Cancer Radiotherapy using Hadrons

Mitul Patel
Collaborator: Andrew Slator
BSc (Hons) Applied Physics, St. Mary's University, Twickenham London
Group Centred Problem Based Learning Unit, APH5001 Atomic and Nuclear Physics
Date submitted: 28/11/2014
Cancer is a disease that occurs when the cells of the human body grow in an uncontrolled way.
There are various types of treatments available for cancer, which are discussed in this report. The
focus of the report is mainly on the hadron therapy for cancer treatment, its biological effects and
the cost effectiveness. It also explains the interaction of radiation with matter and the role it plays
in radiation oncology. Particle accelerators play a key role in cancer treatment, especially in
hadron therapy and these are discussed in the report along with their advantages and
disadvantages. The report also lays out the mechanism of hadron therapy for cancer treatment and
its benefits over conventional X-rays therapy.

[I] Radiotherapy and cancer

The body consists of many types of cells. These cells
grow and divide in a controlled way to produce more
cells. As the cells become old or damaged, they die
and are replaced with new cells. If this process goes
wrong, the normal cells do not die when they should
and the new cells form when the body does not need
them. Thus the cells starts to grow in an uncontrolled
way. These accumulation of cells gives rise to cancer.

moving subatomic particles thus creating high-energy

radiation which is used to treat cancer. This radiation is
mainly focused on the location of the cancer in the
body.[2] The figure 1 shows a patient undergoing
external beam radiotherapy.

[1]

The effects of this fatal disease includes lung,

breast, brain etc. There are many types of treatments
for cancer, most common are surgery, chemotherapy
and radiation therapy. These are described below in
details[1]:
Radiation therapy:- Radiation therapy uses high
energy radiation such as X-rays, gamma rays and
charged particles (such as protons, electrons) to kill
cancer by damaging their DNA. There are two types of
radiotherapy- External beam radiotherapy and internal
radiotherapy.
In external beam radiotherapy, the radiation is
delivered by the machine outside the body. The type of
machine used is called a linear accelerator (also known
as LINAC). This machine accelerates a stream of fast
Mitul Patel

Figure 1. A patient undergoing External beam radiation

therapy. Schematic of the linear accelerator. Credit:
Stanford.edu.

The internal radiotherapy can be given in

many ways. One way is to inject a liquid radiation
source such as radioactive iodine, radioactive radium
inside patients body and kill cancer cells. Another
way is to place the radioactive metal wires, seeds or
tubes inside or close to tumour, this is known as
Brachytherapy (from Greek word short distance).[2]
1


Chemotherapy:- In this case, anti-cancer drugs are
used in order to stop the production of cancer cells.
This drugs are carried by the blood in order to reach
cancer cells. The cancer cells take in the drugs and
eventually die. This drugs are also taken up by normal
healthy tissues, but these tissues can usually repair
damage caused by drugs. The uptake of drugs by
healthy tissues results in side effects, which limits the
dose that physicians can administer. Most of the side
effects will go away when the treatment is over[3].
Surgery:- Surgery is the first established therapy for
cancer. It is quick and effective and still in used today.
The job of surgery therapy is to just cut away tumour
mass from the body. The main disadvantage of this
therapy is that even though the visible tumour mass is
removed from the patients body, it not guarantee the
complete elimination of cancer cells. In order to
completely eliminate cancerous cells, a large extent of
healthy tissue may need to be removed. Removal of
healthy tissue may result in the loss of biological
function and therefore affecting the patients life[4].
In 1897, Roentgen discovered X-rays. Within a few
months of discovery, X-rays were used for both
diagnostic and therapy purposes. At the time due to
lack of advanced technology, X- rays were far from
optimal for radiation. As new and better X-rays
machines become available, many hospitals adopted
X-rays for treatments.[5] The main disadvantage of xrays is that, it not only damage the cancer cells but it
also damages the healthy tissues surrounding the
cancer cells. In 1946, Dr Robert Wilson[6], a physicist
working on -the developing particle accelerators at the
time, proposed the medical use of protons for cancer
treatment. In less than 10 years after his proposal,
protons were used for cancer treatment. In this report
we discuss the principle operation of hadron therapy,
biological effects and the cost-efficiency of hadron
therapy.
[II] Interaction of ionizing radiation with matter
and its role in radiation oncology
There are two types of interaction of radiation with
matter[7]. These are as follows:
(1) Indirect interaction of uncharged
(Photons, neutrons) with matter:
Mitul Patel

