proton approximately
100MV/m of high electric gradients. It will be employed the development of a high
accelerator gradient LINAC for proton therapy.

3.3 Beam transport system
The extracted beam is transported from the accelerator to treatment radiation therapy
room by beam transport system. A beam lines consist of quadruple and dipole magnets,
vacuum chamber and diagnostic instrumentation. An efficient and stable transport of the
beam from the accelerator to the treatment room is needed to achieve a reliable therapy and
reproducible dosimetry. The stability of the centroid of the beam position is adjusted by
focusing magnets to control the beam position and profile, which is called tuning beam line. It
means adjusting the beam optics to transport the given beam to the required location with the
desired physical parameters (Chu et al, 1993).
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 26




3.4 Beam delivery systems and techniques
This system is located at the treatment room; it lies between the beam end line at the
vacuum window and the patient. The beam delivery system has a technical components and a
number of devices to adapt the beam such as; modulating devices and range changing, also
laterally spreading and shaping devices. It also has a number of monitors to manage the
prescribed 3D dose distribution inside the target volume (Wioletta & Waldemer, 2001). In
practice, the role of the beam delivery system technique are divided into two principle
according to the method of the beam spreading as following:
3.4.1 Passive beam shaping
Passive beam shaping is the most commonly used in proton and heavy ion therapy. It
has three steps; a modulator designed modifies the monoenergetic beam from the accelerator
to provide a predefined depth dose modulation. Numerous modulators are available to cover
different depth modulation in tissue. In order additional range shifts are needed to adjust the
modulated Brag peak to the desired radiological depth. Finally, a clinically useful field width
is produced using a double scattering system or a magnetic beam wobbler. It has three major
disadvantages (IAEA, 2007):
The depth dose can only tailored to the distal end of the target due to the fact
which the compensator shifts the SOBP towards the entrance region. A
considerable amount of the high dose region (and high LET region) is located
in the normal tissue in front of the target volume, especially at the lateral field
borders
The amount of material in the beam line is considerable, leading to an increase
in nuclear fragments produced by nuclear interactions with the material of the
beam modifiers. These nuclear fragments have lower energies and lead to a
higher LET and thus an increased biological effective dose of the beam already
in the entrance region
The large number of patient specific beam modifiers, which have to be
manufactured (a compensator and a collimator for each treatment field) and the
necessity to produce a number of modulators that may have to be exchanged
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 27
for different patients.
At HIMAC using the passive depth dose system, the depth dose is fixed by the
modulator hardware, which is designed to achieve a prescribed homogenous biological dose
effective dose for single field. The design of the modulators reflects the fixed dependence of
the RBE with depth for dose level.




3.4.2 Active beam shaping:
This system takes advantage of the electric charge of ions to produce a firmly focused
pencil beam that is deflected laterally by a magnetic field instated the foils in the passive
scattering technique to allow a scanning of the beam over the treatment field. In clinical
applications the target volume is dissected into layers of equal ion energy, each layer is
covered by a grid pixels and the beam is scanned in a row pattern over these pixels (Alferd,
2009). Moreover, the energy from a synchrotron can be switched from pulse to pulse to adapt
the range of the particles in tissue. This technique is able to scan the target volume in three-
dimensional and the dose distribution can be tailored to any irregular shape without any
patient specific devices (such as collimators or compensators) or passive absorbers. Thus, the
high dose region can be conformed to the proximal end of the target volume and the integral
dose as well as the volume receiving high LET radiation is summarized (IAEA, 2007).


Fig. 3.4: Principal of passive beam shaping
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 28




3.5 Gantry design for proton and carbon hadrontherapy facilities
The tumor is treated several times with beams coming from different direction, so the
device that is used to allow directing beam from several directions onto the patient who is
lying on the treatment table and to reduce the dose to the surrounding health tissues is called
gantry. However, the necessity of choosing a gantry or not is influenced by many factors,
mainly by the design of each treatment facility and the kind of tumor to be treated. Building a
gantry for heavy charged particles is a technological challenge. It is lies in the production of
large and heavy gantries still achieving the same position stability of the ion beam. The first
hospital-based gantries had a diameter of 12 meters. The innovation PSI project compact
spot- scanning gantry (Pedroni et al, 1995) is a very good optimization of the size (diameter of
4m) predominantly because of the alternative chosen to move patient during the treatment (Fig
4.5).



