Università degli Studi di Napoli Federico II

Scuola Politecnica e delle Scienze di Base

Collegio di Scienze

Dipartimento di Fisica “Ettore Pancini” Corso di Laurea Magistrale in Fisica

TESI DI LAUREA SPERIMENTALE IN FISICA MEDICA

Dose intercomparison at Italian hadrontherapy centers

Relatori

Prof. Paolo Russo

Prof. Giovanni Mettivier

Candidata

Dott.ssa Federica Guida

Matricola N94/392

Anno Accademico 2017/2018

Università degli Studi di Napoli Federico II

Dose intercomparison at Italian hadrontherapy centers

by

Federica Guida (B.Sc. Physics)

This thesis work was carried out during December 2017 - June 2018, for fulfilling

the requirements for the Diploma di Laurea Magistrale in Fisica (M.Sc. Physics) at

University of Naples "Federico II", Naples, Italy. The Istituto Nazionale di Fisica

Nucleare (INFN) (Italy) approved scientifically and funded the research activities

carried out in this work, within the research project MC-INFN.

The following Institutions kindly provided access to their research or hospital

facilities for the purposes of this work:

Istituto Nazionale di Fisica Nucleare, Italy

Fondazione CNAO, Centro di Adroterapia Oncologica, Pavia, Italy

Centro di Protonterapia, APSS, Trento, Italy

Fondazione Maugeri, Pavia, Italy

3

4

«At Los Alamos, we had been working on one thing, and that was to kill people. When that

became crystallized in my mind by the use of the atomic bomb at Hiroshima, it was a

temptation, to salvage what was left of my conscience, I suppose, and think about saving

people instead of killing them. Because one could hurt people with protons, one could

probably help them too.»

Bob Wilson

5

TABLE OF CONTENTS

Glossary .................................................................................................................................... 6

Introduction ............................................................................................................................. 7

1 Dosimetry for particle beams in hadrontherapy ............................................................. 9

1.1 Principle and Rationale for hadrontherapy.............................................................. 9

1.2 IAEA TRS-398 Code of Practice for Dosimetry to Water ........................................ 11

1.3 Design of an intercomparison study for proton and Carbon ion beams ............... 17

2 Experimental data .......................................................................................................... 26

2.1 Previous comparison between CNAO, FM and CPT ............................................... 26

2.2 Measurements at CATANA in Catania.................................................................... 27

2.3 Measurements at CNAO in Pavia ........................................................................... 32

2.4 Measurements at CPT in Trento ............................................................................ 39

2.5 Measurements at Fondazione Maugeri in Pavia.................................................... 43

2.6 Intercomparison between CATANA, CNAO, CPT and FM ...................................... 46

Conclusions ............................................................................................................................ 51

Appendix ................................................................................................................................ 52

Bibliography ........................................................................................................................... 58

Acknowledgements ................................................................................................................ 61

6

GLOSSARY

AIRO: Associazione Italiana Radioterapia Oncologica

INFN: Istituto Nazionale di Fisica Nucleare

CNAO: Centro Nazionale Adronterapia Oncologica

FM: Fondazione Maugeri

CPT: Centro Protonterapia Trento

LNS: Laboratori Nazionali del Sud

CATANA: Centro di AdroTerapia ed Applicazioni Nucleari Avanzate

PTCOG: Particle Therapy Co-Operative Group

HIT: Heidelberger Ionenstrahl-Therapiezentrum (Heidelberg Ion-Beam Therapy

Centre)

RT: RadioTherapy

IMRT: Intensity Modulated Radiation Therapy

PhXRT: Photon-based eXternal beam Radiation Therapy

SOBP: Spread Out Bragg Peak

ICRU: International Commission on Radiation Units and Measurement

QA: Quality Assurance

TPS: Treatment Planning System

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INTRODUCTION

Even if the application of high-energy beams of heavy charged particles to

radiotherapy was first considered in 1946 [1] and the first treatment with hadrons

was held in 1950 [2], the use of proton and ion beams for clinical applications can be

still considered as a pioneer activity. As a matter of fact, analysis of the current state

of hadrontherapy shows a situation of strong expansion, with 73 operating centres

as reported by Particle Therapy co-operative Group (PTCOG) in December 2017 [4].

Most of the centres examined have protons beams available (48 in total, 16 of which

in USA, 15 in Europe, 9 in Japan and 8 in other regions) and 11 provide carbon ions (5

in Japan, 4 in Europe and 2 in China). It should be remarked that 4 of these centres

(Heidelberg, Pavia, Shanghai and Hyogo) have dual accelerators, which can accelerate

both protons and carbon ions.

Particle in use Patient total Date of total

He 2054 1957-1992

Pions 1100 1974-1994

C-ions 21580 1994-2016

Other Ions 433 1975-1992

Protons 149345 1954-2016

TOTAL 174512 1954-2016 Table 1 PTCOG Report [4].

Given that primary standards of absorbed dose to water for proton and Carbon ion

beams remain to be established, and the importance of the verification of the

absolute and spatial dose prior to a patient treatment as part of QA, we aim to

perform the first intercomparison study on nominal doses delivered by the

Treatment Planning System (TPS) in various italian hadrontherapy centers.

Our plan is to use two ionization chambers for reference dosimetry in water,

according to IAEA TRS398 code of practice and to perform measurements of nominal

dose delivered by the TPS, in Italian Hadrontherapy such as CATANA in Catania, CPT

in Trento, and CNAO in Pavia both at single layer and at the center of SOBP. This work

follows Barbato’s thesis [5], using the same experimental setup and, where possible,

the specific reference conditions of every single session of measurements. This thesis

8

is performed also within the activities of the MC-INFN project: we plan to use Geant4

framework to simulate our experimental setup in CATANA and CPT beamlines and to

obtain energies register in detectors.

In the first chapter of this thesis we set the theoretical bases for the study and the

rationale of hadrontherapy, introducing IAEA TRS 398 Code of practice for dosimetry

to water and describing the experimental design we used in therapy facilities

including experimental instruments.

In the second chapter we describe the facilities involved in the intercomparison, the

specific reference conditions of every single session of measurements, the

experimental data and their elaboration. We also recall Barbato’s previous results

[5]. Ultimately, we discuss the preliminary results of the intercomparison and we will

present future prospective.

9

1 DOSIMETRY FOR PARTICLE BEAMS IN HADRONTHERAPY

1.1 PRINCIPLE AND RATIONALE FOR HADRONTHERAPY

According to Associazione Italiana Radioterapia Oncologica (AIRO) more than 60% of

oncological patients receive radiotherapy (RT) or as monotherapy protocol or in

association with a cancer treatment (such as surgery or chemotherapy) [3]. While

recent advances led to the development of highly sophisticated photon-based

external beam radiation (PhXRT) techniques (including intensity-modulated RT

(IMRT), image guided RT (IGRT), and stereotactic body RT (SBRT)), which resulted in

a significant widening of indications and improvement of outcomes, there are still

many tumour sites and histologies that remain challenging to treat with PhXRT. To

overcome these difficulties, in the last 60 years hadrontherapy has made great

advances passing from a stage of pure research to a well-established treatment

modality. Among others, the non-invasive nature of hadrontherapy represents a

suitable alternative to surgery for tumours whose removal would be too debilitating

for the patient and for radioresistant ones (usually located in pancreas, brain,

prostate) which are less likely to be cured by conventional RT, either because of their

biological behaviour or because they are relapses of a previous tumour.

The strength of hadrontherapy lies in the unique physical and radiobiological

properties of proton and ions that can contribute to an overall superior delivery of

radiation dose when compared to PhXRT, such as:

(1) spread-out Bragg peak (SOBP), leading to enhanced dose distribution and

lateral focusing

(2) potential for dose verification via available imaging

(3) superior linear energy transfer

(4) magnetic steering of the ion beams (scanning beams).

