OVERVIEW OF PROTON THERAPY

Since the discovery of the Xrays on November 8,1895,Radiotherapy has become one of the most important methods of cancer treatment.A few year later, Marie Curie and the discovery of Radium (in 1898) has opened up new horizons for radiotherapy and brought several new hopes for patients.

FACULTY OF PHYSICS

NGUYEN THE BON

OVERVIEW OF PROTON THERAPY

Submitted in partial fulfillment of the requirements for the degree of

Bachelor of Science in Physics

(Advanced Program)

Hanoi - 2017

VIETNAM NATIONAL UNIVERSITY, HANOI

VNU UNIVERSITY OF SCIENCE

FACULTY OF PHYSICS

NGUYEN THE BON

OVERVIEW OF PROTON THERAPY

Submitted in partial fulfillment of the requirements for the degree of

Bachelor of Science in Physics (Advanced Program)

Supervisor: NGUYEN VAN HUNG, MSc

This work would not have been possible without the dedication and endeavour of all people who were involved in it, and the collaboration between institutions was determinant for accomplishing the initial goals

I would like to express my deep gratitude to Master Nguyen Xuan Ku who

showed me the road and helped to get me start on the path to this thesis and much more in the future Also, his enthusiasm and dedication were remarkable and an actual example to me

I also would like to thank Master Nguyen Van Hung for the information

shared and for the availability shown for collaborating with this work

I truly thank the teachers at the Faculty of Physics - VNU University of Sciences in general, at the Department of Nuclear Physics in particular, who helped enthusiastically in the process of learning and researching

I am thankful for all the companions in the team of Medical Physicists especially Nguyen Ngoc Chien for helping and contributing many valuable comments in the period of implementing the experimental subjects

Finally, but no less important, special thanks to my family and friends, who stood by and motivated and dedicated to many good feelings to overcome all

difficulties in my study duration

Hanoi, June 2017 Students,

Nguyen The Bon

LIST OF ABBREVIATION

BTS Beams Transport System

CTV Clinical Target Volume

DRR Digitally Reconstruction Radiograph

GTV Gross Target Volume

ITV Internal Target Volume

IMPT Intensity Modulate Proton Therapy

IMRT Intensity Modulated Radiation Therapy

LET Linear Energy Transfer

NPTC Northeast Proton Therapy Center

PSB Passively Scattered Beam

PSI Paul Scherrer Institute

SOBP Spread-out Bragg Peak

TABLE OF CONTENTS

CHAPTER 1: RADIOTHERAPY IN TREATING CANCER PATIENTS 2

1.1 Introduction 2

1.2 Types Of Radiation Therapies 3

1.3 Biological Effects Of Radiation 4

CHAPPER 2 PROTON THERAPY 6

2.1 Proton Therapy History 6

2.2 Basic Physics Of Proton 7

2.2.1 Nature of the particle 7

2.2.2 Proton Interactions Mechanisms 7

2.2.3 Bragg peak 9

2.3 Biological Effectiveness 11

2.3.1 Relative Biological Effectiveness (RBE) 11

2.3.2 Secondary radiation 12

2.4 Equipment For Proton Therapy 12

2.4.1 Proton accelerators 12

2.4.2 Beam line 16

2.4.3 Gantry/ fixed beam 16

2.4.4 Beam delivery system 18

2.4.5 Patient positioning and immobilization issues, motion 23

2.5 Treatment Planning In Proton Therapy 24

2.5.1 Principles 24

2.5.2 Treatment beam parameters 25

CHAPTER 3 PROTON THERAPY IN CLINICAL APPLICATION 27

3.1 Principles 27

3.2 The Clinical Cases Use Of Proton Therapy 28

3.2.1 Prostate cancer 28

3.2.2 Brain tumors 29

3.2.3 Head and neck cancers 30

3.2.4 Lung cancer 31

3.2.5 CNS tumors 31

CONCLUSION 32

REFERENCES 33

LIST OF FIGURES

Figure 1 Cure rate for different cancer treatment strategies [6] 2

Figure 2 Damage to DNA by direct and indirect mechanisms [10] 4

Figure 3 The first working cyclotron from 1929 with a diameter of 5 inches producing 80 keV protons [17] 6

Figure 4 Schematic illustration of proton interaction mechanisms [11] 8

Figure 5 Central axis depth dose distribution for an unmodulated 250-MeV proton beam, showing a narrow Bragg peak [11] 10

