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Advancements of proton therapy

Running Head: ADVANCEMENTS OF PROTON THERAPY 1
ADVANCEMENTS OF PROTON THERAPY
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ADVANCEMENTS OF PROTON THERAPY 2
Abstract
The study explores the advancement of proton therapy. It goes further to explains how
patients with cancer are treated using this technique and also neutron and heavy ion carbon.
Proton therapy advances from conventional treatment that involves X-rays, gamma rays, and
electron therapy. The proton beam therapy physics, mechanism, biological and physical concepts
are detailed. The effectiveness of the PBT in treating different cancers such as head and neck,
prostate, gastrointestinal, thoracic, pediatric and other cancers reveals its competitiveness as
opposed to the conventional type. This efficiency of proton therapy makes it a better option in
the treatment of tumors in children and adults as it results in cancer medication with reduced
adverse effects. Again, neutron and heavy ion carbon have shown their efficiency in treating
different complications brought about by these ailments. There is also a discussion of merits and
demerits of proton therapy in the study. Further research is ongoing to provide promising
advancement that destroys cancer hence hope for a healthy community in the forthcoming days.
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Table of Contents
Abstract ........................................................................................................................................... 2
List of Figures ................................................................................................................................. 4
1.0 INTRODUCTION.............................................................................................................. 6
2.0 PARTICLE THERAPY .................................................................................................... 7
2.1 Proton therapy ................................................................................................................ 7
2.1.1 Physics of Proton Therapy ........................................................................................... 9
2.1.2 PBT Physical Aspect ................................................................................................... 12
2.1.3 PBT Biological Features ............................................................................................. 13
2.2 Proton Therapy Advancements ....................................................................................... 14
2.2.1 Pencil beam scanning (PBS) ...................................................................................... 14
2.2.2 Paralleling PBS ........................................................................................................... 15
2.2.3 Intensity modulated proton therapy (IMPT) ........................................................... 15
2.2.4 Proteus One ................................................................................................................. 16
2.2.5 Pro-Beam System ........................................................................................................ 16
2.2.6 PT-specific version ...................................................................................................... 16
2.3 Neutron therapy ................................................................................................................ 16
2.4 Heavy ion carbon therapy ................................................................................................ 20
3.0 DISCUSSION ........................................................................................................................ 23
3.1 Proton Therapy for different Cancers ............................................................................ 24
3.1.1 Head and neck cancers ............................................................................................... 24
3.1.2 Thoracic tumors .......................................................................................................... 25
3.1.3 Abdominal and pelvic cancers ................................................................................... 26
3.1.4 Pediatric cancers ......................................................................................................... 27
3.1.5 Other tumors ............................................................................................................... 27
3.2 Controversies of PBT ........................................................................................................ 28
3.3 Drawbacks of PBT ............................................................................................................ 28
4.0 CONCLUSION ..................................................................................................................... 30
5.0 RECOMMENDATION ........................................................................................................ 31
REFERENCES ............................................................................................................................ 32
APPENDIX .................................................................................................................................. 34
ADVANCEMENTS OF PROTON THERAPY 4
List of Figures
Figure 1: Proton interaction mechanism {(e) electron, (p) proton, (n) neutron} .......................... 10
Figure 2: an Inelastic nuclear reaction against the energy of proton across nuclear barrier ......... 11
Figure 3: Percentage depth-dose distribution curve of proton beam vs. photon beam ................. 12
Figure 4: Comparison of high LET and low LET electrons ......................................................... 17
Figure 5: Photon therapy ............................................................................................................... 18
Figure 6: Neutron therapy ............................................................................................................. 18
Figure 7: Survival of cancer cell ................................................................................................... 20
Figure 8: Minimized irradiation of C-ions to the adjacent areas .................................................. 21
Figure 9: Target cancer irradiated with heavy ion beams ............................................................. 23
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ADVANCEMENTS OF PROTON THERAPY
1.0 INTRODUCTION
Cancer is a global cause of life destruction with millions of deaths occurring worldwide.
