DISSO 4.1 (1)

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A Meta-Analysis of Proton Beam Therapy (PBT) and
Intensity-Modulated Radiation Therapy (IMRT) in the
Treatment of Prostate Cancer’.
Presented to the Faculty of Life Sciences
Anglia Ruskin University
Cambridge
In partial fulfilment of the requirements for
the Bachelors (Hons) of Science in Biomedical Sciences
By
Omar Naveed
April 2016

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I would strongly like to thank Don Keiller,
for the guidance, motivation and encouragement
I needed to finish my thesis.

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Table of Contents
Introduction .………………………………………………………………………….4
I. Prostate Cancer……………………………………………….……………....4
II. Proton Beam Therapy……………………………………………….………..9
III. Intensity-Modulated radiation therapy …………………………………….13
IV. Null Hypothesis ………………………………………………………………15
V. Alternative hypothesis ………………………….……………………………15
VI. Aim…………………….………………………………………………………15
Methodology………………………………………………………………………….16
I. Data sources………………………………………………………………….16
II. Criteria of selection……………………………………………………..……17
Results …..……………………………………………………………………………19
I. Fox plott…………………..………………………………………………….19
II. t- test……………………………………………….…………………..……...21
III. error bar graph………………………………………………………………21
Discussion…………………………………………….……………………………….23
I. Toxicity of PBT and IMRT…………………………………….……………26
II. Cost of PBT and IMRT………………………………….…………….……..27
III. Cancers Treated with PBT…………………………………….…………….28
IV. Future of PBT ………………………………………………….………….....29
Conclusion……………………………………………………………….…………….29
Acknowledgement……………………………………………………….……………31
References……..……………………………………………………..……………….31

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Introduction
Prostate Cancer (PC)
Prostate cancer is a prevalent malignant disease in males and a main cause of death in
the UK. According to the Cancer Research U.K. they estimated approximately 47,000
new cases of diagnosed patients and >11 thousand deaths annually. This is an
overwhelming 130 new cases diagnosed every day. Worldwide prostate cancer has
been estimated to occur in approximately 1.11 million men; an estimated 1 in 8 men
will be diagnosed with prostate cancer throughout their lifespan. PC also known as
adenocarcinoma, or glandular cancer which is characterized by semen-secreting
prostate gland cells that are highly sensitive to suffering mutations. Initially, small
groups of cancer cells remain confined, these are known as carcinoma in situ and
Prostatic intraepithelial neoplasia (PIN), (Costello and Franklin, 2014). The
developmental progression of these cancerous cells involve its spread to neighbouring
prostate tissue known as the stroma. In addition, the tumour may invade nearby
organs including the seminal vesicles or the rectum and enter the bloodstream and
lymphatic system affecting other regions in the body such as bones and lymph nodes.
This process is known as metastasis (Gundem et al., 2015). Furthermore, prostate
differentiation as well as prostate cancer growth and progression are dependent upon
androgen receptor (AR) signaling; which is encoded by a single copy gene situated at
Xq11.2-q12, (Velcheti et al., 2008). This protein consists of approximately 919 amino
acids in length. The length of polyglutamine repeats may vary between 18-22 repeats.
However, long repeats (>40) has been largely related with developing prostate cancer
(Velcheti et al., 2008).
The role of Z1P1 in prostate cancer
Study by Christudoss et al., (2011), shows that ZIP1 is accountable for the active
transport of zinc into prostate cells. The importance of zinc is to simply help the cell
metabolize citrate, an important component of semen. In this process prostate cells
typically use enormous amounts of energy (ATP) in order to accomplish this task.
Prostate cancer cells generally lack zinc resulting in its growth and spread. The lack of
zinc occurs through silencing of the gene that produces the transporter protein ZIP1.

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ZIP1 is a tumour suppressor gene product for the gene SLC39A1. Furthermore,
Costello and Franklin, (2014) shows that downregulation of Z1P1 and decreased zinc
are evident in PIN. Recent study by Song and Ho, (2014) shows that Zinc maintains
DNA integrity by modulating the expression effects of zinc on the inhibition of
terminal oxidation, induction of mitochondrial pathogenesis, and suppression of
NFκB activity. In the event of zinc depletion in prostate epithelial cells (PrEC), p53
becomes compromised, hence DNA repair is ineffective, thus leading to compromised
DNA integrity.
The role of P13k & Akt in prostate cancer
Protein kinase B (Akt), is a downstream effector of phosphatidylinositol 3-kinase
(PI3K). It is often implicated in prostate cancer. Study by Gosh et al., (2003) shows
that Akt activation is vital for the progression of prostate cancer to an androgen-
independent state. In their study they found that Akt phosphorylation is accompanied
by the inactivation of ERK, a member of the mitogen activated protein kinase (MAPK)
family. Furthermore, PI3k/Akt signaling cascade is involved in transforming growth
factor beta/SMAD signaling cascade to ensure prostate cancer cell survival and
protection against apoptosis.
Autophagy Cell Death in prostate cancer cells
The mechanism of autophagy in cancer cells are directly mediated by the Beclin1
protein which is encoded by the BECN1 gene (Fig. 1), which in turn modulates the
signaling pathways, that autophagy is directly involved (Focaccetti et al., 2015).