These properties should theoretically lead to optimal delivery of radiation to the

tumour while simultaneously sparing at risk adjacent structures: maximally safe and

10

potentially curative doses. Nowadays there are two different clinical applications for

proton and ion beam [6]: the treatment of ocular tumors (uveal melanoma, choroidal

metastases, conjunctival tumors, eyelid tumors) and the treatment of large and deep-

seated tumors. For the ocular treatments energies lower than 90 MeV with field size

smaller than 4x4 cm2. For deep-seated tumors, energies between 50 and 250 MeV,

corresponding to a range in water up to 25 g/cm2 (in mass length units, product of

the actual thickness in cm and the material density in g/cm3), are used.

Figure 1 Attenuation in water for different particle used in clinical therapy. In red is drawn the Bragg Peak and in Blue it is shown the SOBP. It is clearly visible the advantage of protons and ions for deeply located tumors.

In the case of high energy protons, incident particles interact with target nuclei and

produce low-energy protons or heavy ions. Carbon ions are heavier than protons and

are known to exhibit a significantly increased biological effectiveness in the Bragg

peak; but, on the other hand, passing through human tissues or beam modulating

devices, they produce fragmented nuclei that reach deeper regions than Carbon ions

themselves, resulting in a tail, in the depth-dose distribution, at the distal end of the

typical Bragg peak, as can be seen in Figure 1.

A common index used to quantify the biological effects of radiations is the Biological

effective dose (DBE), defined as

DBE(Gy) = D(Gy) ∙ RBE

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where RBE is the Relative Biological Effectiveness (the ratio of biological effectiveness

of one type of ionizing radiation relative to a reference one, typically 6 MV photons)

and D is the (physical) absorbed dose, defined as the mean energy imparted to matter

per unit mass by ionizing radiation and measured by the unit Gray (Figure 2).

Figure 2 Three depth–dose distributions—physical dose, biologic dose, and clinical dose—for spread-out Bragg

peak for 290 MeV/n carbon beam. [12]

1.2 IAEA TRS-398 CODE OF PRACTICE FOR DOSIMETRY TO WATER

The TRS 398 Code of Practice [8] was published in 1996 by the International Atomic

Energy Agency on behalf of the IAEA, the European Society for Therapeutic Radiology

and Oncology (ESTRO), the World Health Organization (WHO) and the Pan-American

Health Organization (PAHO). This protocol responds to the need for a unified

approach for calibration and use of ionization chambers in determining absorbed

dose to water for external beams in radiotherapy and hadrontherapy. These

standards of absorbed dose to water represent the main difference from previous

protocols (TRS-381 and TRS-277) which were based on air kerma standards.

Moreover, one of the major goals of this international code of practice is to establish

uniformity for the dosimetry of all radiation beam types used in cancer therapy in

most countries, using the same formalism as specifically introduced by Hartmann et

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al. [7] in 1999 for scanned particle beams. Cylindrical ionization chambers are

recommended for reference dosimetry, provided that the measure is limited to the

entrance plateau region of a sufficiently high-energy particle beam, or the SOBP

width is ≥ 2 cm in water; if not, chambers with better spatial resolution, like plane-

parallel chambers (as PTW Advanced Markus used in this intercomparison), must be

used. In a clinical treatment for tumour eradication, it is generally required an

accuracy of ± 5% at the level 1σ in the delivery of an absorbed dose to a target

volume, as concluded by the International Commission on Radiation Units and

Measurement (ICRU) in its in Report 24 [9].

According to the protocol, the absorbed dose to water at the reference depth, zref, in

a water phantom irradiated by a beam of quality Q (𝐷𝑤,𝑄) can be written as

𝐷𝑤,𝑄 = 𝑀𝑄 ∙ 𝑁𝐷,𝑤,𝑄0 ∙ 𝑘𝑄,𝑄0

where 𝑀𝑄 is the reading of the electrometer corrected for all the influence

quantities, 𝑁𝐷,𝑤,𝑄0 is a calibration factor in terms of absorbed dose to water,

measured in air using a60Co beam and 𝑘𝑄,𝑄0 is a factor that corrects for the effects of

the differences between the reference beam quality Q0 and the actual used quality

Q. We will omit the subscript Q0 if referred to a 60Co beam.

However, the calibration factor 𝑁𝐷,𝑤,𝑄0 for an ionization chamber is valid only for the

reference conditions that apply to the calibration. Any departure from the reference

conditions should be corrected so it is necessary to define the appropriate factors

that can influence the quantity under measurements; they may vary in nature as, for

example, pressure, temperature and polarization voltage or may be related to the

radiation field (e.g. beam quality, dose rate, field size, depth in a phantom). It is

possible to correct for the effect of these influence quantities by applying appropriate

factors. Assuming that influence quantities act independently from each other, a

product of correction factors can be applied, ∏𝑘𝑖, where each correction factor ki is

related to one influence quantity only. The independence of the ki holds for the

common corrections for pressure and temperature, polarity, collection efficiency,

etc. so we can define the fully corrected charge reading as

𝑀𝑄 = 𝑀𝑟𝑎𝑤 ∙ 𝑘𝑇𝑃 ∙ 𝑘𝑠 ∙ 𝑘𝑝𝑜𝑙

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where 𝑀𝑟𝑎𝑤 is the reading on the dosimeter without corrections.

As all the chambers recommended by TRS 398 are open to the ambient air, the mass

of air in the cavity volume is subject to atmospheric variations. The factor 𝑘𝑇𝑃 defined

as

𝑘𝑇𝑃 = (273.2 + 𝑇)𝑃0(273.2 + 𝑇0)𝑃

where temperature T and pressure P correspond to those of the cavity air mass of

the ionization chamber and T0 and P0 correspond to reference conditions, is used.

The factor kpol accounts for the effect, on a chamber reading, of using opposite

polarity potentials. When a chamber is used in a beam that produces a measurable

polarity effect, the true reading is taken to be the mean of the absolute values of

readings M+ and M- taken at both polarities

𝑘𝑝𝑜𝑙 =|𝑀+| + |𝑀−|

2𝑀

where M is the electrometer reading obtained with the polarity used routinely,

positive or negative.

The incomplete collection of charge in an ionization chamber cavity owning to the

recombination of ions requires the use of a correction factor ks. In pulsed-scanned

beam the dose rate during a pulse is relatively high and recombination is often

significant, and it is recommended that the correction factor is derived using the two-

voltage method. This method assumes a linear dependence of 1/M on 1/V and uses

the measured values, under the same irradiation conditions, of the collected charges

M1 and M2 at the polarizing voltages V1 and V2 respectively. V1 is the normal operating

voltage and V2 a lower voltage, so that is equal to or larger than 3. The factor is

obtained from

𝑘𝑠 = 𝑎0 + 𝑎1 (𝑀1

𝑀2) + 𝑎2 (

𝑀1

𝑀2)2

The constants ai depend on the pulsed or pulsed-scanned technique and on the

voltages applied, according to tabulated values [8].

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The most important factor is kQ ,Q0, defined as the ratio, at the qualities Q and Q0 , of

the calibration factors in terms of adsorbed dose to water of the ionization chamber:

kQ,Q0 =ND,w,Q

ND,w,Q0=

Dw,Q/MQ

Dw,Q0/MQ0

In many cases, when no direct calibration at the user quality and no experimental

data are available, and where Bragg-Gray theory can be applied, the correction

factors can be calculated theoretically as the ratio, for the qualities Q and Q0, of the

products of Spencer-Attix water/air stopping power ratio sw,air , of the main energy

expended in air per ion pair formed wair , and the perturbation factor p at the

different beam qualities

kQ,Q0 =(sw,air)Q

(wair)Q

(sw,air)Q0(wair)Q0

pQ

pQ0

In Code of Practice 398, tabulated values for kQ,Q0 are given for the most common

used ionization chambers, depending on the beam quality index, called residual

range, defined as

Rres = Rρ – z

where z is the depth of measurement and Rρ is the practical range (both expressed

in g/cm2), which is defined as the depth at which the absorbed dose beyond the

Bragg peak or SOBP falls to 10% of its maximum value.