It is a multicellular and multi-genic disease that can happen in all types of cells and organs. If not
treated the cellular growth can spread and lead to life loss of an individual. As a result, there
exists continuous progress in the advancement of cancer treatment that can help cure the ailment.
At the same time, the improvement minimizes radiation to the uninfected areas making it safer
and more effective.
X-ray discovery in the earlier days was the first cancer treatment that was clinically
useful. From then, radiation therapy emerged which was applicable in the medical specialty
where a group of science and health professionals gathered (Schippers & Lomax, 2011). The
radiotherapy is of great importance in cancer medication with a high application of cost
efficiency. Furthermore, there is a rapid advancement in this field which continues to grow due
to the radiation therapy machines, computerized planning devices, and imaging techniques.
Tumors, especially the brain ones are highly distinct in their prognoses and treatment.
There is curing of some patients conservatively, although others require a profound combination
of chemotherapy, radiation, and surgery. These therapies aim to destroy the cells that have
tumors and to hinder regrowth while protecting the healthy cells from destruction. More so, the
treatment is essential for children. This therapy is possible since their growing brains and bodies
are highly sensitive to the prolong radiation effect.
Radiation therapy destroys cancer cells. Likewise, it inhibits the growth of such tissues
by relaying energy particles to the infected area or the surrounding healthy tissues where the
ADVANCEMENTS OF PROTON THERAPY 7
tumor occurs. The extended treatment region facilitates the possibility that cancer may also
happen in healthy parts. Frequently, this area has some healthy cells which if damaged may
cause prolonged side effects. This research focuses on exploring proton therapy advancement
that aid in the effective treatment of cancer for long-term benefits of patients and also studies
neutrons and heavy-ion carbon particles.
2.0 PARTICLE THERAPY
Particle therapy is a type of radiotherapy that operates externally using energetic beams
of neutrons, protons or heavy ion for cancer treatment. This therapy is sometimes called hadron
therapy. Particle therapy works by targeting energetic particles at the tumor cells. As a result,
they damage the DNA tissues destroying the cancerous cells. The inability of the abnormal cells
to repair themselves after damage, make them vulnerable to the reaction.
2.1 Proton therapy
Proton beam therapy (PBT) was applicable in the early days although its use is still
present in the treatment of a variety of cancers today. Its usage is due to its outstanding physical
characteristics and superior dosimetry factors. PBT is radiation therapy (RT) type that improves
the survival rate of people living with cancer by enhancing treatment local tumor rate (Schippers
& Lomax, 2011). At the same time, PBT reduces the injury that could occur in healthy body
parts. Utilization of PBT results in fewer harmful effects and higher healing efficiency as
opposed to conventional RT that uses beams of X-ray. Thus, despite the high cost of PBT
equipment, there is a construction of its facilities worldwide.
A proposition of PBT took place in 1946 by William (Schippers & Lomax, 2011). After a
dozen years, it was published at the laboratory of Lawrence-Berkeley by researchers (Schippers
& Lomax, 2011). Later decades, other centers that used proton treatment emerged globally
ADVANCEMENTS OF PROTON THERAPY 8
making PBT approximately 60 years usage in the clinical setting. Its practicability by the end of
2015 was for about ten thousands victims who had varieties of cancers. Over the last decades, the
number of the upcoming programs of this treatment is developing. The reason behind the
development is that the distribution of proton dose is better than that of conventional photon one.
PBT is likely to improve patient survival rate by increasing the rate of treatment in the
affected area while at the same time decreasing the adverse effect induced. In contrary to the
conventional medication, its denser sub-atomic particles are capable of delivering their energy
more accurately to the affected cells without spreading to the subsequent tissues. According to
Schippers & Lomax (2011), photon therapy involves higher side effects which make PBT a
better option.