The hydrotherapy aims for gantries-despite the higher magnetic rigidity. Th! rigidity i"
d!fin!d #" th! $r%duct %f th! b!nding r#diu" #nd th! r!quir!d m#gn!tic fi!ld "tr!ngth. In
proton therapy several facilities are already running gantries in routine process with a
magnetic rigidity of about 2.5 Tm. However, this situation is not yet reached in carbon
therapy due to higher magnetic rigidity of about 6.5 Tm.

Fig. 3.5: The exocentric PSI Gantry (PSI Web pages)
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 29

The area of the treatment for proton gantry (Fig. 4.6), the gantry typically directs the beam from one side to the tumour and around one axis (Weinrich, 2006). In general, the tumour is positioned at the crossing of this two axis that is called the isocentre at this point. Gantries that are built in this type are the standard layout

In radiotherapy and are called isocentric gantries. Therefore, at PSI used the exocentric
gantry for proton Gantry 1, which the patient table has a different position for each gantry
angle. A set of the used gantry angles is exemplified in Figure 3.7


















Fig. 3.6: Layout of proton gantry delivered by Mitsubishi; after (Weinrich, 2006)
Fig. 3.7: Calcification of the different types of gantries; after (Kraft, 2000).

HADRON THERAPY FOR CANCER USING HEAVY IONS
Page Su

Then the advantage is that it can be built in a more compact manner; and it is shown in figure
3.8




In tables 4.1 and 4.2 an overview the important parameters of some proton and carbon
gantries in Europe and Japan.
Table 4.1: Proton Gantries in Europe & Japan; after (Weinrich, 2006)

Town No. Status Type Energy Length Radius Dipoles Quads
Germany
Munich 4 Validation Isocentric 250 MeV 10.1 m 5 m 2 7
Switzerland
Villingen Gantry 1
Operation
Excentric 230 MeV 10.2 m 1.4 m 3 7
Switzerland
Villingen Gantry 2 Assembly Isocentric 230 MeV 11.6 m 3.2 m 3 7
Japan
Fig. 3.8: the exocentric Gantry 1 at PSI; after (Weinrich, 2006)
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page S1
Hyogo 2
Operation
Isocentric 230 MeV 9.5 m 4.8 m 2 7
Chiba 2
Operation
Isocentric
235 MeV
10.7 m 5 m 2 9
Tsukuba 2
Operation
Isocentric
250 MeV
9 m 5 m 3 6
Shizuoka 2 Operation Isocentric
235 MeV
9 m 4.8 m 3 4

In addition, the treatments with carbon ions are currently delivered in three facilities;
HIMAC, HIBM in Japan and GSI Germany, table 4.2 shown the properties of some carbon
gantries.
Table 4.2: Carbon Gantries in Germany & Japan; after (Weinrich, 2006)

Town No. Status Type Energy Length Radius Dipoles Quads
Germany
Heidelberg 1 Assembly Isocentric
430
MeV/u
19 m 5.6 m 3 8
Japan
Chiba 1
Design
Isocentric
400
MeV/u
16.9 m 7.1 m 3 7