The overall perturbation factor p includes all departures from the ideal Bragg-Gray

detector conditions:

p = pcav ∙ pdis ∙ pcel ∙ pwall

In particular, the perturbation of the electron fluence entering the cavity is accounted

by the factor pcav.

The shift of the effective point of measurement zref , due to the presence of the

central electrode, is accounted by the displacing factor pdis or by shifting the

reference point of the chamber (the center of the cavity volume of the chamber on

the chamber axis) by a proper compensating amount, recommended as 0.75 times

15

the internal radius rcyl of the cylindrical chamber (i.e PTW Farmer). For the parallel

plate ionization chamber (i.e PTW advanced Markus) the water-equivalent thickness

of the phantom window or the waterproofing sleeves must also be taken into account

in pwall or in zref shift.

The factor pcel corrects the response for the effect of the central electrode, an

energy-dependent variation of the chamber response related to the size and

composition of the central electrode [4]: the value pcel = 1.0 is used in the IAEA

Code of Practice along with the stated uncertainty of 0.4% (for all cylindrical

ionization chambers) and it is not considered for parallel plate chambers such as

Advanced Markus.

The factor pwall accounts for the non medium-equivalence, that represents the

different radiation response of the chamber wall material from that of the phantom

material.

Experimental information on perturbation factors in proton beams is currently only

available for a limited number of ionization chambers at a specific proton energy.

When no data are available, all components are taken to be unity, with uncertainties:

0.2% for pdis, 0.6% for pwall, 0.4% for pcel, and negligible uncertainty for pcav .

For Carbon beams, because of the unavailability of experimental information, p is

always taken to be unity, with an overall uncertainty of 1.0%. The determination of

all correction and perturbation factors for this thesis work will be discussed in the

second chapter, together with the description of the measurements at the different

medical facilities.

Uncertainties of measurements are expressed as standard or relative standard

uncertainties (corresponding to one standard deviation). Estimates of the uncertainty

in dose determination for the different radiation types are given in the appropriate

sections of the TRS-398 Code of Practice. The uncertainties associated with the

physical quantities and procedures involved in the determination of the absorbed

dose to water in the user proton beam can be divided into two steps:

Step 1: considers uncertainties up to the calibration of the user chamber in terms of

ND,w at a standards laboratory;

16

Step 2: deals with the subsequent calibration of the user proton beam using this

chamber and includes the uncertainty of kQ as well as that associated with

measurements at the reference depth in a water phantom. Estimates of the

uncertainties in these two steps are given in Figure 4, yielding a combined standard

uncertainty of 2.0 % (cylindrical chambers) and 2.3% (plane-parallel chambers) for

the determination of the absorbed dose to water in a clinical proton beam.

Figure 3 Estimated relative standard uncertainty of 𝑫𝒘,𝑸 at the reference depth in water for a clinical proton

beam, based on a chamber calibration in 𝑪𝒐𝟔𝟎 Gamma radiation [8].

For Carbon ions beams, uncertainties are larger if compared to the dosimetry of

proton beams, because of the larger contribution from kQ uncertainty (2.8 rather

than 1.7 % ), leading to a global standard uncertainty of 3.0 % for cylindrical

chambers and 3.4% for plate-parallel one, as shown in Figure 5.

Figure 4 Estimated relative standard uncertainty of 𝑫𝒘,𝑸 at the reference depth in water for a clinical ion beam,

based on a chamber calibration in 𝑪𝒐𝟔𝟎 Gamma radiation. [8]

17

For photon beams, kQ uncertainty is 1.0 %, and the global standard uncertainty is

1.5 %, as shown in Figure 6.

Figure 5 Estimated relative standard uncertainty of 𝑫𝒘,𝑸 at the reference depth in water for a clinical photon

beam, based on a chamber calibration in 𝑪𝒐𝟔𝟎 Gamma radiation. [8]

1.3 DESIGN OF AN INTERCOMPARISON STUDY FOR PROTON AND CARBON ION BEAMS

This work aims to perform and partially complete the intercomparison started in [5].

To compare nominal doses delivered by the Treatment Planning Systems (TPS) in

various Italian therapy centres, we will use the same experimental setup used in

Barbato’s work [5] and a new plate-parallel ionization chamber suitable for beams

with a narrow SOBP.

Figure 6 Experimental setup for reference dosimetry in water.

The setup is the follow: a water phantom is placed in a proton or Carbon ions beam,

so that the beam’s central axis crosses the center of the entrance window (Figure 6).

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An ionization chamber (or an EBT-3 film piece) is placed in the phantom at a reference

depth of 2 cm in water, and then irradiated. As stated in Code of practice, it is kept in

account the displaced of the effective point of measurements to correct for the factor

pdis . In the following paragraphs we will briefly describe every piece of the

experimental setup and, where possible, we will describe how to analyse them.

1.3.1.1 Water phantom

In this work we aim to determine the absorbed dose to water at the reference depth

in a homogeneous water phantom. According to TRS 398 it is better not to use plastic

phantoms as in general they are responsible for the largest discrepancies in the

determination of absorbed dose for most beam types. This is mainly due to density

variations between different batches and to the approximate nature of the

procedures for scaling depths and absorbed dose (or fluence) from plastic to water.

In the code of practice, it is also stated that a “good” phantom should extend to at

least 5 cm beyond all four sides of the largest field size employed at the depth of

measurement.

Figure 7 Water Phantom [11]

In our measurements all the water phantom used had the same specification. For

example, the PTW 41023 (Fig. 7) is a water phantom specifically designed for

calibration measurements in radiation therapy using a horizontal beam. The

ionization chamber can be placed at different water depths by using waterproof

acrylic adapter and a calliper on the phantom top, from less than 15 mm up to

260 mm . The PMMA sleeve has a sufficiently thin wall to allow the chamber to

19

achieve thermal equilibrium with the water in less than 10 min and is designed to

allow the air pressure in the chamber to reach ambient air pressure quickly. The

external phantom dimensions are approximately 30 × 30 × 30 cm3 , and the

entrance window in one of the walls has the thickness of 3 mm and the size of

150 × 150 mm2.

1.3.1.2 Ionization chambers

Following the recommendation of the code of practice, we use three different

ionization chambers: PTW Farmer type 30010-1, PTW Semiflex 31010 and PTW

Advanced Markus type 34045, respectively two cylindrical and a plane-parallel one.

The PTW Farmer is a cylindrical ionization chamber with a sensitive volume V of 0.6

cc. It is fully guarded (i.e. electric current leaking through the HV insulator is

intercepted by a grounded guard electrode) vented to air and not waterproof unless

the build-up cap is positioned. All the important dimensions are listed in Figure 8. The

Farmer type has the wall of the sensitive volume V (radius 3.05 mm and length

23.0 mm ) made of PMMA ( 0.355 mm, 1.19 g/cm3 ) and graphite

(0.09 mm, 1.85 g/cm3)), the central electrode in Al 99.98 (diameter 1.1 mm) and

the build up cap (which has been replaced by the waterproof sleeve of the water

phantom) made of PMMA (4.55 mm thick).

The acrylic wall ensures the ruggedness of the chamber, protecting it from

mechanical damage and dirt; it shields the active volume from charged particles that

Figure 8 (a)PTW Farmer and (b) schematic of his dimensions and materials. [16]

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originate outside the wall, and is a source of secondary charged particles that

contribute to the dose in V, providing charged-particle equilibrium (CPE), which is

essential for kerma-dose equivalence.