Figure 6.Comparison of typical cell survival curves for low linear energy transfer X-rays and high LET radiation such as heavy charged particles [11] 11

Figure 7 Plan view of the classical cyclotron accelerator [9] 13

Figure 8: Proton therapy cyclotron offered by Varian [11] 14

Figure 9: Schematic diagram illustrating the principle of proton acceleration in a synchrotron [11] 15

Figure 10 Floor plan of the Northeast Proton Therapy Center [20] 16

Figure 11 One of the gantries at the Northeast Proton Therapy Center [20] 17

Figure 12 The nozzle at the NPTC [20] 18

Figure 13 A final aperture and a patient-specific range compensator [20] 19

Figure 14 Three types of range modulation wheels [20] 20

Figure 15 The principle of passive beam spreading 20

Figure 16 The principle of beam scanning[20] 22

Figure 17 Proton therapy requires, like all highly conformal treatment modalities, a significant effort in patient setup and immobilization This figure shows the setup using orthogonal x-rays (one x-ray source is integrated into the nozzle) and flat panel detectors [20] 23

Figure 18 Spread-out Bragg peak (SOBP) depth dose distribution [11] 26 Figure 19 Comparison of photon intensity-modulated radiation therapy (IMRT) plan (left) and proton therapy plan (right) [15] 27 Figure 20 Comparison of dose distribution for IMRT and IMPT (right) [21] 28 Figure 21 Comparison showing the area of the body affected by radiation using Conventional Radiotherapy (First Image) and Pencil Beam Proton Therapy (second image) [21] 29 Figure 22 Comparison showing the area of the body affected by radiation using Conventional Radiotherapy (First Image) and Pencil Beam Proton Therapy (second image) [21] 30 Figure 23 Comparison showing the area of the body affected by radiation using Conventional Radiotherapy (First Image) and Pencil Beam Proton Therapy (second image) [21] 31

LIST OF TABLES

Table 1 Summary of proton interaction types, targets, ejectiles, influence on

projectile, and selected dosimetric manifestrtions [19] 9 Table 2 Accelerator technology comparisons for some parameters [20] 15

INTRODUCTION

Since the discovery of the X-rays on November 8, 1895, Radiotherapy has become one of the most important methods of cancer treatment A few years later, Marie Curie and the discovery of Radium (in 1898) has opened up new horizons for radiotherapy and brought several new hopes for patients

Nowadays, in traditional radiotherapy X-rays are still used and it is also the most common type of radiation in a medical context The basic principle of radiotherapy is to use ionizing radiation (internal or/and external) to deposit energy

in a tumor to kill the cancer cells The current cancer therapy methods mainly include surgery, chemotherapy, radiotherapy or a combination of these The techniques in radiotherapy have evolved during the century, all with the same goals, i.e to concentrate the dose to the target tissue and spare as much as possible of the healthy organs and tissues Despite the new advanced technologies in radiotherapy there is still need to improve radiation treatment methods

In this thesis, I will introduce an emerging radiation treatment tool – proton therapy, which is call ―the state of the art‖ technique in radiation therapy Besides, this special technique have been presented to point out advantages as well as

disadvantages so that we can make decision to use in clinical applications

The contents of my thesis are represented in 3 chapters as follows:

Chapter 1: Radiotherapy in Treating Cancer Patients

Chapter 2: Overview of Proton Therapy

Chapter 3: Proton Therapy in Clinical Application

CHAPTER 1: RADIOTHERAPY IN TREATING CANCER PATIENTS

1.1 INTRODUCTION

Cancer is a group of various diseases in which cells divide uncontrollably In economically developed countries, cancer is the number one cause of death Globally, around 12.7 million cancer cases in 2008 and 7.6 million cancer deaths are estimated by GLOBOCAN [12] The main treatment options are surgery (the physically removing of the cancer), chemotherapy (the use of drugs which are designed to attack the cancer cells) and radiotherapy (where radiation is used to kill the cancerous cells) Usually, a combination of these treatments is used to achieve optimal results [16]

Figure 1 Cure rate for different cancer treatment strategies [6]

Since surgery and radiotherapy are local tumor treatment techniques, it is evident that local control of the tumor is a prerequisite for a successful treatment Furthermore, these numbers suggest that the chance of survival increases with local tumor control To date, this has been the best strategy for a successful cancer treatment In the future other treatment methods such as immunotherapy may achieve better results and will help to decrease the number of casualties Until these new treatments are available, surgery and radiotherapy, or a combination of both, will be the most important methods of local tumor control Consequently it is necessary to improve these methods or to complement them with new ones One of these new methods is proton therapy, the irradiation of cancer with protons Based

on ideas dating back to the 1946s, it has gained in importance in recent years

During the last decade, special dedicated center have been built and many are being planned throughout the world