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Nuclear factor-κB(NF-kB) signalling pathway in prostate cancer
The NF-κB includes, NF-κB2 p52/p100, NF-κB1 p50/p105, c-Rel, RelA/p65, and
RelB; which plays a fundamental role at regulating the expression of genes. For
instance, NF-κB cooperates with multiple other signaling molecules and pathways
(Fig. 2) (Hoesel and Schmid, 2013).
Autophagosom Formation
Ambra1 Vps34
Atg114L Vps15Beclin-1
Atg14L Complex
Autophagosome
Maturation RubiconBif1
Ambra1Vps34
UVRAGUVRAG
Ambra1
Vps34
Vps15 Vps15Beclin-1Beclin-1
Rubicon-UVRAG
Complex
UVRAG Complex
FUSION
Lysosome/Endosome
Figure 1. Regulatory function of three Beclin1 containing complexes in different stages of autophagy.
There are three class III PI3K complexes that are involved in autophagosome formation and maturation.
The Atg14L complex (Beclin1–hVps34–Atg14L) functions in autophagosome formation. The UVRAG
complex (Beclin1–hVps34–UVRAG) required for the maturation of autophagosome, while Rubicon–
UVRAG complex (Beclin1–hVps34–UVRAG–Rubicon) negatively regulates this process (Self- made
adapted form) (Focaccetti et al., 2015).

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NUCLEUS
BAFF-R;
CD40; BLys
Ras Kinase
HTLV
EGF
TCR/BCR
TNFR
TLRH2O2
Heat
Shock
PKCMyD88TAX
TRAF3 EGFRRaIB
TRADD/TRAF2
P38
SyK
NIK
TBK
CK II
TAK 1
EGFR
IKKα
IKKy
IKKα
IKKβ
GRB2
NFKB
P100/RelB
P50/P65
➢ Survival
➢ Proliferation
➢ Inflammation
➢ B-cell maturation
P52/RelB P50/p65
Figure 2. Activation of NFKB signaling pathway in ccRCC. Signaling and activation directly linked
TAK1, IKK and P50/P60. Active NF-κB/Rel complexes are further activated by post-translational
modifications(phosphorylation,acetylation,glycosylation)andtranslocatetothenucleus.Sulforaphane
could potentially be used as a therapeutic agent. (Self- made adapted form) (Grivennikov, 2010).

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Proton Beam Therapy
Energised proton particles
Intrinsic Pathway
Extrinsic Pathway
CD 95L TRAIL
CD95 Receptor TRAIL Receptor
FADD
FADD
Bax
Bid
BCL 2
Caspase 9
Caspase 8 Caspase 8
Cytochrome C
Apaf 1
SMAC/ DIABLO
CASPASE 3 IAP
AIF
CAD, ICAD, DFF45
APOPTOSIS

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Mitochondrial- inducing cell death via Proton beam therapy
The mitochondrial apoptotic pathways and signal-transducing molecules are characterized by
death receptors including, CD95 (APO-1/Fas), TNF receptor 1 (TNFRI), TNF-related
apoptosis-inducing ligand-receptor 1 (TRAIL-R1) and TRAIL-R2 are largely involved in
killing tumour cells in response to Proton beam therapy (Stanley et al., 2013). It essentially
triggers an increase in CD95L expression, which is mediated by an activation of NFkB and
transcription factor activator proteins (AP-1) (Fulda and Debatin, 2006). Seen in (Fig. 3).
Proton Beam Therapy (PBT)
Robert R. Wilson, a professor of physics, who was the designer of the Harvard cyclotron, first
introduced the idea of killing cancer cells by using protons. This idea was then confirmed by a
large scale study on protons by Berkeley Radiation Laboratory (Sugerman andLivingston,2014).
In 1998, the National Cancer Centre Hospital East (NCCHE) introduced proton facilities for
the application of clinical use in the treatment of prostate cancer (PC) (Jones, 2016). The proton
boost therapy were then employed in 2001 and the trial protocol has been approved by the
institutional review board (Nihei et al., 2005). The highly discussed and topical concept of
proton beam therapy (PBT) for prostate cancer fueled discussion in the euro-oncological
community questioning its superiority to photon therapy regarding local control, patient
survival, better tolerance to side effects and the continuous of the therapy inquired by patients
(Habl and Debus, 2015). Currently, there are ongoing trials for proton therapy for prostate
cancer and emergence of its biological and clinical data (Schiller et al., 2016).
Figure 3. Mitochondrial apoptotic signaling pathways induced Energized Proton beam
particles. CD95 (APO-1/Fas) and TNF-related apoptosis-inducing ligand (TRAIL) results in
receptor aggregation and recruitment of the adaptor molecule Fas-associated death domain
(FADD) and caspase-8. Following recruitment of caspase-8 which essentially leads to the
activation of caspase-3 through formation of the Cytochrome C/Apaf-1/caspase-9-containing
apoptosome complex. (Self- made adapted) (Fulda and Debatin, 2006).