T% #chi!v! # r!#"%n#bl! b!nding r#diu", much high!r fi!ld "tr!ngth" #nd thu" l#rg!r #nd
h!#vi!r m#gn!t" #r! n!c!""#ry f%r i%n". Whil! th! w!ight %f # $r%t%n g#ntry i" #lr!#dy #r%und
100 t%n" (#t length %f 10m), #n i"%c!ntric g#ntry f%r c#rb%n i%n" i" !x$!ct!d t% h#v! w!ight %f
#b%ut 600 t%n" #t length about %f 18 m.
Th! !n%rm%u" "iz! #nd w!ight %f "uch # g#ntry t%g!th!r with th! high "$#ti#l #ccur#cy
r!quir!d f%r th! b!#m $%"iti%n #t th! i"%c!nt!r i" $r%b#bly th! r!#"%n why n% "uch g#ntry h#"
b!!n built u$ t% n%w. In"t!#d %f fl!xibl! b!#m d!liv!ry "y"t!m", fix!d inclin!d b!#m lin!"
h#v! b!!n r!#liz!d #t th! tw% %$!r#ting clinic#l i%n f#ciliti!" in J#$#n, wh!r! v!rtic#l b!#m"
#nd b!#m" with 45inclin#ti%n #r! #v#il#bl! t%g!th!r with h%riz%nt#l b!#m". &n%th!r
$%""ibility i" t% m%v! th! $#ti!nt r#th!r th#n th! b!#m. &t "%m! $r%t%n #" w!ll #" h!#vy i%n
f#ciliti!", tr!#tm!nt ch#ir" #r! #v#il#bl! %r m%uld" th#t c#n b! r%t#t!d ("!! $#ti!nt $%"iti%ning
f%r d!t#il"). It "h%uld b! m!nti%n!d th#t "iz! #nd w!ight %f # g#ntry c%uld b! r!duc!d by th!
u"! %f "u$!rc%nducting m#gn!t". Th! cry%g!nic" inv%lv!d, h%w!v!r, r!quir!" c%n"id!r#bl!
"$#c! #nd i" m%r! d!lic#t! t% h#ndl! in t!rm" %f "t#bility #nd $#ti!nt "#f!ty.
Hadrontherapy is developing to provide the same geometrical flexibility, as photon
therapy gantries have to be used for also these facilities. At the same time as the proton
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page S2
gantries are in routine operation now this is not achieved for carbon treatment. However,
advanced design efforts have reached the implantation step at GSI, but are under
consideration Riesenrad gantry. Because of the high costs of a gantry, alternatives to gantry
system have been experienced and considered at Chiba, Hyogo and NIRS.

3.6 Cost-effectiveness of hadron therapy in cancer
In the study by Mark Lodge et al (2007), they identified a total of 7209 articles, after
they de-duplication it, they reduced to 5089 articles, then they found the following number of
articles to be relevant to his review: neutron therapy (563), proton therapy (137), ion therapy
(49); economic viability and cost-effectiveness (10). Table 4.3 is shown the results literature
review in comparison with conventional therapy classified by tumour site.

Table 4.2: Results literature review in comparison with conventional therapy classified
by tumour site; after (Lodge et al, 2007)


The current literature shows that the existing data do not suggest the rapid expansion of
hadron therapy, as a major treatment modality would be appropriate. The formation of a
European hadron therapy would offer a simple way of accelerating the rate at which they
obtain high-quality evidence that should be used in assessing the role of hadron therapy in the
management of cancer.
The heavy charge particle therapy will be more expensive than the conventional
radiotherapy (magnetic fields required, concrete thickness, training and level of the
staff)(Goitein, 1997). Oliv


HADRON THERAPY FOR CANCER USING HEAVY IONS
Page SS
)H0I.7/ LC Treatment planning

In this section we well describe the procedure that used for intracranial treatments for
proton therapy (at CPO: Centre de Protonthrapie d'Orsay, French)(Samuel, 2uu1).

4.1 Imaging protocol
Physician counter the tumour and all surrounding critical organ by using the Computed
Tomography (CT scan) data with transverse slices of 1 mm to simulate the dose deposition
inside the patient. They also use Magnetic Resonance Image (MRI). Technical progress in the
software contributed the achievement of the fusion between CT and MRI images. Because CT
scans are based upon the photons interactions in the middle, then a calibration curve helps to
convert from X-rays absorption to protons stopping power (Fig. 4.1)