Conversely, PBT functions remain controversial as a result of the high cost of treatment
that comes with high maintenance and the price of the proton facility. The raised value, however,
may fail to be an issue due to its effectiveness as opposed to photon therapy. It offers improved
life quality and reduces costs that relate to advanced disease treatment. However, its adoption is
not widespread due to some challenges related to cost and technicalities as compared to photon
therapy.
These obstacles, however, do not limit the progress made in this medical system.
Recently, there are about ten centers of proton therapy in the United States and other 38 global
centers (Sakurai et al., 2016). The primary aim of PBT is its superiority in the distribution of
spatial dose in infected individuals. This proton advantage over photons increases its usability
over photon therapy such as volumetric arc therapy and modulated photon therapy (Sheets et al.,
2012).
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In the US, about 80% children and 65% adults still survive after cancer diagnosis (De
Moor et al., 2013). Long-term survivors of photon treated patients are likely to exhibit fertility
complications, cardiovascular diseases, and other cancers. Today, approximately 3% of the
United States citizen is survivors of cancer that amount to 11 million individuals as stated by De
Moor et al. (2013). By 2022 the figure is likely to rise to about 18 million as suggested by De
Moor et al. (2013). Due to these projections, there is growing curiosity in the exploitation of
tissue-sparing potential of proton therapy. There is a high expectation that this therapy will
decrease the complication associated with the treatment of patients.
2.1.1 Physics of Proton Therapy
There exist advances in physics regarding proton therapy that relates to time. Similarly,
there are several mechanisms in the interaction of protons with the nucleus. Many protons move
in a straight path due to a higher mass of about 1832 times than electrons (Paganetti, 2012). In
contrast, those shifting near the nucleus have a repulsive interaction as a result of the more
significant mass of the nucleus that reflects these positive particles from their original path. The
inelastic reactions between the atom and protons are not frequent but have a profound impact.
In such reactions, the positive particles enter the nucleus, although these nuclei may emit
tritons, deuterons, protons, heavier ions or even single or multiple neutrons (Stathakis, 2010).
The figure below illustrates the interaction mechanism of protons where (a) represents energy
loss through interaction, (b) is the proton trajectory deflection as a result of repulsion that scatters
the nucleus. Finally, (c) is the primary proton removal and the making of secondary particles
through inelastic nuclear interaction.
ADVANCEMENTS OF PROTON THERAPY 10
Figure 1: Proton interaction mechanism {(e) electron, (p) proton, (n) neutron}
Source: http://iopscience.iop.org/article/10.1088/0031-9155/60/8/R155/meta
As related to the figure above, there also exists nuclear interaction where proton interacts
through non-elastic atomic reaction with atomic resulting to transform nucleus irreversibly. For
instance, in action where core absorbs a proton, an electron gets ejected. In a therapeutic region,
the main nuclear reaction effect of a proton is usually a little absorption of the dose (Paganetti,
2012). The absorption occurs due to the elimination of primary proton. This reaction gets
compensated by production of secondary protons and other charged particles. As the proton get
depleted gradually, other protons become liberated due to the activity.
The reduced protons number at the range end, occur due to ions that come out and their
absorption occurs within the medium. For a proton to enter a nucleus, it must have enough
energy to overcome the nucleus barrier that becomes determined by the atomic number as shown
below.
ADVANCEMENTS OF PROTON THERAPY 11
Figure 2: An inelastic nuclear reaction against the energy of proton across the atomic barrier
Source: www.nds.iaea.org/endf
The different atomic action is essential to clinical PBT where the result can produce
energetic triton, proton, deuteron,
3
He,
4
He and other ions. 10% of the proton include the
secondary ones that have little and non-negligible effects in the patient scattered dose
distribution (Paganetti, 2012). Heavy carbon ions and deuterons occur in a small amount
accounting for 1% or less of the total dose absorbed during therapy. These particles energy is
little, and they produce their kinetic energy near the creation point.