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A proton beam is created by a cyclotron or synchrotron that isolates the proton from
a hydrogen particle and speeds it up. Thevast massand vitality provides the increasing
speed framework giving protons a particular energy that transport them into a body.
Once the protons are in the body, its speed is reduced due to its mass, charge and
interactions and eventually come to a stop at a certain depth. This is the point where
collaboration mostly occurs with encompassing electrons, causing radiation damage
to the target DNA and generating particle ionization. This ability of proton stopping at
a particular distance can be controlled based on their energy and the depth of
accumulation in the tumour (Fig5b). In contrast, x-rayscontinue to deposit radiation
doses through the target area, damaging nearby healthy tissues and increasing
exposure to side effects (Wisenbaugh et al., 2014).
Proton therapy referred to as proton beam therapy (PBT) have been utilised for clinical
purposes for more than 50 years in the treatment of spinal cord, brain, breast, prostate cancers
and noncancerous diseases. There are number of studies which reported the ability of proton
therapy to spare surrounding healthy tissues however, other studies argued and criticised the
cost-effectiveness of such treatment therefore its use on cancer treatment has not been validated
in comparison with photon therapy (Reiazi et al., 2015). Furthermore, small volumes are
treated and the treatment times are low which led to hypothesised high patient throughput
therefore it should not form the basis of medical decision-making.
Traditional radiation therapy uses photons and electrons particles directly at tumours with the
intention of neoplastic tissue eradication whilst adjacent and surrounding normal tissues are
preserved (Levin et al., 2005 and Sugerman and Livingston, 2014). However, radiation dose
delivered poses serious problem such as the concern for the occurrence of second malignancies
within healthy tissues and other various side effects (Jones, 2016). A form of charged particle
therapy, the proton beam radiotherapy has no exit dose benefit and it function through excellent
dose distribution to neoplastic tissue. With this characteristic, it allows excellent choice of
tumour treatment within its vicinity and avoiding affecting the important organs of the body
such as the brain, spinal cord and especially pediatric malignancies (Levin et al., 2005 and
Anon, 2007).
Similarly to a standard x-ray radiation therapy, PBT is a type of external-beam radiation
therapy which emits painless radiation through the skin (Main, 2016). The mechanism
of radiotherapy (RT) targets the localized PC whilst ensuring minimum application of possible

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dose to surrounding tissues such as bladder and rectum, therefore side effects and toxicities to
patients are avoided (Schiller et al., 2016). The intrinsic physical properties of PBT makes
its utilization appealing in therapeutic radiation oncology (Blanchard et al. 2012).PBT
is an attractive form of therapy due to its physical ability to maintain highly conformal
target distribution dose particularly to the tumour while minimizing dose to
surrounding normal tissues (Chen, 2011). Also, in comparison to photons, the dose
distribution properties of protons are entirely different and the ability to avoid extra-
target radiation which is inherent to photons. Due to the heavier mass of proton
weighing roughly 1800 times of an electron, it confers particular dosimetric
advantages, hence in comparison to photons, heavy particles such as of proton have
the ability to stop within target tissue (Wisenbaugh et al., 2014).
Currently, the favorable treatment in radiotherapy for prostate cancer is photon therapy. Due
to no charge and no mass of photons, it can easily travel to the target tissue. Initially, the
photons increases their energy while interacting with the target material electrons (the body),
thus enhancing the effect of the radiation. This results to “dose accumulation effect” which
means that the entrance surface is reached by the peak dose within few centimeters. As the
dose goes further subsequently through the body, the radiation dose drop-offs after energy
deposition until there is no dose delivered to normal tissues beyond the Braggpeak eventually
exiting the body (Diallo et al., 2009, Nihei et al., 2005 and Chen, 2011). Therefore, PBT
provides better option as radiation dose is safely escalated due to reduced scatter and exit dose
in comparison to photons (Chen, 2011). Furthermore, proton beams have a sharp Bragg
peak; with low energy before the peak and almost zero energy after the peak (Nihei et
al., 2005). Therefore,in proton beam therapy (PBT),normal tissue around thetumour
receives a reduced dose compared to photon radiotherapy, and this is especially
beneficial for pediatric tumours or tumours adjacent to normal tissue for which
irradiation should be strictly avoided (Mizumoto et al. 2016).
The ‘Bragg peak’ refers to the physical depth dose characteristic of charged particles which
can spread out, shaped and conform the volume and depth of an irregular target (Nihei et al.,
2005) (Fig. 4). In addition, recent studies which conducted long term follow up found
that PBT has the ability to reduce rate of secondary malignancies (Sethi et al., 2014).
The tumour control is similar to photon therapy however, latent toxicity and
secondary malignancies is lower due to lower distribution of dose (Mizumoto et al.
2016).

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Due to the different field plans, helical techniques and rapid arc, the doses are significantly
smaller (Kosaki et al., 2012). Gastrointestinal (GI) and genitourinary (GU) are the possible side
effects and may potentially increase risk occurrence of secondary malignancies (Paganetti,
2012) therefore, the photon radiation therapy in terms of its physical characteristic is seemingly
inappropriate in targeting the organs located at a great depth. Studies on multiple dose
escalation demonstrated that by increasing the radiation dose for PC treatment lead to better
biochemical disease-free survival and less clinical failure rates (Chen, 2011).
In addition to the risk of second malignancies developing, this depends on multifactorial
reasons such as dose distribution and volume irradiate as solid cancers are generally found near
or within the primary field of treatment (Diallo et al. 2009). Close distance from the primary
cancer or tissue can also lead to soft tissue and bone sarcoma (Rubino et al. 2005). On the other
hand, Ron et al. (1988) suggested that low doses distributed further outside the dose field have
been linked with the development of second malignancies.
Furthermore, the effect on tumour control with the use of proton therapy is likely similar to
electron or protons however, the dose on significant tissues such as the lung and the heart may
considerably be reduced in order to prevent the future development of very low toxicity
(Gagliardi et al., 1996). A study conducted by Nihei et al. (2005) found that longer exposure
to proton treatment was impractical which may partly due to the development of second
malignancies and complications after the initial treatment. TheRadiation Therapy Oncology
Group (RTOG) conducted studies in the evolution of the safety and efficacy of high-
dose irradiation for prostate cancer using IMRT or 3D-CRT (Zelefsky et al., 2001 and
Michalski et al., 2003). A single proton beam had different type of doses: no exit dose, a
maximal dose at a user-defined depth and low entrance dose. Therefore, proton beamtherapy
(PBT) can create 3Dconformal dose distribution within defined radiation track length
without virtually (Main et al. 2016) emitting extra dose to nearby or surrounding
normal tissues and the probability of cure in comparison to conformal photon
radiotherapy (Archambeau et al., 1974).