particles

* Photons: when an excited atom is de-excited to

lower energy level, an high-energy electromagnetic
radiation is emitted. These electromagnetic radiation
are called photons. There are three physical
phenomena that describe the photon-tissue interaction,
(1) photoelectric effect, (2) Compton effect, (3) pair
production.
II.1.1 Photoelectric effect: The ejection of electrons
from the surface of the metal when the metal is
exposed to light of high frequency. The emitted
electrons is called photoelectrons. Light consists of a
particle called photons as proposed by Albert Einstein.
The energy of the photon is given by the equation in
figure 2.

Figure 2. Schematic view of the photoelectric effect. An

ejection of electrons from the potassium due to photoelectric
effect. Credit: Hyperphysics.

Notice in figure 2 no electrons are emitted when red

light is shone onto the metal, with green light
photoemission occurs, and with blue light, the
electrons are emitted with maximum kinetic energy.
The photoemission occurs only if the frequency of
light is well above threshold frequency. The photons of
red light do not have enough energy in order to
photoemission. Whereas the blue and green light have
enough energy to cause photoemission.[7]
II.1.2 Compton scattering: Compton effect refers to a
collision between a photon and an electron. The
incident photon interacts with the electron and thus
transfers part of the energy to the electron. The photon
scatters with lower energy at different angle to that
of incident angle. The electron recoils with kinetic
energy T, at an angle as shown in figure 2[7].
2


Where I is the transmitted intensity through a tissue
I0 is the incident intensity

linear attenuation coefficient

X thickness of the tissue
A larger value of linear attenuation coefficient means
that the beam passing through a tissue is quickly
attenuated. Whereas a small value of linear attenuation
coefficient means that the tissue is transparent to the
beam.[8]

Figure 3. Schematic view of the Compton scattering

showing an incident photon colliding with an electron.
Credit: HyperPhysics

Figure 5 presents the attenuation process of

photoelectric effect, Compton effect and pair
production.

II.1.3 Pair production: As the photon interacts with a

nucleus in the nuclei field; it disappears producing an
electron-positron. The photon must be above 1.022
MeV.[7]
!!!"#!!"# = 2! ! = 2 0.511 = 1.022

Figure 4. Schematic of pair production.

Credit: Hyperphysics

The photon absorption or scattering in the human

tissue is determined by attenuation . Attenuation is
basically the gradual decrease in intensity of any kind
of flux through a medium[8]. The attenuation of
photons depends on the density and thickness of
tissues. The denser the tissue, the more photon are
attenuated. For example, X- rays are attenuated more
by bone than lung tissue therefore bones produce a
dark shadow when X-rayed where as soft tissue
appears much fainter. The attenuation of photons can
be expressed mathematically and is given by equation
1

= ! !!"
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equation 1

Figure 5. shows the attenuation of gamma ray photon

process.