The PTW Advanced Markus is a plane parallel ionization chamber whose sensitive

volume is 0.02 cc. This kind of chamber is suitable for reference dosimetry for proton

and heavy ion beams, especially for beams having narrow SOBP (like CATANA facility)

and must be used for beams with qualities at the reference depth Rres < 0.5 g cm-2 but

the combined standard uncertainties will be higher than a cylindrical chamber due to

a higher uncertainty on pwall.

Figure 9 (top) PTW Advanced Markus [11] (bottom) its schematics

21

PTW Advanced Markus features a wide guard ring design to avoid perturbation

effects by reducing the influence of scattered radiation from the housing. The

chamber features a flat energy response within the nominal energy range from 2

MeV to 45 MeV.

This chamber is not waterproof unless a protection cap is positioned on the chamber.

Usually for plane-parallel chambers the effective point of measurement coincides

with the reference point, which is a point on the chamber axis at the inner surface of

the entrance foil. But the protection cup introduced a shift in the reference point of

measurement of 1.06 mm of water equivalent thickness due to material layer

upstream from the measuring volume. These materials are: 0.87 mm of PMMA, 0.40

mm of air and 0.03 mm of PE whose sum of area densities is 106 mg/cm3

corresponding to 1.06 mm of water.

PTW Semiflex 31010 is a cylindrical ionization chamber with a sensitive volume V of

0.3 cc and, unless Farmer type, it is waterproof and vented fully guarded. In Figure

(13) all the important dimensions are listed. This chamber has the sensitive volume

Figure 10 Radiography of the Advanced Markus ionization chamber (2.5 mm Al, 80 kV, 300 mAs). The scale in the upper right states the different ratios I/I0

22

made of PMMA (0.55 mm, 1.19 g/cm3) and graphite (0.15 mm, 1.85 g/cm3) with the

centrale elctrode made of aluminium 99.98.

Figure 11 Schematics of the PTW Semiflex 31010 ionization chambers.

1.3.1.3 Dosimeter

The electrometer used is a PTW-Freidburg Unidos E, a high-quality dosimeter for

universal use in radiation therapy and diagnostic radiology. The electrometer used

for the intercomparison is the UNIDOS E by PTW-Freiburg (Fig. 13), a high quality

dosemeter for universal use in radiation therapy and diagnostic radiology. It complies

with the International Electrotechnical Commission (IEC) 60731 Standard and can be

remotely controlled with the PTW DosiCom software via Serial Cable (RS-232). The

measuring range is 200 fA − 1μA and the resolution is 1 fA. [5]

Figure 12 PTW Unidos E electrometer used in this work [11]

The electrometer and the ionization chambers have been both calibrated measuring

absorbed dose to water (Dw ) in a a Co60 beam at temperature T0 = 20° C and

pressure P0 = 1013.25 hPa . The factory-provided calibration factor for Farmer

23

chamber is ND,w,Q0 = 5.381 ∙ 107 Gy/C while for Advanced Markus chamber is

ND,w,Q0 = 1.480 ∙ 109 Gy/C. In electrical mode, the UNIDOS E measures charge C

and current; in radiological mode, it gives the dose as the product C ∙

ND,w,Q0 (corresponding to MQ ∙ ND,w,Q0 uncorrected) and the dose rate.

1.3.1.4 EBT-3 film

Radiochromic films (e. g. Gafchromics EBT-3) are widely used to measure 2-D dose

distributions with high spatial resolution, and for pre-treatment radiotherapy

verification and quality assurance. To measure dose, the increase in film’s optical

density produced by the radiation is converted into absorbed dose using a calibration

curve, mostly nonlinear. The film response strongly depends on beam quality and

LET. In case of clinical beams considered in this study, irradiations lead to a strongly

inhomogeneous dose deposition and a quenching effect affects the film response at

the Bragg peak region. Nevertheless, in the plateau region of the depth-dose curve

for monoenergetic proton beams, the response has been observed to coincide with

the curve for beam [12]. Instead, in the plateau region of monoenergetic Carbon

beams, the relative efficiency, defined as the ratio of doses of photons to that of ions

needed to produce the same film darkening, ranges from about 0.84 to about 0.71

(energies 115-400 MeV/u), corresponding to an energy-dependent under-response

from 16% to 29% [5]. No dependence on the dose and thus on the fluence has been

observed.

Figure 13 Schematics of an EBT3 film

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In this intercomparison EBT-3 films are used to visualize beam profile, since these

films can measure absolute dose as long as there is an established conversion (a

calibration curve) of the film response to dose deposited within reference medium

that caused measured change in transmittance. In case there is no curve available,

they can be used for relative dosimetry if the film batch and the beam quality are the

same. Following Devic et al protocol [11], film were cut into 10x10 cm2 and 5x5 cm2

(in case of CATANA measurements). After irradiation, films were placed at the center

of the flatbed scanner EPSON Perfection V850 Pro, using a paper guide with a mark

to help reproducibility. Three different 48-bit RGB (150 dpi) scans were obtained both

pre- and post irradiations, to get a single average image with reduced noise. Since the

polymer created after irradiation has the highest absorption in the red part of the

optical spectrum, centred at the wavelength of 633 nm, the images were analysed in

the red channel (16-bit), sampling raw data from 5 different regions of interest (as

shown in Figure 13) as the average pixel value (PV) and its corresponding standard

deviation (σPV).

The response of radiochromic films is described by transmittance (the transmitted

light intensity relative to initial intensity)

T =ItransI0

=PVtrans216

Since the quantity of interest in film dosimetry is the actual change of T, it is

preferable to use the change in optical density (OD = − log10 T ) after irradiation,

for every single ROI𝑖

netODi = ODafteri − ODbefore

i

We now consider both the impact of the dark (or background) signal and the

influence of environmental factors (using a control film piece not irradiated):

∆(netODi) = log10PVbefore − PVbckg

PVafter − PVbckg − log10

PVbeforecontrol − PVbckg

PVaftercontrol − PVbckg

and the standard deviation

25

σ∆netODi =1

ln10

√ (σPVbefore)2

(PVbefore − PVbckg)2 +

(σPVafter)2

(PVafter − PVbckg)2 +

+[PVbefore − PVafter

(PVbefore − PVbckg) ∙ (PVafter − PVbckg)]

2

∙ (σbckg)2+

+(σPVbefore

control)2

(PVbeforecontrol − PVbckg)

2 +(σPVafter

control)2

(PVaftercontrol − PVbckg)

2 +

+[PVbefore

control − PVaftercontrol

(PVbeforecontrol − PVbckg) ∙ (PVafter

control − PVbckg)]

2

∙ (σbckg)2

The average optical density change can be calculated using a weighted mean of the

5 sampled ROIs

∆netOD̅̅ ̅̅ ̅̅ ̅̅ ̅̅ = ∑[wi ∙ ∆(netODi)]

5

i=1

with the corresponding normalized weights calculated as

wi =1/(σ∆netODi)

2

∑ [1/(σ∆netODi)2]5

i=1

and the corresponding standard deviation on ∆netOD̅̅ ̅̅ ̅̅ ̅̅ ̅̅

𝜎∆netOD̅̅ ̅̅ ̅̅ ̅̅ ̅̅ ̅ = √5

∑ [1/(σ∆netODi)2]5

i=1

EPSON Perfection V850 Pro is a flatbed scanner with scanning resolution of

6400 DPI (Horizontal x Vertical), with a Matrix CCD with Micro Lens and High Pass

Optics as optical sensor, and White LED, IR LED with ReadyScan LED Technology as

light source.

26

2 EXPERIMENTAL DATA

2.1 PREVIOUS COMPARISON BETWEEN CNAO, FM AND CPT

The idea of a dose intercomparison was born after R. Castriconi’s article [18] where

the need of an intercomparison between hadrontherapy centers was advocated.

