BASICS PHYSICS, TECHNICAL ASPECTS

AND RADIOTHERAPY OBJECTIVES OF

PROTON THERAPY

Author: Dr. Kovács Árpád, Simon Mihály

Lecturer: Dr. Kovács Péter

© Dr. Kovács Árpád, Simon Mihály – 2021

The textbook was made with the support of the following tender:

EFOP-3.4.3-16-2016-00005 Korszerű egyetem a modern városban: Értékközpontúság, nyitottság és

befogadó szemlélet egy 21. századi felsőoktatási modellben

ISBN: 978-963-429-658-4

Publisher: Pécsi Tudományegyetem Egészségtudományi Kar

Pécs, 2021.

Table of contents

1. Introduction ................................................................................................................................................................. 4

1.1. History of proton therapy ....................................................................................................................................... 4

2. Basic physics of proton therapy ................................................................................................................................. 4

2.1. Bragg peak ............................................................................................................................................................. 6

2.2. Beam production .................................................................................................................................................... 7

2.3. Heavy ions .............................................................................................................................................................. 8

2.4. Beam delivery systems ........................................................................................................................................... 8

2.5. Passive beam .......................................................................................................................................................... 9

2.6. Active beam ......................................................................................................................................................... 10

3. Medical Dosimetry .................................................................................................................................................... 11

3.1. Ion chamber dosimetry ......................................................................................................................................... 11

3.2. TLD and film dosimetry....................................................................................................................................... 11

3.3. Dosimetric verification of dose distributions ....................................................................................................... 12

3.4. Beam monitor calibration ..................................................................................................................................... 12

4. Therapy Planning ...................................................................................................................................................... 12

4.1. Imaging for TP ..................................................................................................................................................... 13

4.2. Dose calculation ................................................................................................................................................... 13

4.3. Dose optimization and intensity modulation ........................................................................................................ 13

5. Radiobiology .............................................................................................................................................................. 14

6. Clinical application of proton therapy .................................................................................................................... 16

6.1. Central Nervous System and Base of Skull (Adults) ........................................................................................... 16

6.2. Paediatric intracranial tumors .............................................................................................................................. 16

6.3. Ocular tumors ....................................................................................................................................................... 16

6.4. Chordomas and chondrosarcomas ........................................................................................................................ 17

6.5. Prostate cancer ..................................................................................................................................................... 17

6.6. Lung cancer .......................................................................................................................................................... 18

6.7. Hepatocellular carcinoma..................................................................................................................................... 18

6.8. Breast cancer ........................................................................................................................................................ 18

7. Challenges .................................................................................................................................................................. 19

7.1. Technical challenges ............................................................................................................................................ 19

7.2. Physics challenges ................................................................................................................................................ 20

8. Bibliography .............................................................................................................................................................. 21

4

1. Introduction

1.1. History of proton therapy

According to the Big Bang Theory roughly 13.4

billion years ago hydrogen was the first element to

form in the Universe. The existence of proton was

demonstrated by Ernest Rutherford in 1919.

Robert Wilson 1946, published an article in 1946

proposing that accelerated protons should be

considered for radiation therapy, he explained the

biophysical rationale for proton therapy. (Wilson

1946). 1954 was the year of the first application of

a proton beam treating a human by UC Lawrence

Berkeley Laboratory, (Lawrence et al 1958).

In the following years a number of techniques,

e.g. proton radiosurgical techniques for brain

tumors developed at the Gustaf-Werner Institute

in 1957 and radiosurgery of small intercranial

targets at Harvard Cyclotron Laboratory

(Kjellberg et al 1962), had been developed.

The process of developing further key

technologies for radiotherapy continued, such as

accelerators, magnetically scanned beams,

computed tomographic imaging and magnetic

resonance imaging. In the 70s-80s several physics

facilities, including PSI in Switzerland, started to

treat patients with proton.

In 1989 the world`s first hospital based proton

beam therapy facility opened in Clatterbridge

Cancer Centre UK with low energy proton beams.

The first high-energy proton beam therapy facility

opened in Loma Linda University Medical Center,

California in 1990.

Based on Particle Therapy Cooperative group

(PTCOG) data in 2018 71 specialized proton

therapy center had been registered worldwide and

the total number of patients treated by this

modality reached 149345 by the end of 2016.