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Figure 4. Beam dose distribution and depth-dose characteristics of proton and
photon beams. The example proton beam is of a higher energy than the SOBP for
clarity.

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Figure 5a and 5b. (a) Dose distribution of dynamic conformal photon therapy. (b)
Dose distribution of proton boost therapy. Lateral opposed portals using proton
beam can provide good dose coverage to the prostate and reduce the unnecessary
irradiated volume of both the ventral and dorsal portion of the body. Isodose lines:
orange, 105%; magenta, 100%; yellow, 95%; light green, 90%; light blue, 80%; light
purple, 50%; purple, 20%. Red line shows the planning target volume (Nihei et al.,
2005).
Intensity-Modulated RadiationTherapy (IMRT)
Intensity-Modulated radiation therapy (IMRT) is a fast past technological advancement in the
treatment of cancer in comparison to current treatment which uses 2D technology. However,
it is more expensive in the method of delivering radiation therapy in order to minimize toxicity
(Beadle et al. 2014). Cancers are treated with radiotherapy that uses invisible high-energy x-
rays and other rays such as electrons. IMRT encompasses various techniques referred to as
“inverse planning” that represents the core change.
It has been 20 years since the first child was treated with IMRT(Paulino, 2016). The
utilization of IMRT innovation for the treatment of PC has diffused quickly over the
previous decade, and is currently the standard sort of radiation used to treat this
cancer(Paulino, 2016). It is also creating popularity within oncology community as it
similarly uses radiation dose like proton beam therapy in the treatment of cancer. IMRT is a
stereotactic radiotherapy which utilities multiple fields and angles to locate target such as of
tumour tissues (Wai, 2015). Due to the range of clinical concerns and radiobiological
surrounding this particular therapy, the potential for increased dose and daily increase of
fraction size to the gross of cancer makes the administration of the cancer therapy
discouraging.
The advancement of conformal radiotherapy technique IMRT is the ability of the radiation
intensity across each radiation to be varied enabling more control over distribution of dose
to the objective range. Also, it specifically allow the conformation of high dose region to
create a concave shape to avoid critical damage to other organs in the body (Chiappiniello et

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al, 2016). By controlling and modulating the intensity of radiation beam in multiple small
doses it allows radiation dose of IMRT to conform three-dimensional (3-D) share more
precisely of the tumour tissue. The three-dimensional (3-D) computed tomography (CT) or
MRI images of patients in conjunction with computerized dose calculations aid in the careful
planning in order to determine intensity dose pattern that willbe ableto successfullyconform
to the shape of the tumour tissue and will predict the treatment plan that best satisfies the
constraints (Maddock, 2006). In routine radio therapy, for a six-field 3D conformai plan
for malignancy of the prostate every treatment would take roughly thirty minutes, just
five or six minutes of which was real radiation introduction. Every treatment utilizing
IMRT should be possible within fifteen minutes (Maddock, 2006).
In comparison to conventional radiotherapy techniques, IMRT is more effective as it
administers safe dosage to tumours resulting to lesser side effects. The potential of IMRT to
reduce treatment toxicity are one of its advantages while doses are minimal (Chiappiniello et
al, 2016). In addition, compared to the conventional radiotherapy, IMRT is complex as it
requires longer daily treatment times, safety checks before patient can start initial treatment
and additional planning is needed. In regards to daily treatment, it takes longer as machine
on-time is increased. Therefore, penetration of addition photons through or scattered by
gantry head shielding by patients as total-body dose (Wai, 2015). Typically, leakage dose is
considered of minimal risk. IMRT prevents division and growth of cancers cells thus, slowing
down tumour growth. There are majority of cases where radiation therapy is able to kill all of
the cancer cells therefore eliminating or shrinking tumour cells. The whole-body exposure is
significantly increased in IMRT (Goffman and Glatstein, 2002).
The goal of IMRT is spare normal tissues, however its ability to provide more conformal dose
distributions has allowed increased dose to tumour volumes and accelerated dose delivery.
It has been widely accepted that high-dose areas receive created than 2 Gy per fraction
which is the standard with non-IMRT conventional therapies (Nutting et al., 2011,
Eisbruch et al., 2010 and Lee et al., 2009). IMRT has reduced tumour volumes in
locally recently developed non–small cell lung cancer, proctitis in prostate cancer, and
xerostomia in head and neck cancer (Paulino, 2016).
Lockney et al. (2011) found that latent toxicities were recurring even with the use of
IMRT. Three-fourths of the patients developed facial disfigurement, while one-third