The previous activity in this respect was performed by A. Barbato in his M.Sc thesis

[5]. He studied absorbed dose to water in three different centers: CNAO with proton

and Carbon beam, Fondazione Maugeri with photon and CPT with proton beam. All

the energies used in that work are shown in Table 1. The experimental set up is, for

obvious reasons, the same of this thesis: a water phantom, a dosimeter Unidos E by

PTW-Friedburg and a PTW Farmer type 30010-1 as ionization chamber and all the

measurements were made according to the same dosimetric protocol and formalism.

In every facility involved has been asked to deliver a beam, both as single

monoenergetic layer (to be measured at plateau region) and Spread Out Bragg Peak

(SOBP) to obtain a nominal (biological or physical) dose of 2 Gy at the reference depth

zref=2 cm in the water phantom [5] (Figure 14).

Figure 14 Set up for measurements in [5]. Dimensions are not in scale.

In Barbato’s work the weighted mean of nominal dosed at different facilities is

2.000 ± 0.012 Gy, as shown in Table [1] and it shows an excellent consistency within

27

the experimental uncertainties. The data weighted mean is 2.000 Gy and the

standard deviation is 0.013, consistent with the mean nominal dose. The largest data

deviation relative to the mean nominal dose is 2.8%.

Facility Beam Dose (Gy)

CNAO p 118.19 MeV 1.999 0.039

p 173.61 MeV 2.017 0.039

p SOBP 1.995 0.038

C 208.58 MeV/u 2.015 0.059

C 332.15 MeV/u 2.000 0.059

C SOBP 2.018 0.059

FM Fotoni 6 MV 1.998 0.027

CPT P 118 MeV 1.997 0.038

P 173 MeV 1.993 0.038

p SOBP 1.992 0.038

Table 1 Corrected dose and dose standard uncertainty calculation for the different facilities involved in Barbato's thesis [5]

Figure 15 Dose to water in every facility involved in Barbato's work. [5]

2.2 MEASUREMENTS AT CATANA IN CATANIA

Measurements at Centro di AdroTerapia ed Applicazioni Nucleari Avanzate (CATANA)

in Catania, Italy, were taken on May 10th, 2018.

28

This facility was built in 2002 thanks to the collaboration between INFN-LNS and AOU-

Vittorio Emanuele of Catania, and more than 300 patients was successfully treated

for ocular melanomas with the 62 MeV proton beams accelerated by the INFN-LNS

superconducting cyclotron. The most frequent neoplasia treated with proton beams

is the uveal melanoma, followed by other eye diseases like choroidal metastases,

conjunctival tumors, and eyelid tumors [13]. The CATANA facility is based on a passive

transport system of a 62-MeV proton beam. The proton maximal range, at the

irradiation point, is about 30 mm, ideal for the treatment of eye tumors. The

necessary maximum range and energy modulation are achieved by means of a set of

Perspex absorbers, variable in thickness, and modulator wheels. [13]. Because of the

passive system of dose deliver, only measurements at the center of SOBP are

possible.

Figure 16 Central section of the CATANA proton therapy beamline with some transport (collimators, modulators, and range shifters) and diagnostic (monitor chambers, on-line profile monitoring, and field simulator). [13]

The plan of measurements consists in determination of the absorbed dose to water

𝐷𝑤,𝑄 = 𝑀𝑄 ∙ 𝑁𝐷,𝑤,𝑄0 ∙ 𝑘𝑄,𝑄0

using the PTW TM-35045 Advanced Markus chamber and the PTW TN-30010-1

Farmer chamber, the PTW UNIDOS E electrometer and a custom water phantom

(with the same specifications of PTW 41023 water phantom used in other centers).

The nominal dose delivered by the TPS refers to the reference dosimetry of the

29

CATANA facility made using the Advanced Markus chamber and the PTW UNIDOS

Webline electrometer because plane-parallel chambers are mandatory at low proton

energies. In fact, according to IAEA TRS 398, farmer chamber shouldn’t be used for

the reference dosimetry in centers with beams with qualities at the reference depth

Rres < 0.5 g cm-2. The values of ks and kpol for Farmer chamber are the same used in

[5] whereas for Advanced Markus have been calculated during CPT measurement.

The procedure deduced by IAEA TRS 398 code of Practice and used to determine

these coefficients is explained in section 2.4.

The factort kTP is calculated as

𝑘𝑇𝑃 = (273.2 + 𝑇)𝑃0(273.2 + 𝑇0)𝑃

where T and P are the temperature and the pressure during the measurements. In

this case T=22°C and P=985 hPa while the calibration temperature and pressure for

both chambers can be found in Appendix.

Because of the passive system of beam delivery and the low proton energies, only

SOBP measurements were available. So, we asked to deliver 2 Gy at the center of

SOBP (zref=2.4 cm), according to Table 2.

Table 2 Measuring plan worksheet for absorbed dose to water determination for protons at CATANA

During the measurements the shift of the reference point is taken into account, both

with Farmer chamber and Advanced Markus one, as said in Chapter 1.

30

Each measurement was repeated three times (except for film irradiations), and the

result is their average value, with predicted overall relative standard uncertainty for

protons (2.0% for Farmer measurements and 2.3% for Advanced Markus ones), as

estimated in TRS-398 Code of Practice, which includes, among the appropriate

chambers for the standard measuring protocol, the ion chambers used here.

Figure 18 (a) Ionization chamber was positioned at isocenter with room laser (b) Farmer Chamber placed in water phantom

The water phantom was placed in front of the beam exit window (Fig. 20(b)), and the

center of the phantom was aligned at the isocenter using the room lasers (Fig. 20(a)).

The UNIDOS E needs a warm-up period of 5 minutes, after which the offset current

is sufficiently stable. After selecting the chamber voltage and the measurement range

(HIGH for Farmer and MEDIUM for Advanced Markus), the ion chambers were

connected, and an automatic zeroing was performed by pressing the NULL button.

All the measurements are taken via DOSICOM(Fig.21), a software by PTW which allow

Figure 17 (a) View of CATANA patient room and (b) Particular of the collimator

31

us to connect our dosimeter to a laptop conveniently placed inside the treatment

chamber. Thanks to Dosicom, it is possible to perform remote measurements of dose

in an interval and be sure of taking in consideration the whole duration of the beam.

Figure 19 A screenshot of DOSICOM software during one of the measurements.

Figure 20 SOBP used during measurements in CATANA facility

Beam Ionization Chamber

Charge (nC)

P SOBP Farmer 35.91

36.00

35.97

Advanced Markus 1.314

1.316

1.317

Table 3 Ion chambers measurements at CATANA

32

Chamber ND,W (Gy/C) Mean Charge (nC)

kQ ks kpol kP,T

Farmer 5.381 ·108 36.00 1.0048 1.000 1.001 1.03

A. Markus 1.480 ·109 1.32 1.0048 1.003 1.001 1.03

Table 4 Results for CATANA measurements and correction factors to convert charge to absorbed dose to water

Afterward we place an EBT-3 film inside a phantom and aligned it at the isocenter, as

can be seen in Figure 23. Then it was irradiated to show beam profile since an

absolute calibration is not available.

Figure 21 Placement of EBT-3 film at CATANA facility.

2.3 MEASUREMENTS AT CNAO IN PAVIA

Measurements at Centro Nazionale di Adroterapia Oncologica (CNAO) facility in

Pavia, Italy, has been taken on June 1st, 2018, using the same energies in [5] and

shown in Table 5. This facility has been in function since 2013 with both ion and

proton beams and since the beginning of 2017 a treated for ocular tumours, like the

one in CATANA, is available, with more than 100 patients treated [6].