The rationale of proton therapy is strongly related

to radiobiology (Jackel 2009), the possibility of

concentrating the proton beam to the cancer cells

while avoiding or minimizing the radiation effect

to the surrounding normal tissues is called dose

conformation. (Weber et. el 2009) defines the

rationale of proton therapy in its superior spatial

dose distribution in the patient, Weber also found

that the advantage of proton to photon namely

providing highly conformal and uniform dose to

the cancer cells has been wildly lessened by

advances in photon therapy.

However, studies indicates, that the advantage of

proton therapy in normal tissue sparing never been

more apparent or important (Valdivieso et al

2012), approximately 65% of adults and 80% of

children survive 5 years after their cancer

diagnosis.

2. Basic physics of proton therapy

As mentioned before the very first element formed

in the universe was hydrogen and the proton is the

nucleus of the hydrogen atom. It carries the unit of

5

positive charge (1.6 x 10-19

Coulombs) and has a

mass of 1.6 x 10-27

kg which is ~ 1840 times the

mass of one electron.

Given the charge of the protons as they pass

through medium they interact with atomic

electrons and atomic nuclei through Coulomb

force. Nuclear reactions are also possible, but

those are very rare. Interactions based on

Coulomb force can be inelastic collisions with

atomic electrons or elastic scattering. In an

inelastic collision protons lose part of their kinetic

energy to generate ionization and excitation of

atoms.

Proton beams have sharp lateral distribution due

to the fact that heavier charged particles scatter

through much smaller angles, compared to an

electron beam.

1. figure: Schematic illustration of proton interaction mechanisms: (a) energy loss

via inelastic Coulombic interactions, (b) deflection of proton trajectory by repulsive Coulomb elastic

scattering with nucleus, (c) removal of primary proton and creation of secondary particles via non-

elastic nuclear interaction (p: proton, e: electron, n:neutron, γ: gamma rays), (Wayne et al, 2015)

Mass stopping power (energy loss per unit path

length in g/cm2) for protons is greater in low

atomic-number (Z) materials than in high-Z

materials. On a per g/cm2 basis, low-Z materials

are more effective in slowing down protons while

high-Z materials scatter protons through larger

angles than the low-Z materials. Accordingly,

scattering foils should be made of high Z materials

to scatter protons with minimal energy loss and

consequently low z materials should be used when

6

energy decrease is desired with minimal

scattering. A combination of high-Z and low-Z

materials can help to control scattering and

reduction in beam energy. Collisions with nuclei

to produce nuclear reactions are rare. The products

of such collisions are excited nuclei, secondary

protons, neutrons, and, in some cases, α particles.

2.1. Bragg Peak

The stopping power is the average rate of energy

loss of a particle per unit path length in a medium.

The linear stopping power is measured in MeVcm-

1. This simply means how much energy is

deposited per cm in the medium by a given

particle. This often referred as the Linear Energy

Transfer (LET) of the particle. The biological

effectiveness of radiation is strongly correlates

with LET.

The rate of energy loss due to ionization of a

charged particle is proportional to the square of

the charge and inversely proportional to the square

of its velocity. In practice as a particle passes

through medium it deposits energy on its` path

and as the velocity of the particle approaches zero

the rate of energy loss becomes maximum. The

depth dose distribution follows this rate of energy

loss.

2. figure: Typical dose deposition as a function of depth for a proton beam

It can be easily seen that a single mono-energetic

proton beam is not capable to cover a treatment

site given the sharp Bragg peak. By adding

weighted proton beams with different energies the

Bragg peaks summing up and create a Spread Out

Bragg Peak (SOBP).

7

3. figure: Spread-out Bragg Peak. The difference in energy and intensity of the individual beams summing

up in a spread-out peak enabling the treatment of extensive tumor sites

2.2. Beam production:

Protons can be accelerated by a linear accelerator,

a cyclotron or a synchrotron. Accelerators in

medical use should share the same principle that a

high enough beam intensity and energy should be

reached to deliver the treatment in a short time

(~2-3 mins). Linear accelerators are rarely used

simply because of their space requirements.

Cyclotrons and synchrotrons differ in several

aspects of beam specification and space

requirements. Cyclotrons are heavy and have a

limited energy variability. Cyclotrons mostly

isochronous, meaning all particles in the

accelerator revolve at the same frequency

allowing the system to deliver a continuous beam

and high dose rates. A synchrotron is a circular

accelerator ring. Synchrotrons are much more

variable in energy, which is a clear advantage over

cyclotrons. Another consequence of a cyclotron is

secondary radiation, in this respect a synchrotron

is a much more flexible variation. However

synchrotrons are much bigger and operating in

pulse mode.