(2) Direct interaction of charged particles (electrons,

protons, heavy ions) with coulomb forces.
* Heavy ions:- Ions are basically atoms whose
electrons are removed, therefore the total number of
electrons is not equal to the total number of protons
and thus the atom have a net positive or negative
electric charge. Ions can be accelerated to high
energies in various types of accelerators which are
discussed later in the report. The physical and
biological properties of the heavy ions makes it
possible to be used for cancer treatment. Currently
there are two main types of ions therapy- light
hydrogen ion i.e proton and heavy carbon ion. These
particles are produced in an ion source and are
3


accelerated to about half the rate of speed of light in
order to reach the required depth in the patients.[8]
* Electron:- Electrons are negatively charged particles.
Electrons can be accelerated to high energies using
linear accelerators and can be used for cancer
treatment. As the electrons travels the material, they
lose energy due to coulomb interactions and this
energy loss is given by the modified Bethe-bloch
equation given in equation 3 in the next section.[9]
* Proton:- Protons are positively charged particles.
Protons are 2000 times massive than the electrons.
When the proton travels through a tissue, they slow
down due to coulomb interaction with the electrons of
the atoms in the material. This reduces the energy of
the proton. Maximum interaction occur at the end
range i.e. when the protons completely stop and thus
results maximum (Bragg peak) energy release within
the targeted area as shown in figure 6 and figure 7.
They can travel few centimetres in biological matter
depending on their energy.[9]

Figure 7. shows an example of a proton therapy for a rare

orbital tumour in a child at Massachusetts General
Hospital, Boston, USA. The X-ray comparison shows how
that beam deposits radiation dose to a much wider area than
that of proton therapy.

Charged particle energy Loss

As the charged particles travel through the material,
they lose energy due to the interaction with the
electrons of the atoms in the materials. This interaction
either excites or ionizes an atoms. The energy lost by
the charged particles is given by Bethe-Bloch formula
given in equation 2. This formula is only valid for
heavy charged particles, given that the particles
velocity is much larger relative to the orbital electron
velocity. [10]
!"

!" =

!!! ! ! !
!! ! !

equation 2

Where B is given by
= [ln
Figure 6. Shows the relative depth of proton in tissue and
the characteristics Bragg peak

2! !
!
!
1 ! !

With the meaning of its components

Z atomic number of absorber atoms
m0 electron rest mass
V velocity of the charged particles
I average excitation and ionization potential
B stopping number
E charge of the charged particles
C speed of light
The equation 2 is no valid for electrons, mainly due to
its small mass the energy loss is different than that of
heavy particles. Thus the equation 2 is modified for
electrons and is given in equation 3

Mitul Patel


!"

!!! !

!" = !

!!

equation 3

Where B is given below

2! !
= ln
2 ! (1 !
ln 2

2 1 ! 1 + ! + 1

1
! + (1 1 ! )!
8
!

Here =
!

Using the energy loss, the range of the charged

particles in a medium can be calculated, given by
equation 3

!"
!"

equation 3

[III] Hadron therapies for cancer treatment

Hadron therapy is a new technique for cancer
treatment. It uses baryons (hadrons consisting of 3
quarks) such as protons, carbon ions to treat cancer. In
order to kill cancer it is important to deliver a defined
dose distribution within the target volume while
preserving the surrounding volume. In other words,
deliver a maximum dose accurately to the tumour and
preserve the surrounding healthy tissues located near
the tumour[11]. For this reason, Wilson in 1946
considered charged particles based on their physical
characteristics. Currently only protons and carbon ions
are in clinical use.
The protons and carbon ions hit the target much more
precisely than X-rays and produce more consistent
damage as shown in figure 8 below.[9]

Mitul Patel

Figure 8. Shows the damage to DNA caused by X-rays and

heavy ions. Credit: Hadron therapy physics and
simulations[12].

The protons and heavy ions deposits maximum energy

in the last few millimetres at the end of the energy
path, this is called Bragg peak as shown in figure 6.
The advantage of using carbon ions is that it deposits
more energy in the Bragg peak than proton due to its
increased RBE of radiation beam at the end of the
energy path.
Accelerators for Hadron Therapy:- There are various
types of accelerators used in the radiation therapy (RT)
ranging from LINAC, used to generate X-rays to
proton cyclotron for radionuclide and Synchrotron
accelerator for heavy ions. We shall discuss only two
accelerators here; Cyclotron and synchrotrons
accelerators.[12]
The principle operation of Cyclotron involves the use
of electric field produced by oscillating voltage in
order to accelerate charged particles across a gap
between the two D-Shaped magnetic field regions[].
The magnetic field bends the charged particles in a
semi-circular path. Whilst this happens, the electric
field reverses the polarity and so to accelerate the
particles as they travel through the gap again. In this
way the charged particles are accelerated at high
energy see figure 9. The particle energy that can be
reached by a cyclotron is limited by the size of the
magnets and the strengths of the magnetic fields.[13]


Figure 10. Shows the image of cyclotron used for proton
therapy. Credit: Penn medicine[].