1.2 TYPES OF RADIATION THERAPIES

Three main types of radiation therapies can be distinguished according to the position of the radiation source [8]: brachytherapy, unsealed source therapy and external beam therapy

Brachytherapy uses sealed sources placed directly in the disease area In unsealed source therapy, the radiation source is injected into the body or given by ingestion External beam therapy makes use of an external beam of particles aimed at the disease side The three main types of external beam therapies are: fast neutron therapy, electron therapy, photon therapy, and heavy charged particle therapy Electrons have a finite range through tissue, sparing tissue behind the tumor side[8] This is a big advantage of electron therapy, since normal tissue as well as possible critical organs behind the tumor can be spared using this type of therapy However, due to the strong scatter interactions with matter, the electrons deviate strongly from their incident trajectory, making electron therapy only suitable for treating shallow tumors (< 5cm deep) A second disadvantage, due to the strong scatter interactions of the electrons, is that hot and cold spots (spots were the dose is locally very different from the dose in the surrounding tissue) are created in areas were highly heterogeneities are present in the tissue (for example near a bone structure) As a consequence, electron therapy is not suitable for treating tumors lying in or near strong heterogeneities tissue, like a tumor in the head

The advantage of photons in the use of external beam radiation is the large penetration depth and the skin sparing property [14] Due to these properties, photon therapy is the most commonly used type of therapy for deep lying tumors (> 5cm deep) The most advanced form of photon therapy is IMRT (Intensity Modulated Radiation Therapy) IMRT uses modulated intensity beams to deliver precise radiation which conform to the three-dimensional shape of the tumor [16] The most common form of heavy charge particle therapy is proton therapy This type of therapy can offer a superior dose distribution compared to the conventional treatment types, as will be demonstrated in the following section

1.3 BIOLOGICAL EFFECTS OF RADIATION

Radiotherapy uses ionizing radiation to treat disease tissue in the body Excitations

of the electrons energy structure and ionizations of the molecules occur due to the interaction of the radiation with the tissue of the patient The effects on the patient

of radiation is assumed to be due to the damage of DNA The damage to DNA can

be created either directly or indirectly: direct if an altered electron structure is created (like the fraction of a chemical bond) due to the interaction of the radiation with the DNA, and indirect if the DNA is damaged by free radicals which are created due to the interaction of the radiation with substances in the neighborhood

of the DNA (Fig 2)

Figure 2 Damage to DNA by direct and indirect mechanisms [10]

The most important effects of DNA damage are [16]: damage to nitrogenous bases, cross links between DNA-DNA or DNA-protein, single-strand breaks, and double-strand breaks The cells in the tissue of a patient are able to repair most of the damage due to the radiation; most single-strand breaks are repaired even within the first few minutes Double strand-breaks, however, are more difficult to repair since the broken of piece of the DNA may not be close to the damaged DNA The possible consequences of damaged DNA to a cell are roughly: the repair of the damage with full recovery of the cell, the creation of a modified cell, and cell death Cancerous cells appear to be more sensitive to radiation and are less able to repair the damage compared to normal cells: after radiation, normal cells appear to recover more fully than cancerous cells do However, normal tissue is affected by the radiation as well, creating modified cells in normal tissue, which may result in

undesirable long term side effects for the patient Especially sensitive to these long term side effects are children as their organs are in a developing state Also, children are more likely to live longer if cured, increasing the change of encountering long term side effects Example of such long term side effects are: IQ loss, growth hormone deficiency, hypothyroidism, hearing loss, and secondary cancer[20]

CHAPPER 2 PROTON THERAPY

2.1 PROTON THERAPY HISTORY

In 1929 Emest O.Lawrence invented the cyclotron (for which he received the Nobel Prize in 1939) and made it possible to accelerate nuclear particles to very high velocities The first working cyclotron from 1929 is shown in Figure 3

In a scientific article from 1946, Professor Robert Rathbun Wilson, first proposed the theory of radiation therapy using accelerated protons Previously, cancer treatment with particles and ions had been limited due to the capacity of the accelerator, but with the new high-energy accelerators they became of therapeutic interest Wilson discussed the advantage of concentrating high doses in the target utilizing the Bragg peak and how this could spare the surrounding healthy tissue [18]