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developed growth hormone deficiency, dental problems, or cataracts. No secondary
malignant solid tumours occurred, however one patient developed acute myeloid
leukemia and another had myelodysplastic syndrome. It has been reported that IMRT
is beneficial in children with other types of tumours. Grade 3 and 4 ototoxicity in
medulloblastoma incidence has been reduced from 64% using 2D radiotherapy and
25% with IMRT (Paulino et al., 2010).
Hypothesis:
Null hypothesis
H0: Proton Beam therapy (PBT) and Intensity-Modulated radiation therapy (IMRT) are both
equally effective in the treatment of prostate cancer (PC).
Alternative Hypothesis
H1: Proton Beam therapy (PBT) is a better treatment for prostate cancer in comparison to
Intensity-Modulated radiation therapy (IMRT).
Aim: To identify which has greater toxicity and side effects by means of therapy
between PBT and IMRT in the treatment of prostate cancer (PC).
Methodology
This study was performed using meta-analysis which involved an in depth study and analysis
of data from journals and articles in association between the proton beam therapy (PBT)
and intensity-modulated radiation therapy (IMRT) in the treatment of prostate
cancer.
Data sources
The strategy employed to performed the meta-analysis project is through scientific websites
containing database of peer reviewed journals and articles from certified scientific websites
containing database of
• PubMed

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• BritishJournal of Cancer
• Japanese Journal of Clinical Oncology
• International Journal of RadiationOncology
• Radiology
• IranianJournal of Cancer Prevention
• Acta Oncologica
• The BritishJournal of Radiology
• Cancer Research UK
• Cancer Biology &Therapy
• PLOS One
• Oncogene
• CurrentDrug Metabolism
• Cell
• Nature
• CurrentOpinion inClinical NutritionandMetabolicCare
• MolecularCancer
• Science Translational Medicine
• The OchsnerJournal
• La radiologiamedica(Radiol Med)
• HealthPhysics
• The New EnglandJournal of Medicine (NEJM)
• Oxford University Press (Journals)
• The Journal of Clinical Endocrinology &Metabolism
• Journal of the European Society forMedical Oncology
• Journal of the National CancerInstitute
• Journal of Clinical Oncology
• The Journal of Radiation Research
• SystematicReviews
• Physics inMedicine andBiology
• Radiotherapy &Oncology
• Cancer Medicine

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• Cancer
• Reviews inUrology
• Radiation Research
• Wiley Online Library
• The Lancet Oncology
• PharmacoEconomics &Outcomes News
• Journal of ProtonTherapy (JPT)
• JAMA
• WorldHealthOrganisation (WHO)
Criteria of selection
The method of journal extraction in order to identify the eligibility criteria of articles and
journals is according to the aim of the study. Through the use of inclusion and exclusion, it
helped determine whether the journals containing the information are of great significance and
are vital to achieve the aim that the study has undertaken. It is paramount that each journals
and articles are reliable and credible as this would affect the fate of the results by adhering to
the ‘checklist’ below presented in bullet points. By creating a standardised form for data
collection, it created a structure for the research of journal extraction organised, straightforward
and time efficient. The standardised form that were executed is a tabulated spreadsheet which
contained various segments: authors, publication year, and journal title and journal website
link. Carefully chosen search terms are also used for specificity of journals and articles such as
proton beam therapy (PBT).
By creating a list of how the data or information are selected, it generated a constructed plan
in the selection of suitable materials and data for the project as demonstrated below:
• Journals on cancer in general.
• All the journals on prostate cancer.
• Recent journals within past 10 yrs.
• Journals on Proton Beam Therapy
• Journals on Intensity Modulated Radiation therapy (IMRT)
• Journals with cost of PBT and IMRT
• Journals on cancers treated by PBT

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• Journals including countries offering proton therapy
• Journals on toxicity of radiotherapy
• Journals on side effects and risks of PBT and IMRT
• Journals on the efficiency of PBT and IMRT
• Journals linking PBT and/or IMRT in the treatment of prostate cancer.
• Journals on the epidemiology of individuals affected by cancer, in particular PC
The search terms included: PBT and/or proton beam therapy, IMRT and/or intensity-
modulated radiation therapy, radiotherapy, proton therapy, photon therapy, x-rays, radiation
to cure cancer, prostate cancer, risks of radiation exposure, cancer,
The statistical analysis used was Forest plot and the effect size chosen are relative risk (RR).
The relative risk is chosen as effect size due to the four articles which provided similar RR
values which is easier to calculate and present. The forest plot was chosen to present the data
from the four articles as it provided graphical representation of a meta-analysis including the
list of the authors and date providing detailed and simple presentation of data found. T-test
were also used to compare the effectiveness of PBT and IMRT treatments and whether to reject
or accept the null hypothesis and/or alternative hypothesis. The error bars are used to indicate
uncertainty of the measurement and they provide precise measurement for reliable and valid
data.
Results

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Figure 7. T-test of the effectiveness of PBT and IMRT is used to show
similar or different variability between scores. From the result of
Levene’s Test for Equality of Variances it shows that p < 0.05 therefore
the two treatments have unequal variances or significantly difference.
The Sig (2-Tailed) value is 0.463 therefore no statistically significant
differences between means of the two treatments. Therefore, the null
hypothesis is rejected as there is no difference in the variances between
groups.
Figure 8a and 8b. Error bar graphs representing mean ±2 SE intervals and the 95% confidence
intervals. The standard error (SE) bars overlap graph 8a and 8b, therefore the difference between the
two means is not statistically significant (P>0.05).
*N = 2, T = -0.899, N = 2, P = 0.163 for IMRT and 0.522 for PBT.
8a 8b