Fig. 4.1: Calibration curves for intracranial treatment (CPO); after (Samuel, 2uu1)
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page S4
4.2 Organs contouring
ICRU is fixed standardised volumes of contouring:
I. Gross Tumour Volume (GTV); tumour visible on the images.
II. Clinical Target volumes (CTV); tumour with possible microscopic
extension.
III. Planning Target Volumes (PTV); positive margins of treatment including
the treatment uncertainties.
4.3 Dose calculation algorithms
Numerous models are used for the dose calculating as the following:
I. The ray-tracing model is a one-dimension model. The SOBP parameters are
matched to the different densities and thickness for one direction of the
tissue. It is incorrect and limited for example to bone and air cavities,
because of scattering effect.
II. The classical Monte-Carlo model is very efficient.
III. The pencil beam models are good compromise between accuracy and
calculation time.
4.4 Choice of the ports
To deliver the prescribed dose to the tumour and do not exceed the maximal dose for
surrounding healthy critical organs; the dosimetrist must find the good compromise. For
example the maxima(empiric data known by physician) dose for the optic chiasma is 55
Gy.
4.5 Positioning and treatments
The ballistic properties that are used for hadron therapy have a specific positioning
system. At CPO, 1mm and 1 used for basic requirement for intracranial proton therapy.
Therefore, a specific system (frames, mask, foams, byte blocks,.) is used with patient
immobilizer to adjust the real position to the reference position prescribed by the planning
system of treatment 4 or 5 of fiduciary markers are fixed in the patient skull (Fig. 4.2). The
DRR (Digital Reconstructed radiography) extracted from CT data are compared with the axial
and the perpendicular X-rays radiography of the patient seated. The robot moves to position
the patient in several iterations by specific software, while there are other techniques such as
anatomic references or CCD camera (NAC) avoids the implantation of marks (Fig. 4.2). Then
the dose during the treatment is monitored with transmission ionisation chamber. And in
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page SS
passive scattering technique, the classical irradiation last is about 1 minute (2 Gy EQ CO per
session, 2 Gy/min). Besides, there is no specific perception or pain of the patient during the
treatment.




On other hand, the comparison of treatment plans using photon and proton is shown in
Figure 4.3 with different number of fields for cancer of Glandular parotid that locates nearest
to the ear, as we can see that on the left image, 100% dose is delivered by overlapping two
beams of photon from two entry points. The attenuation after beams hits the tumour; the
remaining doses are received by other part of the head up to 30%. Moreover, the use of
photon beam of 5 fields in middle image; the doses receive by other parts beyond the tumour
is lessen since lower energy beams can be used to overlapping at the tumour location but
remain delivering 100% dose to tumour. As a result, a large amount of healthy tissues are
irradiated. However, the proton beams in 3 fields on the right image; as described with the
depth-dose profile of proton treatment that the doses received by other body parts after the
Bragg peak is very small as shown in this treatment due to doses are very conformed to the
tumour site.