In order to accelerate particles at such high energies,

another type of accelerators is used- synchrotrons
accelerators.

Figure 9. Schematic view of cyclotron

In most proton facilities, cyclotron accelerators are

used in order to produce proton beams with sufficient
energy. The main advantage of using cyclotron beam
is that it produces continuous beam with fixed energy
which makes the design simple and no sophisticated
controls are needed which simplifies the operation.
The acceleration process in cyclotron is much faster,
typically < 40 sec, therefore it is possible to switch the
beam on and off rapidly. Also the cost of construction
and operation is much lower than any other
accelerator. Thus, this characteristics make the
cyclotron attractive for therapy.
The disadvantage of using cyclotron is that it cannot be
used for deep-seated tumours due to the limited energy
range. As discussed before the charged particles slow
down when travelling through the tissue and thus have
a finite range. The energy of the charged particles is
therefore proportional to the depth of the target volume
within the tissue. The cyclotron (see figure 10)
currently being used in proton therapy have an energy
range of about 70Mev, therefore it can only be used for
treating ocular tumours. For cyclotron to treat all kind
of tumours, it needs to deliver a beam with an energy
of about 230Mev corresponding to a range in a tissue
of 32cm.[13]

Synchrotrons accelerators can be used to accelerate

heavy ions, protons at energies such as 200 Mev for
protons and 480 Mev/u (u = atomic mass unit) for
heavy ions. The main advantage of it is that it can be
used for deep-seated tumours as these charged
particles are accelerated at high energies and therefore
can penetrate far . The main disadvantage is that the
design and operation of synchrotrons are much more
complicated and its more costly than cyclotrons.[14]
[IV] Biological effects of hadron therapy
The radiobiological properties of charged particles are
different than that of the photons. The charged
particles are more effective than the photons. The
biological effects are divided into two categories as
follows:
Linear energy transfer (LET): LET is defined as the
amount of energy lost by the photons or particles per
unit length as they travel though a matter. The LET is
identical to the retarding force that is acting on the
charged particle as it travels through the material. It is
inversely proportional to the square of the velocity and
directly proportional to the square of the charge.[15]
It plays an important in radiology, as it describes the
damage caused by the amount of radiation on the cells
along the path. The ions produce many ionizations in a
short distance and therefore have high linear energy
transfer. With high LET, the dose required to kill
cancer cells ( also damaging to surrounding tissues) is
smaller.
Relative biological effectiveness (RBE):- RBE is
defined as the ratio of the dose of X-rays to the dose of
charged particles radiation in order to cause the same
level of effect. RBE depends on both the dose and the
biological endpoint. It also depends on the type of
radiation as different types of radiation have different
RBE. The figure 11 below shows the relationship
between LET and RBE.[15]

Mitul Patel

Figure 11. shows the relationship between RBE and LET.