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Table 1. Comparison of PBT and IMRT on morbidity and disease control
in localised PC, patterns of care and early toxicity and two case matched
with N value, group value, outcome, standard error (SE) value, variance
and weight value in different columns.
Title N group Outcome- Standard error
(SE)
Variance Weight
Intensity-Modulated
Radiation Therapy, Proton
Therapy, or Conformal
Radiation Therapy and
Morbidity and Disease
Control in Localized Prostate
Cancer. 12976 1368 0.105 0.0028 0.001 123082.292
Proton Versus Intensity-
Modulated Radiotherapy for
Prostate Cancer: Patterns of
Care and Early Toxicity
27647 553 0.02 0.001 0.001
1382200.01
6
A case-matched study of
toxicity outcomes after
proton therapy and intensity-
modulated radiation therapy
for prostate cancer
394 213 0.541 0.037 0.001 728.807
A case-matched study of
toxicity outcomes after
proton therapy and intensity-
modulated radiation therapy
for prostate cancer
394 181 0.459 0.034 0.001 857.657
Efficacy using PBT & IMRT
P.B.T has a significantly reduced radiation dose drop-off in adjacent tissue. Trofimov
et al, (2007) established the delivery dose range to be 68 – 79 GCE (Cobalt Gray
Equivalent) for P.B.T in contrast to 35 – 59 GY dose for I.M.R.T. This is further
confirmed by the Bragg peak. Based on this evidence and further information

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presented by (FIGURE?) the N.H.S, should strongly consider the application of this
therapy in the U.K.
The 95% CI show no significant trend. However, there is a statistically significant
difference in the variability scale between I.M.R.T and P.B.T, meaning that the
recurrence rate for I.M.R.T is significantly higher than for P.B.T. This is supported by
the clinical trials conducted via the National Association for Proton Therapy, (2014).
showing that 97% of patients with prostate cancer displayed no signs of recurrence.
This is a significant result which should be highly considered by the N.H.S. Table one
highlight key points regarding the treatment of prostate cancer using PBT and IMRT.
Discussion
The result gathered from Figures 6, 7 and 8 showed no statistically difference when comparing
PBT and IMRT treatment for prostate cancer (PC) therefore it agrees with the null hypothesis
(H0) which stated that proton beam therapy (PBT) and intensity-modulated radiation therapy
(IMRT) are both equally effective in the treatment of prostate cancer (PC). However, Fig. 6
presented that the treatment PBT is favoured by the four studies in comparison to IMRT. This
in effect agrees with the alternative hypothesis which states that PBT is a better treatment
compared to IMRT.
In general, radiation treatment may cause damage to the organs adjacent to the prostate which
can lead to long term urinary and gastrointestinal morbidity, hip fractures and erectile
dysfunction. There are data in the past 10 years which demonstrated that long term risk of
morbidity is directly linked with the radiation dose received by each organ (Michalski et al.,
2010, Roach et al., 2010 and Fiorino et al., 2009). Hence, the development of dose guidelines
for rectum and bowel, bladder and femoral heads which are widely used and standard operating
procedure of radiation treatment (Sheets et al., 2012). In addition, there are no consistent
association found between radiation dose and structure and erectile dysfunction therefore dose
guidelines is not developed (Roach et al., 2010).

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The study by Sheets et al. (2012) found no significant difference in PBT and IMRT treated
patients in incontinence diagnoses, hip fractures and erectile dysfunction. There were no
statistically significant difference in the gastrointestinal and other toxicity found between PRT
and IMRT post treatment of 6 or 12 months. Previous studies found that the distribution of
radiation dose is improved in PBT compared with IMRT whereby the amount of bladder
exposed to low and intermediated levels of radiation is reduced (Trofimov et al., 2007 and
Mock et al., 2005). Early toxicity is predicted by the amount of low doses to which the bladder
is exposed to (Karlsdottir et al., 2004). Also, the radiation reduced to the bladder may be
accountable for the temporary improvement in 6 months toxicity with PRT/PBT. In addition,
PBT treated patients have higher chance of being diagnosed of gastrointestinal related disease
and undergo for the disease related procedure. Another recent study also found higher
gastrointestinal morbidity rates in PBT treated patients (Kim et al., 2011) relative to IMRT
patients. Studies by Sheets et al. (2012) and Kim et al. (2011) noted a statistically significant
reduction of gastrointestinal toxicity for patients undergoing IMRT compared with PBT. This
may be due to the higher vulnerability to organ movement of PBT which can lead to unintended
higher dose to the rectum in comparison to IMRT. It is unknown whether greater image
guidance may reduce gastrointestinal morbidity (Sheets et al., 2012). On the other hand,
patients receiving IMRT are less likely to be diagnosed of gastrointestinal morbidity, hip
fracture and less likely to receive additional cancer therapy, however more likely to receive
diagnosis of erectile dysfunction.