Approximately high beams of protons occur in the equipment delivered to the patients,
and they produce neutrons that bring about safety hazards. The personnel ensures that they limit
the exposure of neutron to the patients. Care must be taken to harden and shield the electronic
system so that the neutrons do not damage them. Attention is also necessary when activating the
neutrons in water, air, and other materials. The strength of neutrons is highly dependent on the
direction and the energy of the proton beam (Schippers & Lomax, 2011).
ADVANCEMENTS OF PROTON THERAPY 12
2.1.2 PBT Physical Aspect
There exist heavily charged particles called protons that have a relatively higher mass
than electrons. This mass and induced acceleration provide every proton a particular momentum
that becomes produced after moving to a specified direction where it slows down after meeting
with the targeted section. This interaction increases the energy deposited at the end of the proton
path. Here, there is no further delivery of the dose hence called Bragg peak (Stathakis, 2010).
This property offers a significant advantage over electrons or photons. Thus, instead of
traversing the target, there is movement hindrance of these protons at the depth where energy is
necessary. There is no exit dose which entirely spares destruction of healthy tissues.
Generation of beams of these positively charged particles is by synchrotron or cyclotron
which accelerate them to the required target. The figure below shows the percentage distribution
of depth-dose proton beam curve versus photon beam. The curve implies that at a certain depth,
the proton beam does not offer extra dose, unlike the photon beam.
Figure 3: Percentage depth-dose distribution curve of proton beam vs. photon beam
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772792/
ADVANCEMENTS OF PROTON THERAPY 13
In the curve above the conventional radiation depicts a reducing deposition of energy
with raising depth of the tissue. On the other hand, protons demonstrate an increased build-up of
energy with penetrating intensity that leads to a Bragg peak. Protons that penetrate through the
tissue decelerate when losing power in the nuclear or atomic interaction events. This movement
decreases the proton energy and as a result increases the interaction with the electrons in orbit
(Paganetti, 2012).
Optimum interaction with these harmful particles occurs at the range end leading to the
release of maximum energy within the required area. This characteristic is more advantageous
than that of photon radiation because there is deposition of maximum intensity in the targeted
region which is generally created by the Bragg peak spread-out. As a result, there is a high
possibility of tumor volume coverage with increased accuracy. Also, the technique offers lower
doses to the uninfected tissues than the electron technique. Similarly, there is a slight difference
between the two methods at the lateral penumbra (Paganetti, 2012). The level of penumbra for
proton beams is broader than that of a photon.
2.1.3 PBT Biological Features
In radiotherapy, the determination of proton dose is by multiplication of the relative
biological efficiency (RBE) and physical treatment. Therefore, the natural and clinical impact
may vary when the dose is constant, and the radiation quality deviates. Paganetti (2012)
explained that RBE helps to link the effect to a radiation of
60
Co. RBT exterior uses electrons
and photons where the RBE usually is 1. The distribution properties of proton dose differ unlike
those of photons. This variation enables them to avoid targeting surrounding areas.
ADVANCEMENTS OF PROTON THERAPY 14
The momentum usually slows down after interactions that become associated with the
charge and their mass. They are then stopped abruptly at a particular depth where the proton
interact with the surrounding electrons releasing energy that causes molecule ionization
destruction of radiation of the target cell’s DNA (Westerly et al.,2013). These protons have
reduced linear strength, and the damage they cause on the tissue is generally by the break of a
single strand of DNA. It results in loss of sub-lethal radiation and its subsequent repair.
The determination of biological impacts is by every dose per treatment which is usually
higher than
60
Co and X-ray energy. In such an instance, the proton RBE is generally 1.1. Near
the edge of the proton range, the power raises hence increasing the RBE. Given that RBE used in
proton planning is 1.1, then the changing RBE at the range end is usually ignored (Schippers &
Lomax, 2011). The PBT with angles is not applicable in treating critical organs with tumors.
Instead, multiple beams are suitable in such an area to spread out the uncertainty range end. Use
of pencil beam scanning requires an evaluation of the dynamic delivery interaction with the
shifting target and then minimized (Westerly et al., 2013).