8

Type Synchrotron

(rapid cyle)

Synchrotron

(slow cyle)

Cyclotron

Energy level selection Continuous Continuous Fixed

Size (diameter) [m] 10 6 4

Average power (beam

on)[kW]

200 370 300

Emittance (RMS

unnorm.) [μm]

0.2 1-3 10

Repetition rate [Hz] 60 0.5 Continuous

Duty factor (beam-on

time)

Pulses 20% Continuous

Type Synchrotron

(rapid cyle)

Synchrotron

(slow cyle)

Cyclotron

Energy level selection Continuous Continuous Fixed

1. table: Accelerator technology comparisons for some parameters (Coutrakon et al., 1999)

2.3. Heavy ions

One of the basic features of heavy ions is their

strongly increased energy loss or LET when

compared with protons, which is responsible for

their RBE characteristic. Consequently, the ion

energy required to treat deep-seated tumors is

much higher; while a proton beam of 150 MeV

can penetrate 16 cm in water particle acceleration

in synchrotrons is somewhat more complex and

maybe more cost intensive than in cyclotrons.

Nevertheless, there are also some proton therapy

centers based on synchrotrons.

Ion sources for heavier ions are more difficult to

design than for protons, where simple hydrogen

gas targets of high purity are available. To inject

the ions into a synchrotron ring, they have to be

accelerated first in a linear accelerator (linac)

injector to several MeV/u. Such a linac consists of

a radiofrequency cavity and a drift tube and has a

length of several meters. All these components

make ion beam production considerably more

costly than proton beams. Differences also arise as

cyclotrons are delivering constant beam intensity,

while a synchrotron beam is pulsed. An advantage

of the latter is, however, that beam parameters like

energy, focus and intensity can be changed from

pulse to pulse.

2.4. Beam delivery systems

A typical proton therapy facility consists of an

accelerator and multiple treatment rooms. A single

accelerator can provide therapeutic beam into

9

several rooms, beam transport is controlled by

magnets to selectively drive a proton beam into

the desired room. The particle beam is focused

and its diameter is kept as small as possible during

the transport, only when it enters the room is

spread out to the required cross section.

4. figure: Schematic drawing of a complex proton beam therapy facility at UCLH

There are two basic methods to shape the beam and to tailor the dose to the target volume

2.5. Passive beam

Passive beam delivery techniques use double-

scattering systems or wobbling magnets in

combination with scatterers to produce large

particle fields (Hug, 2001). The particle field is

then confined to the tumor cross section by

individually manufactured collimators or multileaf

collimators. To generate the SOBP, a rotating

modulator wheel is inserted into the beam. This

device introduces material of varying thickness

into the beam that results in a periodical

modulation of the range. Alternatively, a static

filter of varying thickness may be applied. This

so-called ridge-filter uses bar-ridge energy

absorbers to produce a homogeneous range

modulation over the lateral extension of the

treatment field. Each modulator wheel or ridge

filter is connected to a specific SOBP and is

selected according to the extension of the tumor in

depth. To adjust the SOBP to the distal edge of the

tumor, range shifters are used.

Finally, compensators manufactured for the

individual field of each patient can be used to

adjust the dose distribution to the distal edge of

the tumor. As the extension of the SOBP remains

constant over the tumor cross section, the dose

conformation at the distal edge is connected to

high doses in the normal tissue at the proximal

edge of the tumor (Khan, 2014).

10

5. figure: Passive scattering system

2.6. Active Beam

Another way of beam delivery is called active

beam shaping or pencil beam shaping (Verhey et

al 1998). This system takes advantage of the

electric charge of the particles, in order to produce

a tightly focused pencil beam that is then deflected

laterally by two magnetic dipoles to allow a

scanning of the beam over the treatment field. PSI

in Switzerland was the first institute to implement

scanning with proton beams, in their system the

region of interest is divided into voxels and each

voxel has a specific dose level which is delivered

by the system by placing the Bragg peak within

the voxels. When the beam is produced with a

synchrotron, the energy can be switched from

pulse to pulse in order to adapt the range of the

particles in tissue. This way, a target volume can

be scanned in three dimensions and the dose

distribution can be tailored to any irregular shape

without any passive absorbers or patient-specific

devices, like compensators or collimators.

Therefore, the high-dose region can also be

conformed to the proximal end of the target

volume and the integral dose as well as the non-

target volume receiving high-LET radiation is

minimized. Beam scanning delivery is ideally

suited for intensity-modulated proton therapy

(IMPT).