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Figure 9. Rates of the probability of additional treatment in cancer patients months after
treatment of Intensity-Modulated Radiation Therapy vs Proton Therapy (Sheets et al.,
2012).
Furthermore, there is only a small association in the reduction of genitourinary toxicity at 6
months post-treatment of patients that received PRT (PBT) compared to IMRT, however at 12
months no difference were found (Fig. 9). Although overall, the rates of additional cancer
therapy showed no statistical differences between the two comparative treatments (Fig. 9). In
Fig. 6, Fang et al. (2014) found no statistical difference between PBT and IMRT using the
variables late clinical gastrointestinal (GI) and genitourinary (GU) toxicities in patients with
prostate cancer who received PBT versus IMRT. Although this study measured two particular
variables in comparison to the three studies that were used in the forest plot, Fang et al., (2014)
found no GI and GU toxicity by comparing PBT and IMRT.
The probability of additional treatment of IMRT and PBT is similar after 38 months, however
the probability of additional treatment begins to dramatically increase after 40 months of
IMRT. A high peak of the probability of additional treatment after IMRT occurs within 5 years
onwards compared to PBT which remains constant (Fig. 9). Therefore, recurrence of PC is
higher in IMRT than PBT. This is further supported by Fig. 6 which ultimately favored PBT
treatment to IMRT.
Currently, the lack of data regarding on the patterns of use and actual cost of PBT hinders its
development and application. However, PBT slowly disseminating and as a result there are
now nine PRT centers in place in the United states and Table 2. shows countries which
currently provided proton therapy.
The study by Yu, et.al. (2012) has some limitations such as the lack of few patient-reported
outcome data and treatment-related information, no knowledge regarding the radiation dose
and field size where IMRT patients may have received higher radiation dose which could
provide an explanation in the observed increase in 6-month toxicity. It is important that a
longitudinal study regarding comparison of both treatments should take place before
widespread application of PRT/PBT for further justification in the treatment of prostate cancer
(Yu et.al., 2012).
There are new postulated treatments for treating prostate cancer which is convincing such as
minimally invasive prostatectomy and IMRT. However, the lack of data comparing new
against older treatment outcomes proves it difficult for the development of the newer
treatments (Sheets et al., 2012). Despite the high-cost prostate cancer treatment and the high

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profile of proton therapy, there have been an increased in the development of building multiple
proton facilities in which direct-to-consumer advertising is likely to lead to a large increase in
its utilization (Schippers et al.,2011 and Institute for Clinical and Economic Review, 2007).
PBT & IMRT toxicity
The side effects observed were gastro-intestinal(GI) and gastro-urinary(GU) morbidity, erectile
dysfunction, and hip fractures (Sheets, et.al.,2012) (Yu, et.al., 2012) (Fang, et.al., 2014). Both IMRT
and PBT showed these complications. Taking all the variables in consideration, Fang, et al., 2014, test
showed no significant differences of number of patients suffering from acute GI nor GU toxicity with
patients after treated with PBT or IMRT for PC. Fang, et al,. 2014 also proved there is the same risk of
late GI and GU toxicity in patients going through PBT and IMRT, taking all variables in consideration,
PBT did show a minute decline of other complications, the findings on toxicity was compared with cost
from reimbursement per patient and PBT was 1.7 times that of IMRT. (Yu, et.al., 2012). Sheets et al
(2012) results also showed roughly the same number of complications and stated “The potential
advantage of proton therapy compared with IMRT is unclear.”
As aforementioned, the various side effects can immediately appear and some can occur latent
or later in life without the patient’s knowledge. Histologically, radiation-induced tumour shows
differently in comparison to the existing disease. The typical latent stage for a radiation-
associated tumour is several years and cancer patient survivors remain at an increased risk of
developing secondary malignancies even after 30—40 years after initial radiation treatment
Chaturvedi et al. 2007). Minniti et al. (2005) and Kuttesch et al. (1996) performed an over 25
year follow up and estimated that the cumulative risk of radiation therapy is 2–11% in patients.
There is a possibility of increased risk after ~10 year of other tumour types such as non-
Hodgkin’s lymphoma and acute nonlymphomatic leukemia and others has even higher risk of
more than 20 years after radiation therapy (Foss Abrahamsen et al. 2002). Therefore, latency
stage may not possibly exceed paediatric patients’ life expectancy in particular. Younger
patients are of more increasing concern of developing second malignancies ((Neglia et al. 2006
and Ron, 2006). An ongoing institutional retrospective study, The Childhood Cancer Survivor
Study presented over 14,000 cases (Bassal et al. 2006; Ronckers et al. 2006 and Armstrong et
al. 2010, 2011). In addition, the use of photon treatment led to significant side effects such as
the high risk of cardiac disease in women which account to 43% higher than the general
population and radiation pneumonitis (Lundkvist et al., 2005 and Rutqvist et al., 2003).
The dose-response relationship in irradiating prostate cancer have previously been reported
with a higher dose >70 Gy (SI unit of absorbed radiation) had shown potential benefit for