2.2 Proton Therapy Advancements
Proton therapy is ever growing and involves a combination of various innovation that
shows an enlarging role for proton therapy. These advancements are as a result of new
technologies that increase the precision even better. The improvements are:
2.2.1 Pencil beam scanning (PBS)
The PBS is a type of proton therapy that further raises the dose conformity. It deposits
more radiation than the previous PBT directly in the infected cells, while still preserving the
healthy tissues from harm. The advantages of this therapy are many enabling more patients to get
assistance from it. It reduces or nearly gets rid of the neutron scattering, more so when treating
ADVANCEMENTS OF PROTON THERAPY 15
pediatric cancer. This therapy increases the chance to dose paint hence sparing healthy tissues in
the surrounding from the high dose tumor capacities (Westerly et al., 2013). Moreover, it is
faster implying that patients with multiple complications can get treatment in only 30 minutes.
This speed allows for more patients to become treated as per the schedules.
This type offers a narrower and single proton beam which becomes magnetically moved
across cancer. It does not need a beam-shaping gadget. This kind of technology provides a more
accurate 3-D beam that corresponds to the depth and shape of the tumor (Gill et al., 2014).
Further, the PBS reduces the impacts that surround healthy brain tissues, critical organs and the
cells adjacent to the infected region hence decreasing the side effect. Such therapy is more
appropriate for cancers with complex shapes that are near vital organs.
2.2.2 Paralleling PBS
This technology help in hardware downscaling. Gill et al. (2014) claimed that the
advances in imaging are essential in enhancing treatment planning and facilitating adaptive
treatment by enabling optimization of the medication as cancer reduces over time. Such
advancement minimizes the proton therapy cost as they shorten the planning and treatment
duration. They also aid in making the facilities and equipment smaller which in turn benefit the
payer, patients, and the hospital system as well as the overall society.
2.2.3 Intensity modulated proton therapy (IMPT)
It is a faster technology developed by Mevion, and it is made from Hyper-scan PBS
hence quicker and precise. It is made for a single room and has features such as adaptive aperture
and reduced profile minute multi-leaf collimator which acquires 2-3mm correct sizes necessary
for all energy (Sheets et al., 2012). The Mevion also had a plan of partnering with the photon
makers to combine the CBCT mechanism to enhance the volumetric images. The IBA treated
ADVANCEMENTS OF PROTON THERAPY 16
50,000 patients in 2016 September with their system after introducing a small proton therapy
system called Proteus One.
2.2.4 Proteus One
This innovation operates in a single room whereby it offers different methods of delivery
such as IMPT and other proton therapy mechanisms that are image-guided. The centers made
globally by the IBA occur in countries like UK, France, Belgium and Japan (Sakurai et al.,
2016).
2.2.5 Pro-Beam System
The technology is an even smaller version made by Varian that provides similar benefits
as the other proton therapy techniques including extensive peak scanning that facilitates
application of rays simultaneously from a various angle for IMPT (Schippers & Lomax, 2011).
Moreover, the space for its cyclotron is more effective than the linear accelerators.
2.2.6 PT-specific version
This model uses software called eclipse planning that conjoins with both systems of Pro-
Beam treatment. This software uses many protocols such as standardization and automation to
ensure the workflow is smoothly carried out especially the Smart Segmentation (Sakurai et al.,
2016). There include other characteristics such ass field specific target (FST) that aid in
compensation of range uncertainty, target motion difficulties as well as setup error that surrounds
the target volume in the facility.
2.3 Neutron therapy
This therapy type is highly efficient in treating cancer, unlike the conventional radiation
that does not destroy the radio-resistant anomalies. While traditional therapy involves electrons
and X-ray radiation, hadron therapy uses the protons and neutrons generated by the use of
ADVANCEMENTS OF PROTON THERAPY 17
deuteron or proton accelerators. The main impact of ionizing radiation is to kill the ability of
tissues to divide by breaking down their DNA strands (Barth et al., 2012).