11

6. figure: Pencil beam scanning system

There are a few clear advantages of scanned beam

delivery over passive scattering, a) it can “paint”

al physically possible dose distribution b) efficient

use of protons compared to passive scattering in

which more than 50% of protons are absorbed or

scattered c) requires no patient specific hardware

d) the neutron background is substantially reduced

and e) it allows IMPT. Of course there are

disadvantages and the biggest one is the “interplay

effects” which induced by organ motion.

3. Medical Dosimetry

3.1. Ion chamber dosimetry

The determination of absorbed dose to water in all

operating ion facilities is currently based on

ionization chamber dosimetry (Makie et al. 1985,

Boyer et al 1985). For this purpose, commercial

ionization chambers (mainly thimble type

chambers) are used, which are calibrated by the

secondary standard dosimetry laboratory (SSDL)

in a field of Co-60 in terms of absorbed dose to

water. This procedure is recommended also in the

latest Code of Practice of the International Atomic

Energy Agency, the technical report series TRS-

398, which is currently the only international

guideline for clinical dosimetry of ion beams in

the energy range of 50 to 250 MeV (Makie et al

1997).

3.2. TLD and film dosimetry

A general problem when using any kind of solid

state detectors for ion beam dosimetry, is the

effect of quenching of the signal in regions with

increased LET. For protons this effect is rather

limited and can be corrected for as a function of

depth. This way even absolute dose measurements

in proton fields can be achieved. For heavier ions

the increase in LET is much larger and in addition,

due to nuclear fragmentation, the LET varies

considerably with depth (Dong, 2015). It is thus

not possible to use either films or TLDs for an

absorbed dose determination. Rather they are used

for relative measurements or QA purposes

(Jackson et al 2012).

12

3.3. Dosimetric verification of dose

distributions

In the case of a passive beam delivery technique,

the dosimetric verification of a beam of protons or

ions is practically identical to conventional (non-

IMRT) RT. Here the treatment field can be

measured, e.g. by scanning a single ion chamber

through the treatment field in a water phantom. If

active beam delivery is used, the scanning of ion

chambers is not possible and hence multichannel

dosimetry systems are needed in order to do

efficient dosimetric verification. For this purpose,

dedicated systems have been developed which

allow, for instance, positioning a set of many

individual ion chambers in a water phantom and

measure doses at various points in the field

simultaneously (Sisterson J. 2005). Another

possibility is to use multichannel detectors like for

instance, segmented ion chamber arrays (e.g.

PTW 729). Although a quantitative dose

determination in not possible with film detectors,

they are still important to check geometric

parameters of the treatment fields.

3.4. Beam monitor calibration

Like the dosimetric verification, also the

calibration of beam monitors for passive systems

can be performed in the same way as in

conventional RT. This typically includes an

individual calibration of eachtreatment field in

terms of monitor units at the reference point. If

proper modelling of the beam line is performed,

also an empirical calibration for each combination

of beam shaping elements can be achieved (Kooy

et. al 2003). If a scanning system is used together

with an energy selection system, the monitor

calibration typically has to be done energy

specific, i.e. a calibration of all beam energies has

to be done in order to achieve a proper treatment

field. In this case, the reference point may be

chosen to lie in the entrance region of the

individual Bragg peaks, rather than in the SOBP

as in the case of passive systems (Jackel et. Al

2004).

4. THERAPY PLANNING

For the active beam shaping system, a research

therapy planning system (TPS) was developed

(Kramer et. al 2000, Jackel et al 2001), which

fulfils the needs of the beam scanning system.

While a modulator for passive beam shaping is

designed to achieve a prescribed homogeneous

biologically effective dose for a single field. A 3D

scanning system can produce nearly arbitrary

shapes of the spread-out Bragg peak (SOBP).The

shape of the SOBP therefore has to be optimized

separately for every scan point in the irradiation

field. The introduction of a 3D scanning system,

thus, has some important consequences for the

TPS:

The particle number at every scan point

and the energy has to be optimized

separately.

The capability for intensity modulated RT

with ions should be taken into account.

13

All fields of a treatment plan are applied

on the same day to avoid uncertainties in

the resulting dose due to set-up errors.

The dose per fraction should be variable

for every patient.

The scanner control data (energy, beam

position, particle number at every beam

spot) have to be optimized for each field of

every patient.