Fig. 4.2: Patient in position treatment at CPO, after (Samuel,2uu1)
Fig. 4.3: Treatment plan comparison of using photon and proton
HADRON THERAPY FOR CANCER USING HEAVY IONS
Page S6
)H0I.7/ NC Conclusion
There is a worldwide interest in the development of heavy charged particles therapy as
a conformal tool in radiotherapy. Due to hadron that has its unique depth-dose track with low
entry dose and an ionising intensity peak near the of its range, i.e Bragg Peak.
Wh!r!#" th! fir"t f#ciliti!" w!r! b#"!d %n r!"!#rch c!nt!r" in nucl!#r $hy"ic", th!
curr!nt t!nd!ncy g%!" t%w#rd" # $r%gr!""iv! int!gr#ti%n in"id! th! h%"$it#l, with m%d!rn
!qui$m!nt d!v!l%$!d "$!cific#lly f%r thi" #$$lic#ti%n. Du! t% it" "!v!r#l inn%v#ting
t!chniqu!" #nd %rg#niz#ti%n", %n! %f th! m#in ch#ll!ng! %f thi" th!r#$y i" t% r!#ch # r%utin!
r#t! %f tr!#tm!nt.
F%r it" inh!r!nt b#lli"tic qu#liti!", h!#vy ch#rg!d $#rticl!" b!#m" c#n incr!#"! th! d%"!
t% th! t#rg!t v%lum!, l%w!ring th! int!gr#l d%"! d!liv!r!d t% th! $#ti!nt #nd $r%t!cting critic#l
%rg#n" . F%r # c!rt#in numb!r %f clinic#l indic#ti%n", th! $r%t%n" c%n"titut! #lr!#dy th! b!"t
ch%ic! $r%v!n by clinic#l tri#l". F%r %th!r indic#ti%n", th! $%t!nti#l b!n!fit %f $r%t%n" "till
r!quir!" # clinic#l v#lid#ti%n, #" w!ll #" c%"t-!ff!ctiv!n!"" "tudi!" c%m$#ring with #lt!rn#tiv!
t!chniqu!" "uch #" c%nf%rm#l #$$r%#ch!" with $h%t%n b!#m". H!#vy i%n" b!#m" will h#v! t%
c%nfirm in th! n!xt y!#r" th!ir #ttr#ctiv! bi%l%gic#l $r%$!rti!".
Mutu#l t!chn%l%gic#l tr#n"f!r b!tw!!n c%nf%rm#l t!chniqu!" m#k!" it $%""ibl! t%
incr!#"! th! qu#lity #nd th! $r!ci"i%n %f tr!#tm!nt" #nd c%n"%lid#t! th! $l#c! %f h!#vy
ch#rg!d $#rticl!" th!r#$y within th! th!r#$!utic #r"!n#l %f tr!#tm!nt #g#in"t th! c#nc!r.



















HADRON THERAPY FOR CANCER USING HEAVY IONS
Page S7
@7G7/7317-

1. Goitein M, Radiation Oncology; A Physicist# s-Eye view, (Biological and Medical
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1S. Samuel N, 3( &E) !"#$" &'($) *+, ")(-. $"(,/)0 &(,1#$')2 #3 ,(0#+1"),(&.4
Pioceeuings foi the couise; Theiapy, )&@* #11767/0.4/ +1H446 ZXE0/.=167
#11767/0.4/- G4/ :78=1=37 038 W38B-./=7-Y 1uth -17th Nay 2uu1 - Piuhonice
(CZ)
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1S. }an }. Wilkens, 0we 0elfke, 5#,)$1 6+7&(,#2+3 +* 8#+'+/#$(''. 9&1#7#:)0
;&,)(0<+=1 8,(// >)(?2 *+, >,+1+32 (30 6(,@+3 A+32) *9(389&(>G9&E HG789&E GI
;&#>&(>G9 J96GEGKLMN>GEGKLM<CLO>6O, PGE753 Q?) *OO73 ., . H&97&8L ,??F, <&K3O
,D,R,DD
16. Baialu Paganetti 3( &E) B)'(1#-) @#+'+/#$(' )**)$1#-)3)22 CB8DE -('=)2 *+,
&,+1+34 *9(389&(>G9&E HG789&E GI ;&#>&(>G9 J96GEGKLMN>GEGKLM<CLO>6O, PGE753 A1)
*OO73 ,, . H793 ,??,, <&K3O :?QR:,.
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HADRON THERAPY FOR CANCER USING HEAVY IONS
Page S9
Appendix A: Proton Beam Facilities at the world & Particle Therapy Facilities in
operation

HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 4u
Appendix B: Hadron therapy patient statistics (data received per end of Feb 2009);
( from PTCOG website:
http://ptcog.web.psi.ch/Archive/Patientstatisticsupdate02Mar2009.pdf) log on 2

/9/2009.




HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 41











HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 42
Appendix C: Hadron therapy facilities in planning stages or under construction and in
operation



HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 4S






HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 44






HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 4S
Appendix D: Hadron therapy design and layout of;

1. HIMAC FACILITIES



2. HIT FACILITIES






HADRON THERAPY FOR CANCER USING HEAVY IONS
Page 46


3. PIMMS FACILITES





4. CANO FACILITIES