Figure 3 The first working cyclotron from 1929 with a diameter of 5 inches

producing 80 keV protons [17]

In 1954, the first human was treated with proton beams at the Lawrence Berkeley Laboratory In Sweden the first proton therapy treatment was carried out in Uppsala

in 1957 using a broad beam and the spread-out Bragg peak technique In 1961 the Harvard Cyclotron Laboratory (HCL), in which Wilson was involved in the design, started collaboration with Massachusetts General Hospital (MGH) with the aim to pursue clinical proton therapy It was shut down in 2002 and had by then treated 9,116 patients The first hospital based proton therapy clinic in the United States

was constructed in 1990 at Loma Linda University Medical Center (LLUMC), in Loma Linda, California A synchrotron producing 250 MeV protons were used, designed and constructed by Fermilab [18]

Today there are 16 proton therapy centers in operation in the United States and 46 centers worldwide (PTCOG 2014) The Particle Therapy Cooperative Group

(PTCOG) reported that at least 105,743 patients had been treated worldwide by the end of 2013 (PTCOG 2014)

2.2 BASIC PHYSICS OF PROTON

2.2.1 Nature of the particle

The proton is a subatomic particle, a nucleon, which in Greek is spelled πρῶτον and means ―first‖ [13]

According to the Big Bang Theory, hydrogen was the first element to form in the universe (~100 seconds after the creation of the universe about 13.7 billion years ago) Proton is the nucleus of the hydrogen atom It carries a unit positive charge (1.6 × 10-19 C) and has a mass of 1.6× 10-27 kg (~1,840 times the mass of electron) Proton has long been considered as a fundamental particle of nature It consists of three quarks ( two up and one down) held together by gluons Proton is the most stable particle (half-life of >1032 years) and decays into a neutron, a positron, and a neutrino The existence of proton was first demonstrated by Ernest Rutherford in

1919 [11]

2.2.2 Proton Interactions Mechanisms

The basis for the therapeutic suitability of proton therapy is the interaction of protons with matter Protons have a high ionization rate at the end of their range, they have a tendency to go in a straight line through tissue, and the standard deviation in the range of the protons is very low These properties of interaction enable us to accurately aim a proton beam at the tumor side while sparing the surrounding normal tissue [16] A protons travel through a medium, they interact with atomic electrons and atomic nuclei of the medium through Coulomb force Rare collisions with atomic nuclei causing nuclear reactions are also possible Figure 4 illustrates several mechanisms by which a proton interacts with an atom or nucleus: Coulomb interactions with atomic electrons, Coulomb interactions with the atomic nucleus, nuclear reactions, and Bremsstrahlung

To a first-order approximation, protons continuously lose kinetic energy via frequent inelastic Coulomb interactions with atomic electrons Most protons travel

in a nearly straight line because their rest mass is 1832 times greater than that of an electron In contrast, a proton passing close to the atomic nucleus experiences a repulsive elastic Coulomb interaction which, owing to the large mass of the nucleus, deflects the proton from its original straight-line trajectory

Non-elastic nuclear reactions between protons and the atomic nucleus are less frequent but, in terms of the fate of an individual proton, have a much more profound effect In a nuclear reaction, the projectile proton enters the nucleus; the nucleus may emit a proton, deuteron, triton, or heavier ion or one or more neutrons Finally, proton Bremsstrahlung is theoretically possible, but at therapeutic proton beam energies this effect is negligible Table 1 summarizes the proton interaction types, interaction targets, principal ejectiles, influence on the proton beam, and dosimetric manifestations [19]

Figure 4 Schematic illustration of proton interaction mechanisms [11]

Table 1 Summary of proton interaction types, targets, ejectiles, influence on

projectile, and selected dosimetric manifestrtions [19]

2.2.3 Bragg peak

The average rate of energy loss of a particles per unit path length in a medium

is called the stopping power The linear stopping power is measured in units of

MeV/cm It is also referred to as the linear energy transfer (LET) of the particle LET of charged particles in a medium is hence a measure of the energy deposited per unit length and is defined as:

Where dE is the average energy locally imparted to the medium by a charged particles of specified energy in traversing a distance of dl

Figure 5 Central axis depth dose distribution for an unmodulated 250-MeV proton

beam, showing a narrow Bragg peak [11] LET is usually expressed as keV/µm in water These basic parameters, namely stopping power and LET, are closely related to dose deposition in a medium and with the biologic effectiveness of radiation