An RBE model that allows the calculation

of a local RBE at every point in the patient

has to be implemented.

4.1. Imaging for TP

While it is a common standard to use CT and MR

images to outline the tumor and organs at risk,

CT data is still the only quantitative source of

electron density needed to calculate the range of

the ions in tissue. A calibration of CT numbers to

ion ranges relative to water is needed. These

relations are usually empirical and are only valid

for a certain well defined imaging protocol (Jakel

et al. 2000).

4.2. Dose calculation

The dose calculation for active beam shaping

systems relies on measured data for the depth–

dose curves, instead of the measured depth–dose

data for the SOBP resulting from the modulators,

data for single energies needed. If the applied dose

is variable, it is necessary to base the calculation

of absorbed dose on absolute particle numbers

rather than on relative values. For the calculation

of the absorbed dose, the integral data including

all fragments are sufficient. Before the actual dose

calculation starts, the target volume is divided into

slices of equal radiological depth (Here the same

empirical methods of range calculation as for

passive systems are used). Each slice then

corresponds to the range of ions at certain energy

of the accelerator. The scan positions of the raster

scanner are then defined as a quadratic grid for

each energy. In the last step, the particle number

at each scan point is optimized iteratively until a

predefined dose at each point is reached.

4.3. Dose optimization and intensity

modulation

The most straightforward optimization of

(biological effective) dose is a technique which

may be called single field uniform dose

optimization. In the case of passive systems, this

is achieved by an optimization of the design of the

range modulator. In the case of protons a

homogeneous absorbed dose throughout the depth

modulation is produced. For heavier ions the

increase of RBE with LET and thus depth

necessitates a decrease of the absorbed dose

(Kempe et al 2007).

In the case of scanning systems, much more

flexibility introduced into the possible

optimization of a single field. The additional

degree of freedom of depth–dose modulation

enables several

techniques, like the individual biological modeling

of RBE (see below) and the use of intensity

14

modulated particle therapy (IMPT) (Sarfehnia et

al 2010). IMPT can be achieved by various

approaches as follows: an IMRT-like optimization

of dose in 2D (keeping the depth modulation

fixed), a 2+1 2D optimization (with an additional,

but fixed depth–dose modulation

throughout the field) or a real 3D optimization of

all individual scan spots. The more degrees of

freedom are used, the more it becomes important

to have additional dose constraints in order not to

produce degenerated solutions of the optimization

process (Lomax A. J. 2008).

5. Radiobiology

Relative biologic effectiveness (RBE) of any

radiation is the ratio of the dose of 250-kVp x-rays

to produce a specified biologic effect to the dose

of the given radiation to produce the same 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 g 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) (Khan, 2014).

The RBE value of protons beams can`t be fixed,

but for 70 – 250 MeV protons range typically

from 0.9 to 1.9, with an accepted 'generic' value of

1.1 in clinical proton therapy. Consequently, the

equivalent 60

Co photon dose is the proton dose

multiplied by 1.1. This calculated dose is defined

as the Cobalt Gray Equivalent (CGE) dose and

this is used to calculate and compare doses

between modalities (Weber et al., 2006).

Nuclear interactions are of importance for proton

radiation therapy for three reasons. First, they

contribute to the total absorbed dose. Second, they

may have high-LET values causing an increase of

the beam’s relative biological effectiveness

(RBE). Third, they produce secondary neutrons

leading to dose deposition outside the target

volume (Paganetti, 2002).

The common analytical methods of proton dose

calculation in radiation therapy involve

approximations that may be reflected in

uncertainties in the predicted absorbed dose.

Besides the dose from electromagnetic

interactions (Petti 1992), part of the total dose in

proton therapy is due to secondary protons,

deuterons, tritons, 3 He and α-particles liberated in

nuclear interactions (and due to nuclear recoils). A

dose build-up effect in the entrance region of a

Bragg curve (i.e. the spatial pattern of dose as a

function of depth) interpreted as being due to

secondary particle dose was first confirmed by the

measurements in a 185 MeV proton beam

(Carlsson 1977). In analytical pencil-beam

algorithms, the influence of nuclear interactions is

usually assumed to be small and they are included

only through their (measured) contribution to the

depth–dose distribution (Hong et al 1996, Russell

et al 1995).