CNAO equips a synchrotron and beam monitor (BM) systems, providing actively

scanned proton (60-250 MeV) and Carbon ions (100- 400 MeV/u) pencil beams.

CNAO is designed to work with ions with 1 ≤ Z ≤ 6 and possibly with oxygen ions,

although with reduced penetration. The beam is capable of achieving, in water,

33

depths between 3 and 27 g/cm−2 and its intensity is such to administer 2 Gy for a

volume of 1 l in about 1 minute.

Table 5 Measuring plan worksheet for absorbed dose to water determination for protons and carbon ion at CNAO

The sources, the injection lines and the linear accelerator are housed inside the

synchrotron ring. Outside the ring there are four extraction lines, about 50 m long

each, leading the extracted beam into three treatment rooms. In each of the two side

rooms a horizontal beam is driven, while in the central hall both a horizontal and a

vertical beam are directed [19].

The energy is varied by the synchrotron, and within the slice the beam moves

horizontally and vertically thanks to the finely laminated scanning magnets,

“painting” the slice with a pencil beam. In this way the beam is directed to the various

points of the tumour (voxel = volume pixel) by varying its position without adding

additional thicknesses on the path of the beam that can lower its quality. In case of

treatments of moving targets, a multi-painting (or rescanning) technique is applied

to mitigate the dose delivery errors associated with tumour movement.

Figure 22 Layout of the high technology of CNAO [19]

34

Again, the measurement plan consists in in determination of the absorbed dose to

water

𝐷𝑤,𝑄 = 𝑀𝑄 ∙ 𝑁𝐷,𝑤,𝑄0 ∙ 𝑘𝑄,𝑄0

using the PTW TM-35045 Advanced Markus chamber and the PTW TN-30010-1

Farmer chamber, the PTW UNIDOS E electrometer and PTW 41023 water phantom.

At CNAO facility the determination of the nominal dose delivered by TPS is obtained

mainly using the ionization chamber PTW 30013 Farmer and the PTW UNIDOS

Webline electrometer as reported in [19].

For protons the quality factor 𝑘𝑄 is a function of the beam quality index Rres and it

varies by approximately 0.3% (its tabulated values for protons are reported in [8]).

Instead for Carbon beams 𝑘𝑄 is taken to be equal to 1.032 and independent of the

beam quality, due to the lack of experimental data.

To obtain 𝑀𝑄 several coefficients must be taken into account, e.g. kTP ks and kpol. The

first one is calculated

𝑘𝑇𝑃 = (273.2 + 𝑇)𝑃0(273.2 + 𝑇0)𝑃

Figure 23 (a) View of the synchrotron and beam lines

35

where T and P are the temperature and the pressure detected during the

measurements (i.e. when the cavity air of the chambers reach thermal equilibrium).

For CNAO calculation, T=22°C and P=1008 hPa while the calibration temperature and

pressure for both chambers can be found in Appendix.

Following the work from Mirandola et al. [17] based on beam commissioning at

CNAO with the use of PTW 30013 Farmer, it is possible to determine ks and kpol for

our Farmer chambers. In this work it is shown that both for proton and for carbon

ions beams, the polarity effect is negligible, so the factor is taken near unity. Instead

to determine ks, it is used the approximation to a continuous scanned beam, as the

spill duration is 1s, much longer than the chamber collection time; according to IAEA

TRS 398 [8], the ion recombination is evaluated using the two-voltage method.

For PTW Advance Markus coefficients from CPT measurements, which will be

presented in paragraph 2.4, were used.

In addition to these coefficients, a comprehensive term kc12 = 1.03 is recommended

in case of Carbon ions beam. This term is needed because to consider the different

values for Wair reported in literature [21], and to the underestimation of 𝐷𝑤,𝑄 found

by independent studies [22] [23], when an ion chamber is used into a Carbon beam.

Using the same protocol of [5] each measurement was taken three times in

accordance of the plan worksheet shown in Table 5, both in single layer and at the

center of SOBP. The beams have been delivered in order to obtain a nominal dose

of 2 Gy (with the standard uncertainty described in [8] and in Chapter 1) at the

reference depth of 2 cm in the water phantom (for single layer beams), keeping into

account the displacement of the point of measurement. The experimental setup is

placed with the same recommendations used in CATANA measurements, as show in

Figure 25.

For the single layers of proton beam (monoenergetic scanned pencil beam), selected

energies were 118.19 and 173.61 MeV, corresponding to a Bragg peak depth in

water of about 101 and 201 mm respectively, so that the measurements were made

in plateau region. Square uniform dose fields of 6 × 6 cm2 were created using

36

20 × 20 = 400 spots 3 mm FWHM large, with a fluence of 150.00 ∙ 106 and

203.17 ∙ 106 particles/spot for the low and the high energy respectively.

For the single layers of Carbon ions beam, selected energies were 208.58 and

332.15 MeV/u (Bragg peak depth of 90 and 200 mm in water respectively), and

square uniform dose fields of 6 × 6 cm2 were created using 30 × 30 = 900 spots

(spot size 2 mm), with a fluence of 2.95 ∙ 106 and 4.06 ∙ 106 particles/spot for the

low and the high energy beams, respectively. When a Carbon beam is used ripple

filters are necessary for scanning carbon ion beams to reduce the number of energy

Figure 24 PTW Advanced Markus placed in water phantom and centered with laser

37

steps required to deliver homogeneous SOBP. The proper selection of ripple filters

also allows a reduction in the possible transverse and depth-dose inhomogeneities

that could appear in non-isocentric conditions. The SOBP modulated scanning

proton beam (energies from 89.2 to 130.6 MeV) was delivered to create a cubic

uniform dose field of 6 × 6 × 6 cm3 (SOBP width = 6 cm), using 31 isoenergetic

layers, 2 mm spaced. The reference depth is at the center of the SOBP, zref = 9 cm.

In order to take in account the biological effectiveness of modulated beams, and to

obtain a biological dose of 2 Gy at zref , a physical dose of 1.77 Gy was delivered. For

the dose intercomparison, a multiplication factor of kRBE = 2/1.77 = 1.13 will be

used, considered as RBE representative and deduced from LEM models.

Figure 25 A screenshot of CNAO control beam monitor during Caron ion beam delivery. It is possible to see the shape of a single layer on the right.

For the Carbon ions SOBP, a cubic uniform dose field of 6 × 6 × 6 cm3 was created,

and a physical dose of 0.865 Gy was delivered ( kRBE = 2/0.865 = 2.31 ). In

agreement with Barbato’s work [5] the measurements results show high

38

reproducibility, as can be seen from Table 6, both for PTW Farmer and Advanced

Markus.

𝐁𝐞𝐚𝐦 Charge (nC) Mean (nC)

p Single Layer

118.19 MeV

1.314 1.308

1.306

1.304

p Single Layer

173.61 MeV

1.317 1.313

1.314

1.310

p SOBP

1.182 1.182

1.184

1.180

C Single Layer

208.58 MeV/u

1.271 1.273

1.274

1.274

C Single Layer

332.15 MeV/u

1.273 1.271

1.266

1.276

C SOBP

0.546 0.546

0.548

0.545

Table 6 PTW Advanced Markus chamber results at CNAO

Beam Mean Charge (nC)

