DISSO 4.1 (1)

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 SciencesAnglia Ruskin University

Cambridge

In partial fulfilment of the requirements forthe Bachelors (Hons) of Science in Biomedical Sciences

ByOmar 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 cancerStudy 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

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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. 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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Autophagosom Formation

Ambra1Vps34

Atg114LVps15Beclin-1

Atg14L Complex

Autophagosome Maturation

Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1

RubiconBif1

Ambra1Vps34

UVRAGUVRAG Ambra1 Vps34

Vps15 Vps15Beclin-1Beclin-1

Rubicon-UVRAG Complex

UVRAG ComplexFUSION

Lysosome/Endosome

Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34

Atg114LAtg114LAtg114LAtg114LAtg114LAtg114LAtg114LAtg114LAtg114LAtg114LAtg114LAtg114LAtg114LAtg114LAtg114LAtg114LAtg114LAtg114LAtg114LAtg114LAtg114LVps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1

Atg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L ComplexAtg14L Complex

RubiconRubiconRubiconRubiconRubiconRubiconRubiconRubiconRubiconRubiconRubiconRubiconRubiconRubiconRubiconRubiconRubiconRubiconRubiconRubiconRubiconBif1Bif1Bif1Bif1Bif1Bif1Bif1Bif1Bif1Bif1Bif1Bif1Bif1Bif1Bif1Bif1Bif1Bif1Bif1Bif1Bif1

Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34

UVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAGUVRAG Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1Ambra1 Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Vps34Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15 Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Vps15Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1Beclin-1

Rubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG ComplexRubicon-UVRAG Complex

UVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG ComplexUVRAG Complex

Nuclear factor- κ B (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).

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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.,

BAFF-R; CD40; BLys

Ras Kinase

HTLV EGF

TCR/BCRTNFR

TLRH2O2Heat Shock

PKCMyD88TAX

TRAF3 EGFRRaIBTRADD/TRAF2

P38

SyK

NIK TBK

CK II

TAK 1

EGFR

IKKα

IKKyIKKαIKKβ

GRB2

NFKBP100/RelB

P50/P65






















BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys BAFF-R; CD40; BLys

TRAF3TRAF3TRAF3TRAF3TRAF3TRAF3TRAF3TRAF3TRAF3TRAF3TRAF3TRAF3TRAF3TRAF3TRAF3TRAF3TRAF3TRAF3TRAF3TRAF3TRAF3

NIKNIKNIKNIKNIKNIKNIKNIKNIKNIKNIKNIKNIKNIKNIKNIKNIKNIKNIKNIKNIK

TAK 1TAK 1TAK 1TAK 1TAK 1TAK 1TAK 1TAK 1TAK 1TAK 1TAK 1TAK 1TAK 1TAK 1TAK 1TAK 1TAK 1TAK 1TAK 1TAK 1TAK 1IKKαIKKαIKKαIKKαIKKαIKKαIKKαIKKαIKKαIKKαIKKαIKKαIKKαIKKαIKKαIKKαIKKαIKKαIKKαIKKαIKKα

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβ

IKKyIKKαIKKβNFKB

P100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelBNFKBP100/RelB

P50/P65P50/P65P50/P65P50/P65P50/P65P50/P65P50/P65P50/P65P50/P65P50/P65P50/P65P50/P65P50/P65P50/P65P50/P65P50/P65P50/P65P50/P65P50/P65P50/P65P50/P65

NUCLEUS

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➢ 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) and translocate to the nucleus. Sulforaphane could potentially be used as a therapeutic agent. (Self- made adapted form) (Grivennikov, 2010).

Proton Beam TherapyEnergised proton particles

Intrinsic Pathway

Extrinsic PathwayCD 95L TRAIL

CD95 Receptor TRAIL Receptor

FADDFADD

Bax

Bid

BCL 2

Caspase 9

Caspase 8 Caspase 8

Cytochrome C

Apaf 1
































































Intrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic PathwayIntrinsic Pathway

CD 95LCD 95LCD 95LCD 95LCD 95LCD 95LCD 95LCD 95LCD 95LCD 95LCD 95LCD 95LCD 95LCD 95LCD 95LCD 95LCD 95LCD 95LCD 95LCD 95LCD 95L TRAILTRAILTRAILTRAILTRAILTRAILTRAILTRAILTRAILTRAILTRAILTRAILTRAILTRAILTRAILTRAILTRAILTRAILTRAILTRAILTRAIL

CD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 ReceptorCD95 Receptor TRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL ReceptorTRAIL Receptor

FADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADDFADD

BCL 2BCL 2BCL 2BCL 2BCL 2BCL 2BCL 2BCL 2BCL 2BCL 2BCL 2BCL 2BCL 2BCL 2BCL 2BCL 2BCL 2BCL 2BCL 2BCL 2BCL 2

BaxBaxBaxBaxBaxBaxBaxBaxBaxBaxBaxBaxBaxBaxBaxBaxBaxBaxBaxBaxBax

BidBidBidBidBidBidBidBidBidBidBidBidBidBidBidBidBidBidBidBidBid

Caspase 9Caspase 9Caspase 9Caspase 9Caspase 9Caspase 9Caspase 9Caspase 9Caspase 9Caspase 9Caspase 9Caspase 9Caspase 9Caspase 9Caspase 9Caspase 9Caspase 9Caspase 9Caspase 9Caspase 9Caspase 9

Cytochrome CCytochrome CCytochrome CCytochrome CCytochrome CCytochrome CCytochrome CCytochrome CCytochrome CCytochrome CCytochrome CCytochrome CCytochrome CCytochrome CCytochrome CCytochrome CCytochrome CCytochrome CCytochrome CCytochrome CCytochrome C

Apaf 1Apaf 1Apaf 1Apaf 1Apaf 1Apaf 1Apaf 1Apaf 1Apaf 1Apaf 1Apaf 1Apaf 1Apaf 1Apaf 1Apaf 1Apaf 1Apaf 1Apaf 1Apaf 1Apaf 1Apaf 1

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 and

Livingston, 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)

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SMAC/ DIABLO

CASPASE 3 IAP

AIFCAD, ICAD, DFF45

APOPTOSIS

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).

SMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLOSMAC/ DIABLO

CASPASE 3CASPASE 3CASPASE 3CASPASE 3CASPASE 3CASPASE 3CASPASE 3CASPASE 3CASPASE 3CASPASE 3CASPASE 3CASPASE 3CASPASE 3CASPASE 3CASPASE 3CASPASE 3CASPASE 3CASPASE 3CASPASE 3CASPASE 3CASPASE 3 IAP IAP IAP IAP IAP IAP IAP IAP IAP IAP IAP IAP IAP IAP IAP IAP IAP IAP IAP IAP IAP

AIFAIFAIFAIFAIFAIFAIFAIFAIFAIFAIFAIFAIFAIFAIFAIFAIFAIFAIFAIFAIFCAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45CAD, ICAD, DFF45

APOPTOSISAPOPTOSISAPOPTOSISAPOPTOSISAPOPTOSISAPOPTOSISAPOPTOSISAPOPTOSISAPOPTOSISAPOPTOSISAPOPTOSISAPOPTOSISAPOPTOSISAPOPTOSISAPOPTOSISAPOPTOSISAPOPTOSISAPOPTOSISAPOPTOSISAPOPTOSISAPOPTOSIS

(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).

A proton beam is created by a cyclotron or synchrotron that isolates the proton from a hydrogen particle and speeds it up. The vast mass and 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-rays continue 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

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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 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

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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 the tumour 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).

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. The Radiation

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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 beam therapy (PBT) can create 3D conformal 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).

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 R adiation Therapy (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.

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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 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 will be able to successfully

conform 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

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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 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).

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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).

MethodologyThis 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

• British Journal of Cancer

• Japanese Journal of Clinical Oncology

• International Journal of Radiation Oncology

• Radiology

• Iranian Journal of Cancer Prevention

• Acta Oncologica

• The British Journal of Radiology

• Cancer Research UK

• Cancer Biology & Therapy

• PLOS One

• Oncogene

• Current Drug Metabolism

• Cell

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• Nature

• Current Opinion in Clinical Nutrition and Metabolic Care

• Molecular Cancer

• Science Translational Medicine

• The Ochsner Journal

• La radiologia medica (Radiol Med)

• Health Physics

• The New England Journal of Medicine (NEJM)

• Oxford University Press (Journals)

• The Journal of Clinical Endocrinology & Metabolism

• Journal of the European Society for Medical Oncology

• Journal of the National Cancer Institute

• Journal of Clinical Oncology

• The Journal of Radiation Research

• Systematic Reviews

• Physics in Medicine and Biology

• Radiotherapy & Oncology

• Cancer Medicine

• Cancer

• Reviews in Urology

• Radiation Research

• Wiley Online Library

• The Lancet Oncology

• PharmacoEconomics & Outcomes News

• Journal of Proton Therapy (JPT)

• JAMA

• World Health Organisation (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

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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

• 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

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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 6. A forest plot showing that the treatment Proton Beam therapy is safer therefore, more effective in treating Prostate

Cancer compared to Photon Radiotherapy from four clinical trials from 2012 - 2014. The overall effect estimate is 1.06, therefore

. The boxes from each line represents the effect estimate and weight for each study.

= 73.1%.

Individuals studies by Sheets et al. (2012) and Yu et al. (2012) does not overlap 1, therefore has statistical significance however

the studies by Fang et al. (2014) overlaps 1, therefore therefore no statistical significance.

PBT

IMRT

PBTPBTPBTPBTPBTPBTPBTPBTPBTPBTPBTPBTPBTPBTPBTPBTPBTPBTPBTPBTPBT

IMRTIMRTIMRTIMRTIMRTIMRTIMRTIMRTIMRTIMRTIMRTIMRTIMRTIMRTIMRTIMRTIMRTIMRTIMRTIMRTIMRT

Figure 7. T-test of the

effectiveness of PBT and IMRT is used

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Figure 9. Shows the four studies used to generate a forest plot (Fig.6) with weight, odds ratio (OR), upper confidence and

patient population value using Evidence Partners which is a Systematic Review and Literature Review Software .

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.

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

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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

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 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.

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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).

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

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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.

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.

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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

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

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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

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.

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Costs of PBT & IMRT

Outpatient setting is the only way of receiving PBT meaning the only way of means of treat-

ment is private institutions located in certain areas for exam and does not involve hospital ad-

mittance. 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 esti-

mated 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.

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 Foun-

dation Trust.

Table 2: Examples of randomly chosen countries, 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

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http://www.cnao.it/index.php/en/

http://innovation.jinr.ru/section.aspx?id=56

http://www.berlinprotonen.de/

http://www.ncc.go.jp/en/ncce/index.html

http://protontherapie.curie.fr/

http://www.protons.com/proton-therapy/index.page

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)

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

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http://www.proton-cancer-treatment.com/proton-center/

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 compari-

son 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 avail-

able. PBT 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 con-

struction of proton facilities.

Acknowledgement

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

to finish my thesis.

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