Heavy ions exhibit a strong increase of LET in the

Bragg peak region when compared with the

entrance region (Sandison et al 1997). This

increase is due to the track structure as explained

15

above. The radiobiological advantage of high-LET

radiation in tumor therapy is well known from

neutron therapy, but unlike in RT with neutron

beams, in heavy ion RT the high-LET region can

be conformed to the tumor. The increasing

biological effectiveness of ions with larger charge

is shown in Figure 7.

A disadvantage of heavy ions for RT is the

increase of nuclear fragmentation processes,

which

leads to a fragment tail in the depth–dose

distribution that extends beyond the Bragg peak.

Besides the larger effect in cell killing, there are

some more radiobiological effects that make

heavier ions beneficial for tumor therapy. For

example, it is known that for low-LET radiation

the survival of cells depends critically on the

oxygen saturation of tissue. This is due to the

production of oxygen radicals in the cell due to

radiation (Goethem et. al 2009). Many solid

tumors, which exhibit hypoxic areas, are therefore

very resistant to low-LET radiation. For high-LET

radiation, it is known that the oxygen saturation of

tissue plays only a minor role. High-LET particles

should, therefore, be especially useful in the

treatment of radio-resistant tumors. There is also a

smaller variation in the sensitivity of cells in

different parts of the cell cycle when using high-

LET radiation instead of low-LET radiation.

7. figure: RBE for crypt cells of mice after irradiation with

ions in different positions of the spread-out Bragg peak

(SOBP). The modulation of the SOBP was 8–10 cm, the

initial beam energy was 160, 225, 400, 557 and

570 MeV/u for p, He, C, Ne and Ar ions, respectively (Jakel, 2006)

16

6. Clinical application of proton therapy

Clinical use of proton beam therapy (PBT) has

become a major focus of health policy debate in

the (Mark V. Mishra et.al 2016). The rationale for

the use of proton beams in radiotherapy is the

increased tumor control probability (TCP) by

delivering higher doses to the tumor. Like other

highly conformal therapy techniques, proton

therapy is of particular interest for tumors located

close to serial organs. Data are grouped according

to anatomic region.

6.1. Central Nervous System and Base of

Skull (Adults)

In the beginning of 90’s, proton therapy was used

to treat brain metastases and AVM’s at Loma

Linda University, United States (Slater, 2006). At

Harvard Cyclotron Laboratory the investigations

reported long-term success with stereotactic

proton radiosurgery for pituitary adenomas

(Ronson et al 2005), Reporting on patients treated

during the period from 1963 to 1990, they

observed that 98% of 581 patients with

acromegaly had hormone normalization at 20

years post treatment. In a group of 36 patients

with Nelson’s syndrome and 180 patients with

Cushing’s disease, 85% achieved hormone

normalization at 20 years (Kjellberg et al 1990). A

radio-surgical application of protons has been

implemented in the treatment of AVMs (Kjellberg

et al. 1983).

6.2. Paediatric intracranial tumors

The use of proton therapy for paediatric

intracranial tumors has not been widely studied,

there are some publications and ongoing studies,

Most studies are case series with a limited number

of patients included (<30). Benk et al. studied

Base of skull and cervical spine chordomas in

children treated by high-dose irradiation (Benk, V.

et al 1995), another study done by (Habrand, J.L.

1999) was Proton beam therapy (PT) in the

management of CNS tumors in childhood. , Hug

et al studied the Conformal proton radiation

therapy for pediatric low-grade astrocytoma’s

(Hug et al 2002). These studies were

heterogeneous with respect to diagnosis, stage and

treatment. Proton therapy was given as part of a

primary treatment, or as treatment for recurrence.

In most studies an aggressive treatment had been

administered, and local control rates were high.

6.3. Ocular tumors

Proton therapy has emerged as an alternative to

enucleation or ocular brachytherapy in the

treatment of ocular tumors, Seddon et al compared

cancer control rates for patients with uveal

melanomas following proton therapy versus

enucleation (Seddon, 1985). Patients treated with

proton therapy were younger, had smaller tumors

and different locations compared patients on the

control arm treated with surgery. Five year overall

survival was 81% in the proton therapy group and

17

68% in the enucleation group. Cox regression

analysis adjusted for prognostic variables found

no difference in overall survival, RR 1.2 (95% CI

0.9–1.2), or disease free survival, RR 1.0 (95% CI

0.7–1.4) (Olsen et al 2007).