p Single Layer 118.19 Mev 35.0

p Single Layer 173.61 Mev 35.57

p SOBP 31.5

C Single Layer 208.58 MeV/u 34.2

C Single Layer 332.15 MeV/u 33.9

C SOBP 15.01

Table 7 PTW Farmer chamber results at CNAO

39

Beam Chamber ND,W

(Gy/C) kQ ks kpol kP,T kC kRBE

p SOBP Farmer 5.381 ·108 1.029 1.003 1.001 1.012 - 1.13

p 118.19 MeV Farmer 5.381 ·108 1.029 1.003 1.001 1.012 - -

p 173.61 MeV Farmer 5.381 ·108 1.029 1.003 1.001 1.012 - -

C SOBP Farmer 5.381 ·108 1.031 1.005 1.002 1.012 1.03 2.31

C 208.58 MeV/u Farmer 5.381 ·108 1.031 1.008 1.002 1.012 1.03 -

C 332.15 MeV/u Farmer 5.381 ·108 1.031 1.005 1.002 1.012 1.03 -

p SOBP A. Markus 1.480 ·109 1.029 1.003 1.001 1.012 - 1.13

p 118.19 MeV A. Markus 1.480 ·109 1.029 1.000 1.001 1.012 - -

p 173.61 MeV A. Markus 1.480 ·109 1.029 1.000 1.001 1.012 - -

C SOBP A. Markus 1.480 ·109 1.031 1.000 1.001 1.012 1.03 2.31

C 208.58 MeV/u A. Markus 1.480 ·109 1.031 1.000 1.001 1.012 1.03 -

C 332.15 MeV/u A. Markus 1.480 ·109 1.031 1.000 1.001 1.012 1.03 - Table 8 Corrective factors to convert charge to absorbed dose to water used in CNAO measurements.

In closing, an EBT-3 film was placed inside the water phantom and aligned at the

isocentre. This film was then irradiated under single layer beams, at the reference

depth zref = 2 cm , without additional depth displacement.

2.4 MEASUREMENTS AT CPT IN TRENTO

Measurements at Centro di Protonterapia di Trento(CPT), in Trento, Italy, were taken

on June 4th, 2018. The facility was inaugurated in 2014 and it is the first proton facility

center with isocentric gantries in Italy, provided with two Gantry Treatment rooms.

It also boasts Pencil Beam Scanning Technology, Multiple Spot Identification and High

Precision Positioning. At the moment, the center focuses on treating tumors that are

found in the brain, the base of skull and the cervical-cephalic region and has adopted

cranio-spinal treatment for tumors of the Central Nervous System, both in children

and adults. [20] Moreover in the facility is available an active scanning proton

therapy by synchronizing the proton beams with the patient respiratory cycle. The

site is equipped with Pencil Beam Scanning (PBS) technology (3 spot sizes available),

based on 230 MeV cyclotron delivery system by IBA [16], a leading provider of

proton therapy solutions for the treatment of cancer. Along the transfer line, a

degrader provides the selection of the protons in the range 70 − 230 MeV.

40

Figure 26 Gantry in patient room at CPT facility.

To obtain the absorbed dose to water two different ionization chamber are used, the

PTW UNIDOS E electrometer and the IBA WP34 water phantom, having the same

specifications (i.e. dimensions and wall materials) as PTW 41023, the water phantom

used in CNAO measurements. According to the measurements plan (Tab. 8), proton

beams were delivered to obtain a nominal biological dose of 2 Gy at the reference

depth zref = 2 cm in the water phantom (keeping in account the effective point of

measurement for the different chambers).

Table 9 Measuring plan worksheet for absorbed dose to water determination for proton at CPT

To calculate the ks and kpol factors for PTW Advanced Markus Chamber, IAEA TRS 398

recommendations are used. The first factor keeps into account the incomplete

collection of charge in an ionization chamber cavity and for its determination is

necessary to use the two-voltage method because the beam of CPT is not pulsed

41

𝑘𝑠 =(𝑉1/𝑉2)

2 − 1

(𝑉1/𝑉2)2 − (𝑀1/𝑀2)

where 𝑀1 and 𝑀2 are the measured values of the collecting charges at the polarizing

voltage 𝑉1 and 𝑉2 respectively, measured using the same irradiation conditions.

The second factor is calculated with

𝑘𝑝𝑜𝑙 =|𝑀+| + |𝑀−|

2𝑀

where M+ is the reading at positive voltage and M- at negative voltage.

Voltage of 100 V, 300 V and -300 V are chosen to perform these measurements (cfr.

Table 10) and the resulting coefficients are shown in Table 13.

Voltages Readings (nC)

100 1.181 1.179 1.183 1.182

300 1.182 1.183 1.184 1.184

-300 1.185 1.191 1.185 1.186 Table 10 Worksheet of voltage and respective measurements. All these measurements were performed at the center of SOBP.

For Farmer coefficients, the same calibration factors of CNAO will be applied since

the beam qualities for proton beams are the same as for the CNAO measurements.

For kPT factor is used the same equation used in CNAO and CATANA calculations with

P= 989 hPa and T=23.08°C, temperature and pressure measured during CPT shift.

Figure 27 Water phantom horizontal positioning in front of the beam exit window.

42

To perform the measurements, we placed the water phantom in front of the beam

exit and the center was aligned with lasers. For the single-layer proton beams, square

uniform dose fields of 6 × 6 cm2 were created using 25 × 25 = 625 spots 2 mm

FWHM wide, and measurement were made, followed by the SOBP measurement.

Figure 29 PTW Farmer in water phantom during measurements at CPT facility.

Figure 28 Vertical positioning of water phantom and centering of Advanced Markus chamber.

43

Beam Mean Charge (nC)

p Single Layer 118.19 MeV 1.165

p Single Layer 173.61 MeV 1.166

p SOBP 1.183

Table 11 Main charges obtained with Advanced Markus chamber at CPT facility

Beam Mean Charge (nC)

p Single Layer 118.19 MeV 31.4

p Single Layer 173.61 MeV 31.4

p SOBP 30.4

Table 12 Main charges obtained with Farmer chamber at CPT facility

Beam Chamber ND,W (Gy/C) kQ ks kpol kP,T kRBE

p SOBP Farmer

5.381 ·108 1.002 1.003 1.001 1.035 1.1

p 118.19 MeV 5.381 ·108 1.002 1.003 1.001 1.035 1.1

p 173.61 MeV 5.381 ·108 1.002 1.003 1.001 1.035 1.1

p SOBP A. Markus

1.480 ·109 1.003 1.000 1.001 1.035 1.1

p 118.19 MeV 1.480 ·109 1.003 1.000 1.001 1.035 1.1

p 173.61 MeV 1.480 ·109 1.003 1.000 1.001 1.035 1.1 Table 13 Correction factors to convert charge to absorbed dose to water used during CPT measurements.

2.5 MEASUREMENTS AT FONDAZIONE MAUGERI IN PAVIA

Measurements at Fondazione Maugeri (FM), in Pavia, Italy, were taken on June 20th,

2018. The FM clinical institute is equipped with a linear accelerator (LINAC) for 6 MV

and 15 MV photons, and 4.5 − 15 MeV electrons for Intraoperative Radiation

Therapy (IORT), Three-Dimensional Conformal Radiation Therapy (3DCRT), Image-

guided radiation therapy (IGRT) and Intensity Modulated Radiation Therapy (IMRT-

VMAT). In accordance to what done in other centers, the measurements plan is

𝐷𝑤,𝑄 = 𝑀𝑄 ∙ 𝑁𝐷,𝑤,𝑄0 ∙ 𝑘𝑄,𝑄0

44

using the PTW TM-35045 Advanced Markus chamber, the PTW TN-30010-1 Farmer

chamber and PTW-31010 Semiflex chamber, the PTW UNIDOS E electrometer and

PTW 41023 water phantom.

Figure 30 Measuring plan worksheet for absorbed dose to water determination for photon at FM

Each chamber has a different ks, kpol and kq coefficients and they are determined

both using literature reference and via direct measurements, when not available a

reference. For Farmer chamber we used the coefficients given in [5], for Advanced

Markus the same found in CPT measurements and for Semiflex we used

G.Bruggmoser’s article [26] as a reference. Other correction factors for Farmer and

Semiflex chambers were taken to be equal to the ones used at FM for reference

dosimetry, made using the PTW 30013 Farmer chamber (with the same

specifications of our Farmer chamber) and the PTW UNIDOS Webline electrometer.