As can be seen from the figure, at low LET the

damaged caused by the particle to cancer cells is low,
therefore RBE is low and hence the dose required to
kill cells is high. Whereas at high LET, the damaged
caused by particle is high therefore RBE is high and
hence low dose is required.
[V] Cost effectiveness of hadron therapy
The biological and physical effects of protons, heavy
ions provides the advantage in the treatment of
tumours as we discussed. Due to the potential benefits
of hadron therapy, over 40 hadron therapy centres are
being setup or under construction around the world.
In 2008, researchers[16] carried out a systematic
literature review to identify reports on the efficacy of
hadron therapy focusing mainly on the proton and
heavy ions therapy. They discovered a total of 7209
articles, reduced to 5089 articles after de-duplication.
Of these 5089 articles 563 were of neutron therapy,
137 proton therapy and 49 of ion therapy. The
literature review only included studies of at least 20
patients with a follow-up period of at least 2 years.
Around 110,000 patients have been treated with proton
therapy up to now since 1954 with hadron therapy.
About 85% patients are treated with proton therapy up
to now and 10% patients have been treated with carbon
ions since 1994. In the remaining cases ions other than
carbon and pions were used. The figure 12 show the
number of proton therapy centres around the world
since 1950 to 2015.[12]

Figure 12. shows the increase in the number of proton

therapies around world since 1950 and 2015.

[VI] Example of treatment cancer using hadron

therapy
* Skull Base tumour:- The skull base tumours are
basically growth of abnormal cells in different areas at
the bottom of the skull base. Even though these
tumours are benign, they can be life threatening as they
are invasive. There are many kinds of skull base
tumours for example chrodoma, chondrosarcoma etc.
the treatment of skull base tumour is challenging
because of the positions of these tumours. These
tumours sit under the brain. Charged particles can be
used to treat the skull base tumours due to its high dose
i.e. 70Gy, whilst photons can reach up to 50Gy in this
case.[12]
A 5 year control rate of 82% has been obtained using
proton therapy for this tumour, for chrodoma 63%
using helium ions during 5 years.
[VII] Conclusion
At present, proton therapy has grown into an advanced,
cutting edge clinical modality and is applied in many
different techniques in order to control various types of
tumour. The main advantage of hadron therapy is
based on both the physical and biological effects due
to which the radiation can be directly delivered to the
tumour, sparing the surrounding healthy tissues. As
shown in this report, there is a significant interest in
hadron therapy mainly due to is potential benefits over
conventional X-rays.
References

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[1] National Cancer Institute,
http://www.cancer.gov/cancertopics/factsheet/Therapy/
radiation
[2] Cancer Research Uk,
http://www.cancerresearchuk.org/aboutcancer/cancersin-general/treatment/radiotherapy/
[3] Macmillan Cancer Support,
http://www.macmillan.org.uk/Cancerinformation/Can
certreatment/Treatmenttypes/Chemotherapy/Chemo
therapy.aspx
[4] Paula L. Petti & Lennox, Hadronic radiotherapy.
doi:94143- 0226
[5] X-rays, http://en.wikipedia.org/wiki/X-ray
[5] Robert R Wilson, (1946), Radiological use of fast
protons.
[7] Krane Kenneth S, 2nd. Ed (1955), Introduction to
nuclear physics.
[8] J.T. Bushberg, J. Anthony Seibert, Edwin M.
Leidholdt and John M. Boone, 3rd. ed, The essential
Physics of Medical Physics.
[9] Marcos D Nunes, Hadron Therapy Physics with
Simulations.
[10] Dr. Shahid Majid, Concepts of Medical Physics.
[11] Daniela Schulz-Ertner, Md, Oliver Jakel, PhD, and
Wolfgang Schlegel, PhD, Radiation Therapy with
Charged Particles.
[12] European science foundation, Nuclear Physics in
Medicine.
[13] Hyperphysics, http://hyperphysics.phy-
astr.gsu.edu/hbase/magnetic/cyclot.html
[14] HyperPhysics, http://hyperphysics.phy-
astr.gsu.edu/hbase/particles/synchrotron.html
[15] Physics Research Radiation Oncology ,Relative
Biological Effectiveness of proton and heavy ions.
[16] Loge M, Pijls- Johannesma, et, at, A systematic
literature review of the clinical and cost effectiveness

Mitul Patel

of hadron therapy in cancer Radiotherapy and

Oncology: journal of the European Society for
Therapeutic Radiology and oncology. Elsevier Ireland
2007, vol38, pp.110-122