A study analyzed medical records for patients

with choroidal melanoma treated with proton

therapy or brachytherapy. Local recurrence,

mortality and visual acuity were analyzed, but the

model was not appropriately adjusted for possible

confounders (only basal tumor diameter). Patients

treated with proton therapy had a higher mortality

rate (9.4%) compared to patients given

brachytherapy (3.7% and 5.0% for 125

I or 106

Ru,

respectively), but a lower rate of local recurrence

(5.2%), compared with 4.2% and 10.7% for 125

I

or 106

Ru, respectively (Wilson, M.W. and

Hungerford, J.L. 1999) and (Olsen et al 2007).

6.4. Chordomas and chondrosarcomas

Chordomas and chondrosarcomas in the head and

neck region are usually treated with surgery

and/or radiotherapy. Conventional radiotherapy

with doses of 50–55 Gy do not provide sufficient

cancer control, but higher doses may be offset by

toxic effects on surrounding neurological tissues.

A study randomized 96 patients with chordomas

and chondrosarcomas of the skull base to receive

66.6 or 72 CGE with a combination of proton and

photons by (Santoni,et al 1998) The only

publication identified from this study reported

temporal lobe damage without analyzing patents

by initial allocation group, and was not able to

relate temporal lobe damage to treatment strategy.

Overall temporal lobe damage was 7.6% at 2

years and 13.2% after 5 years.

Nine case-series reported results for around 500

patients treated with proton therapy alone or as a

supplement to conventional radiotherapy, Proton

therapy was given as part of primary treatment or

for recurrence. Five and 10 year survival was 94%

and 86%, respectively, for the whole population

(Debus et al. 1997). Two studies reported lower

overall survival for chordomas compared with

chondrosarcomas, at 3 year follow up 87–88% and

94–100%, respectively (Hug et al. 1999 and Noel

et al. 2002).

6.5. Prostate cancer

Men with prostate cancer comprise approximately

65% of all patients treated with protons at Loma

Linda University Medical Center; this population

represents the largest series of patients treated

with protons for prostate cancer anywhere in the

world. A series of reports from LLURM

investigators, and a multi-institutional randomized

controlled study, have demonstrated that proton

radiation enables delivery of effective doses of

ionizing energy to the desired prostatic CTV while

limiting radiation exposure of nearby tissues, thus

yielding few or no side effects in most patients

treated. Initial studies used total doses that were

10% greater than was typical at the time, and

18

preliminary results were encouraging (Slater,

Rossi, et al 1999).

6.6. Lung cancer

Based on the American society of oncology, there are

170,000 new lung cancer cases every year in United

States, previous researchers at Loma Linda

University Hospital encouraging the use of proton

therapy for stage one lung cancer (Bush et al

1999), and a later report indicated that excess

pulmonary toxicity did not occur when higher-

than-conventional doses of radiation at a higher-

than- conventional dose per fraction were

delivered via conformal radiation techniques with

protons (Bonnet et al 2001).

A study, investigating the role of PT in NSCLC

therapy, conducted for 68 patients, all of them

with stage one non-small-lung cancer were treated

with multi-beam proton radiation therapy. The

delivered treatment was 51 GyE in 10 fractions

over two weeks to the first 22 patients; the

subsequent 46 patients received 60 GyE in 10

fractions over two weeks., all 68 patients data

were analyzed and reported No symptomatic

radiation pneumonitis or late esophageal or

cardiac toxicity were seen; the 3-year local control

and disease-specific survival rates were 74% and

72%, respectively. There was significant

improvement in local tumor control in T1 vs. T2

tumors (87% vs. 49%), with a trend toward

improved survival (Bush et al 2004). In addition

to proton therapy treatment of lung tumours,

controlling tumour displacements remains one of

the biggest challenges (Kovács, et al 2007, 2007,

2009)

6.7. Hepatocellular carcinoma

A study conducted to determine the role of proton

therapy for treating Hepatocellular carcinoma with

34 patients had completed treatment and had been

followed for at least six months (median follow-

up, 20 months). The average tumor size was 5.7

cm. Two-year actuarial data showed a 75% local

tumor control rate and an overall survival rate of

55%. Of patients with an elevated pretreatment

alpha-fetoprotein (AFP), 85% were found to have

declining AFP levels, from a pretreatment mean of

1,405 to 35 at six months after treatment. Six

patients underwent liver transplantation several

months after radiotherapy was completed; two of

these individuals demonstrated no evidence of

residual carcinoma within the explanted liver.

Post-treatment toxicity was minimal and included

a small but significant decline in albumin levels

and increased total bilirubin; three patients

experienced duodenal or colonic bleeding when

bowel was immediately adjacent to the treated

tumor (Bush et al 2004).