The rate of energy loss due to ionization and excitation caused by a charged particle traveling in a medium in proportional to the square of the particle charge and inversely proportional to the square of its velocity As the particle loses energy,

it slows down and the rate of energy loss per unit path length increases As the particle velocity approaches zero near the end of its range, the rate of energy loss becomes maximum The depth dose distribution follows the rate of energy loss in the medium For a mono-energetic proton beam, there is a slow increase in dose with depth initially, followed by a sharp increase near the end of range This sharp

increase or peak in dose deposition at the end of particle range is called the Bragg

peak (Fig 5)

As seen in Figure 5, the Bragg peak of a mono-energetic proton beam is too narrow to cover the extent of most target volumes In order to provide wider depth coverage, the Bragg peak can be spread out by superposition of several beams of

different energies These beams are called the spread-out Bragg peak (SOBP)

beams The SOBP can be realized with a special rotating wheel with varying thickness (range modulator wheel) positioned in the proton beam that gradually slows down the protons within a specific energy range and thus modulated the initial energy of the protons These techniques are discussed in more detail in the next sections

2.3 BIOLOGICAL EFFECTIVENESS

2.3.1 Relative Biological Effectiveness (RBE)

Protons are slightly more biologically effective than photons In other words, lower dose is required to cause the same biological effect The relative biological effectiveness (RBE) of protons is defined as the dose of a reference radiation divided by the proton dose to achieve the same biological effect The specified biologic effect may consist of cell killing, tissue damage, mutations, or any other biologic endpoint The reference radiation for RBE comparison is sometimes chosen to be cobalt-60 γ rays or megavoltage x-rays for which the RBE has been determined to be about 0.85 ± 0.05 (relative to 250 kVp X-rays) [20]

Although the RBE depends on the type and quality of radiation, dose fractionation, and the biologic endpoint, the factor of critical importance related to RBE is the LET The greater the LET, the greater is the RBE Because charged particles, in general, have greater LET than the megavoltage x-rays, the RBE of charged particles is greater than or equal to 1.0 Neutrons also have RBE greater than 1.0, because of the higher LET caused by their interactions involving recoil protons Figure 6 shows typical cell survival curves for high LET charged particles or neutrons and x-rays It is seen that the slope of the survival curve is greater for the higher LET radiations, thus giving rise to higher RBE

Figure 6.Comparison of typical cell survival curves for low linear energy transfer

X-rays and high LET radiation such as heavy charged particles [11]

Because the LET of charged particles increases as the particles slow down near the end of their range, so does their RBE Thus, the RBE of charged particles is greatest

in the region of their Bragg peak

The LET, and therefore the RBE, of a clinical proton beam continuously increases with depth (as its energy decreases), a single rounded-off value of RBE has been adopted Most treatment facilities use an RBE of 1.1 for protons relative to Cobalt60 or megavoltage X-ray beams in their dose prescriptions for all proton energies, dose levels, tissues, and regions covered by SOBP This universal RBE factor of 1.1 has been adopted for practical reasons to bring clinical response to proton and photon beams into rough agreement

2.3.2 Secondary radiation

Protons slowing down in matter lose energy not only by Coulomb interactions but also by nuclear interactions Nuclear interactions cause secondary radiation Protons and neutrons are the most important secondary particles from nuclear interactions because they can carry away energy far from the interaction point Shielding against neutron radiation is therefore important for any proton therapy installation For example, different combinations of apertures may be used in the treatment head; however, neutron production cannot be avoided Shielding may reduce the effect of neutrons generated in the scattering system, the aperture, and the compensator, but neutrons are also generated in the patient itself Nothing can

be done to avoid the latter situation Since the total amount of neutrons produced depends on the amount of material the protons have to penetrate, neutron production can be reduced by extracting to the nozzle the minimum energy needed[20]

2.4 EQUIPMENT FOR PROTON THERAPY

2.4.1 Proton accelerators

The first step in generating a proton beam is to obtain a source of protons which can be accelerated to energies sufficient for treatment This can be performed using hydrogen as the starting product and separating the hydrogen’s electron from its proton by using an electrical field Once protons have been generated, they must be accelerated such that the proton energy is sufficient to reach the distal edge of a tumor Presently, the two most commonly used devices for proton acceleration are cyclotrons and synchrotrons