Figure 4: Comparison of high LET and low LET electrons
Source: (Barth et al., 2012)
Electron, proton, photon radiations use activated radical of low linear energy
transmission (LET). On the other hand, neutrons use high LET radiation to damage the DNA by
use of nuclear interaction as demonstrated in the figure above. Given that the use of low LET
radiation destroys a tumor cell, chances of repairing itself and continuing to grow high unlike
when using high LET radiation that damages the tissues thoroughly preventing them from
regenerating (Barth et al., 2012).
ADVANCEMENTS OF PROTON THERAPY 18
Figure 5: Photon therapy
Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691008/
The figure above is a photon therapy photo. The photon hits the atomic particles in the
cancerous cells hence displacing its outer negative ions (e
-
). Given the atom get hold of the lost
electrons, the DNA of the tumor can reconstruct itself and continue harming the patient (Barth et
al., 2012).
Figure 6: Neutron therapy
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691008/
ADVANCEMENTS OF PROTON THERAPY 19
The figure above is a neutron therapy picture. It illustrates that an incoming neutron can
destroy the cancerous cells via nuclear activities which splits these affected cells into a pair of
distinct atoms that cannot recombine hence preventing further tumor growth.
Generally, fast neutrons can get rid of the massive tumor since they do not require
oxygen to kill these cells. Additionally, the biological effects of neutrons are not dependent on
the stage or time of cancer cells lifecycle as opposed to low LET rays. Neutron destruction of the
tumor cell is via nuclear interaction whereby atoms splitting into the affected cells are effectively
preventing them from recombining (Barth et al., 2012).
In such a case, use of neutrons is efficient and controlling the primary tumors after which
chemotherapy becomes utilized in limiting the spread of this cancer to the other parts. Due to the
neutrons effectiveness biologically, the needed tumor dose necessary for killing the cancer cell is
approximately one-third of those used by proton, electron or photons. Neutron therapy full
course requires about 10-12 treatments, unlike low LET radiation that needs 30-40 medication.
This medication is offered in the Fermilab and the Northern Illinois University (Barth et al.,
2012).
Neutrons deposit increased energy along the cancer path unlike gamma or X-rays
resulting to more damage of such cells. The use of cyclotron accelerator that releases a proton
and a strong magnet bend series with the aim of targeting the beryllium area that produces
neutrons after an interaction. The uniqueness of this neutron makes it only available in the US at
three locations. Its utility has made it possible to treat more than 3100 people. The figure below
is an illustration of the relative efficiency of neutrons and photon therapy. For one to reduce the
tumor cells number to 0.001 fractions of the previous number, a photon dose of 28 grays as
opposed to the 7 gray of the neutron is necessary as stated by Barth et al. (2012). The reduced
ADVANCEMENTS OF PROTON THERAPY 20
grays indicate that the neutrons are more efficient four times than photons in eradicating the
cancer cell.
Figure 7: Survival of cancer cell
Source: https://www.sciencedirect.com/topics/medicine-and-dentistry/cell-survival-curve
The neutron has high effectiveness on ACC type of cells, unlike other cancer types. It has
successfully destroyed the cancer of the salivary gland, the inoperable sarcomas, adenoid-cystic
carcinoma and prostate cancer. It also can ruin tumors of the neck and the head and with it,
comes with other advancements in this research that provide other alternative measures to cancer
eradication.
2.4 Heavy ion carbon therapy
Application of this treatment is based on an essential principle of acquiring the exact dose
localization in the targeted area. At the same time, it aims at decreasing damage to the tissues
surrounding the tumor. Therapy of charged particles containing carbon ions and protons
facilitates high deposition of localized energy utilized for raising the radiation doses to the target
area while reducing irradiation to the adjacent healthy cells as shown below. Moreover, the
beams of the carbon ions have some biological merits concerning reduced oxygen facilitation