6.8. Breast cancer

At present, the role of radiotherapy in the

multidisciplinary management of breast cancer is

well established (Coates et al 2015), Postoperative

irradiation reduces breast and lymph node

recurrences, and improves survival, mainly in

19

high-risk population. Treatment of local or loco-

regional breast areas with conventional radiation

techniques can include a significant amount of

normal tissue and organs at risk in the irradiated

volume, with the risk of treatment-related normal

tissue injury and worsening quality of life (Brown

et al 2015).

Recently, proton therapy has been also explored in

breast cancer treatment. This indication is not

recommended for routine referral because of

insufficient evidence, but inclusion in clinical

studies or treatment of individual cases should be

considered in a multidisciplinary setting (Patel et

al 2014). The potential of protons for coverage of

target tissues and sparing of normal structures has

been evaluated in several dosimetric studies, in

silico planning studies (Orecchiaa et al 2015),

several studies investigated the dose distribution

of protons in left-sided breast cancer, evaluating

the dose reduction to the heart. A comparative

treatment planning on 20 left-sided breast cancer

patients, with increasingly complex loco-regional

volumes including the internal mammary chain,

showed that IMPT allowed the best target

coverage and lowest dose to neighboring organs.

Cardiac dose lowered by a factor of above 20

when compared to IMRT, potentially reducing the

risk of cardiovascular toxicity (Ares et al 2010),

another study on five patients after mastectomy

and bilateral breast implants compared IMPT

versus three-dimensional (3D) conformal photons

(Jimenez et al 2013).

7. Challenges

7.1. Technical challenges

Proton beams for radiation therapy are generated

by using a particle accelerator, either a cyclotron

or a synchrotron. Both have their pros and cons.

Cyclotrons are smaller in size, but generally allow

the extraction of only one fixed beam energy. This

means that energy changes have to be achieved by

placing absorber material in the beamline,

typically right at the exit of the beam from the

cyclotron. A synchrotron produces a significantly

smaller beam (in cross-section) and can switch

energy on sub-second timescales. On the other

hand, its pulsed beam delivery makes it less

flexible for some modulation techniques.

Currently most proton therapy accelerators are

large, such that they are sited outside of the

treatment room. In fact, a proton accelerator will

typically feed several treatment rooms, with a

significant amount of space needed to transport

the beam from the accelerator using magnets for

bending, steering and focusing. In contrast, photon

LINACS, including all beam shaping and

monitoring devices, easily fit into a single room.

Proton facilities are therefore typically larger than

photon treatment facilities, not least because a

complete radiation delivery system also contains a

gantry to rotate the entire treatment head around

the patient. Most proton gantries have diameters

of several meters, owing to the magnetic field

20

strength required to bend the beam path of protons

with energies of up to 250 MeV. The cost of a

proton delivery system is also higher than that of a

photon machine, in part because of room

requirements when using a 360° gantry. A number

of studies have assessed the need for a full

rotational gantry and whether specific beam

angles might be sufficient. A full 360° gantry

might not be required for most treatments, for

example, with the use of a robotic couch with six

degrees of freedom and with patients being treated

in a lying or seated position.

7.2. Physics challenges

Dose uncertainties: When prescribing and

delivering dose we rely on the dose distributions

shown by the treatment planning program after

optimization. However, there is always

uncertainty when predicting the dose and the dose

distribution may not be delivered precisely as

planned. In radiation therapy, the aim is to deliver

the dose to within 2.5% of the prescribed dose.

This value was suggested by international

regulatory bodies.

Dose calculations are routinely performed using

analytical algorithms that are fast enough to allow

treatment optimization in minutes. While these

techniques are typically sufficiently accurate in

the photon world, they have significant

shortcomings in proton therapy. The steeper dose

gradients present in particle fields expose the

approximations in analytical algorithms, in

particular with respect to scattering of protons at

interfaces such as bone and soft tissue. While too

slow to be used in the clinic in the past, dose

calculations based on particle-track simulations

(‘Monte Carlo’) have recently achieved

efficiencies that make them suitable for use in

treatment planning. Monte Carlo codes offer

superior dose calculations to analytical algorithms

and are considered the gold standard.

Uncertainties can have more severe consequences

in proton therapy versus photon therapy because

of the finite range and the impact of proton

scattering in an inhomogeneous patient geometry.

Understanding uncertainties in proton therapy is

therefore vital when making treatment planning

decisions.

21

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