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prostate cancer (Perez et al., 1980, Hanks et al., 1988 and Schiller et al., 2016). However, other
studies revealed that conventional radiotherapy techniques drastically increased rectal
complications at >70 Gy (Pilepich et al., 1987, Hanks, 1988 and Schiller et al., 2016). This type
of technique which aim to eradicate prostate cancer pivoted its clinical use to the development
of numerous techniques which became widespread such as intensity-modulated radiotherapy
(IMRT), three-dimensional conformal radiotherapy (3D-CRT), brachytherapy and charged
particle therapy (heavy ion and proton). These different techniques enable adequate target dose
coverage with minimal dose to the normal tissues surrounding the tumour tissues with
improved tumour control with adequate toxicity (Nihei et al., 2005). Currently, PBT uses three-
dimensional conformal techniques (3D-CPT) to deliver the radiation via passive beam
scattering method (Main, 2016). Several institutions have gradually introduced proton pencil
beam scanning (PBS) technique which allows intensity-modulated proton therapy (IMPT)
delivery which potentially improve target conformity and spare adjacent normal tissues (Clasie
et al. 2012). Also, morbidity may be prolonged after radiation treatment (Slater et al., 1998).
PBT have been recognized to have reduced side effects in comparison with photon therapy.
However, it is expensive, higher cost of therapy facilities and maintenance remain as a concern
for its utilization.
Costs of PBT & IMRT
Outpatient setting is the only way of receiving PBT meaning the only way of means of
treatment is private institutions located in certain areas for exam and does not involve
hospital admittance. A high capital investment is needed for the construction of a proton
facility, and a large area is needed for the size of the facility (Reza, et.al., 2015). The average
cost of a PBT course not including time spent and commuting cost stands at an average of
£90,000 and estimated cost for a IMRT course stands at £10,200 (NHS Private Patient Tariff,
2012; Zelefsky, et.al., 2006). IMRT is covered by most insurance providers and it should also
be noted that insurance provider may not have PBT covered and if they do, patients will still
need to pay a significant amount. Reiazi et al. (2015) concluded that proton therapy in
particular to treat breast cancer could be cost-effective with appropriate risk groups as targets
and is effective in the reduction of future risk recurrence.
The availability of PBT around the world is minute and in the UK is only 2 locations and the
cost for patients commuting and total time spent, is a disadvantage. Were as IMRT is widely
available in most areas in the United Kingdom. As of February 2016, there are 58 medical
centers that offer PBT worldwide, of which none of them are based in the United Kingdom.

of 41
There has been a £250 million investment done on 2 new centers to be established in the
United Kingdom by the government, that are planned to open in 2018 at the Christie Hospital
NHS Foundation Trust in Manchester and University College London Hospitals NHS
Foundation Trust.
Table 2: Examples of randomly chosencountries, which have established medical centers
that currently offer proton therapy.
Country Who, Where Start of Treatment
USA, CA J. Slater PTC, Loma Linda 1990
France CPO, Orsay 1991
Japan NCC, Kashiwa 1998
Germany HZB, Berlin 1998
Russia JINR 2, Dubna 1999
Italy CNAO, Pavia 2011
Czech Republic PTC Czech r.s.o., Prague 2012
Cancers Treated with PBT
PBT has shown to be successful in the treatment of prostate cancer but not all cancers can be
treated. Proton therapy is useful for treating tumours that have not spread and for tumours
near important parts of the body, such as the eye, the brain, and the spinal cord. It is also used
for treating children, because it lessens the chance of harming healthy, developing tissue,
such as retinoblastoma and orbital rhabdomyosarcoma.
Proton Beam therapy can be used to treat these cancers:
 Central nervous system cancers, including chordoma, chondrosarcoma, and malignant
meningioma. (Suneja G, 2013)(Elnahal SM, 2013)
 Eye cancer, including uveal melanoma or choroidal melanoma (Bensoussan E, 2016)
(Sikuade MJ, 2010)
 Head and neck cancers, including tongue and paranasal sinus cancer and some
nasopharyngeal cancers (Takayama K, 2016)(Ishikawa H, 2015)
 Lung cancer (Parikh RR, 2016) (Ishikawa Y, 2016)

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 Liver cancer (Muroi H, 2015) (Kim S, 2011)
 Spinal and pelvic sarcomas, which are cancers that occur in the soft-tissue and bone
(Soldatos T, 2013)
 Noncancerous brain tumors (Verma V, 2016)
Future of Proton beam therapy
The idea that proton beam therapy would revolutionize the treatment of cancer, was firstly
predicted by the American physicist Robert R. Wilson in 1946, who performed extensive
research using proton beam therapy technology. Despite the high costs involved in developing
a proton center and the high costs of treatment using PBT, its efficacy treating prostate cancer
has been highly significant and a major point in further developing the technology. With the
steady rise of prostate cancer worldwide, the need for developing this technology has been
substantially high. Despite its high costs, it has been clear to be beneficial in the long term in
the treatment of cancer, as it has shown to be highly more effective than the latest photon based
therapy the, IMRT. Having said that, PBT is not only helping in the treatment of patients,
improving their 5year survival rate but it is also helping reshape the economy and the N.H.S.
Although theoretically PBT has been seen to cause less damage to normal tissue surrounding
the area of focus. Studies continue to be conducted in order to evaluate the outcomes between
the different modalities, with identification of the appropriate therapy for different kinds of
cancer. Furthermore, the main focus of the N.H.S is to establish P.B.T as a primary form of
treatment for advanced stages of cancer. It has been speculated to be a standardized form of
treatment by 2018.
Conclusion
In conclusion, it is unclear whether proton beam therapy has potential advantage in comparison
to IMRT. Studies on radiation planning demonstrated that PBT relative to IMRT may
significantly reduce the section of each neighboring organ that receives low radiation doses.
However PBT may be more susceptible to errors related to daily patient positioning, setup and
the movement of the organ during treatment procedure. The relative reimbursement of new
medical technologies needs to be considered carefully so that physicians and hospitals do not
have a financial incentive to adopt a technology before supporting evidence is available. PBT

of 41
is very expensive procedure, but evidence does show of its popularity increasing and new
technologies will be introduced to make it less cost effective. PBT and IMRT have equally
shown to work well against prostate cancer, but by reducing the reoccurrence or side effects
because of the therapy, even by a small figure is a step forward for the fight against cancer. On
this basis all governments and private medical centers should invest, for the construction of
proton facilities.
Acknowledgement
I would strongly like to thank Don Keiller for the guidance, motivation and encouragement I needed
to finish mythesis.
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