Since Advanced Markus coefficients were not available, we used the value listed in

Muir’s article [25] who investigate the behavior of plane-parallel ion chambers in

high-energy photon beams through measurements and Monte Carlo simulations. A

summary of all the coefficients is included in Table (14).At FM a uniform square field

(10 × 10 cm2) of 6 MV photons was delivered in order to obtain a nominal dose of

2 Gy (standard uncertainty of 1.5 %) at the reference depth zref = 2 cm in the water

phantom.

45

The factor kTP was calculated as previously, measuring the pressure inside the

treatment room and the phantom water temperature which correspond to T=22.5°C

and P=1007 hPa.

As in previous measurements the water phantom was placed in front of Gantry

window and centered with respect to isocenter. Every chamber was placed in water

and three measurements were made for each chamber.

Figure 31 Experimental setup used during measurements at Fondazione Maugeri.

46

Beam Chamber Ndw (Gy/C) ks kpol kq ktp

6 MV

Farmer 5.381·109 1.003 1.003 0.988 1.015

Markus 1.48·108 1.0002 1.0015 0.9936 1.015

Semiflex 3.12·108 1.000 1.000 0.993 1.015 Table 14 Corrective factors to convert charge to absorbed dose to water used in FM measurements for each ionization chamber.

The value of measurements with Farmer chambers moves away from the expected

value of 2 Gy of 2.7% (maximum percental error in clinics < 2%).

2.6 INTERCOMPARISON BETWEEN CATANA, CNAO, CPT AND FM

To perform this intercomparison we asked to delivery proton, carbon of photon

beams in order to obtain a nominal physical or biological dose of 2 Gy at the reference

depth in a water phantom. The weighted mean of nominal dosed at the different

facilities is 1.999±0.008 Gy. Tables 15-16-17 list data of the corrected doses

calculated for each ionization chamber.

Figure 32 Placement of Ion chambers in the water phantom

47

Facility Beam Ion chamber Dose (Gy) d (Gy)

CNAO

p SOBP Farmer

2.003 0.040

p 118.19 MeV 1.990 0.039

p 173.61 MeV 2.001 0.040

C SOBP 2.020 0.061

C 208.58 MeV/u 1.998 0.060

C 332.15 MeV/u 1.988 0.059

FM photon 6 MV 1.944 0.029

CATANA p SOBP 2.011 0.040

CPT

p SOBP 1.999 0.040

p 118.19 MeV 1.985 0.040

p 173.61 MeV 1.991 0.040

Facility Beam Ion chamber Dose (Gy) d (Gy)

CNAO

p SOBP Advanced Markus

2.007 0.046

p 118.19 MeV 2.019 0.046

p 173.61 MeV 2.028 0.047

C SOBP 2.002 0.068

C 208.58 MeV/u 2.026 0.069

C 332.15 MeV/u 2.024 0.069

FM photon 6 MV 1.981 0.297

CATANA p SOBP 2.019 0.046

CPT

p SOBP 2.005 0.046

p 118.19 MeV 1.967 0.045

p 173.61 MeV 1.970 0.045

FM photon 6 MV Semiflex 1.981 0.029

Table 15 Corrected dose and dose standard uncertainty calculation for the different facilities, using PWT Farmer ionization chamber

Data show a good consistency within the experimental uncertainties both for single

chamber data and for overall data, as can be seen in Figure 37. The weighted mean

measured with Farmer chamber is 1.998±0.014 Gy with a statistical error of 0.003 Gy.

The weighted mean measured with the Advanced Markus chamber is 1.999±0.014

Gy with a statistical error of 0.004 (standard error= standard deviation/ √10 ). The

weighted mean measured in proton facilities is 1.999±0.011.

48

Figura 36 Dose intercomparison results for Advanced Markus measurements.

The comparison between these data and Barbato’s [5] has been made and a good

agreement has been found. Overall the weighted mean for the data in this work is

1.999±0.010 Gy with a standard error of 0.004 Gy while the weighted mean for the

merged data with [5] is 1.999±0.008 Gy with a standard error of 0.003 Gy.

Figure 33 Dose intercomparison results for Advanced Markus, Farmer and Semiflex ion chambers.

49

Figura 37 Dose intercomparison results merging data from this work and data from [5]. The grey point are the measurements in Barbato’s work [5].

To validate this intercomparison Monte Carlo simulation has been programmed. The

first step is to implement Farmer and Advanced Markus chamber geometry in Geant4

framework and to voxelize the sensible volume for each chamber. We aim to simulate

our experimental setup (water phantom + ionization chamber) and obtain as output

the collected charge in the sensitive volume in the chamber.

Figure 34 The real proton therapy beam line installed at Laboratori Nazionali del Sud (INFN) in Catania (b)the graphic output of the advanced example developed for the simulation of the same beam line

50

Figure 35 Sketch of the Hadrontherapy simulation with a water phantom and a PTW Advanced Markus as a detector.

To perform such simulation an application by Università di Catania ed LNS, called

“Hadrontherapy” is available. Hadrontherapy gives the possibility to simulate a

typical hadron therapy treatment beam line (including all its elements) and to

calculate the proton/ion dose distribution curves. In particular in this application

CATANA beam line is simulated and in next months CPT beam line will be added. For

CNAO simulations we aim to use a FLUKA application.

51

CONCLUSIONS

The purpose of this work, performed within MC-INFN project, was to perform the

first intercomparison study on nominal doses delivered by the Treatment Planning

System in Italian hadrontherapy centers, using ionization chambers for reference

dosimetry in water, according to IAEA TRS398 code of practice.

Measurement sites include the following clinical therapy centers: CNAO (Pavia) for

protons and carbon ions; CTP (Trento) and CATANA (Catania) for protons; Fondazione

Maugeri (Pavia) for 6 MV photons as a reference. For ion beams, both single

monoenergetic layer and SOBP, have been delivered to obtain a nominal dose of 2

Gy at the reference depth zref = 2 cm in a water phantom for a 6x6 cm2 particle beam.

The energies used were: in CNAO for protons (118.19 MeV, 173.61 MeV) and for

carbon ions (208.58 MeV/u, 332.15 MeV/u), in Fondazione Maugeri 6 MV, in CATANA

for protons (62 MeV) and in CPT for protons (118 MeV, 173 MeV).

We measured a weighted mean of 1.998±0.010 Gy with a standard error of 0.004 Gy

while the weighted mean for the data merged with [5] is 1.999±0.008 Gy with a

standard error of 0.003 Gy. Overall, absorbed dose for clinical proton beams is

consistent within less than 3% between CNAO and CPT, as well as for 6 MV photons,

in agreement with IAEA TRS-398 code of practice.

This comparison program verified a satisfactory agreement, between the different

facilities involved, for determination of absorbed dose to water.

Additional measurements in European centers such as HIT (Heidelberg Ion therapy

center) in Heidelberg, Germany, MIT (Madburg Ion Therapy Center) at Madburg,

Germany, and MedAustron at Wiener Neustadt, Austria, are foreseen to complete

this work.

52

APPENDIX

This appendix contains the calibration certificates, both for PTW Farmer, PTW

Semiflex and PTW Advanced Markus, used during this thesis work, by the chamber

producer itself (PTW-Freiburg).

53

54

55

56

57

58

BIBLIOGRAPHY

[1] RR. Wilson “Radiological use of fast protons”, Radiology: 47:487-

91.10.1148/47.5.487. (1946).

[2] http://enlight.web.cern.ch/what-is-hadron-therapy

[3] AIRO Linee guida AIRO sulla Garanzia di qualità in Radioterapia

[4] PTCOG https://www.ptcog.ch/

[5] A. Barbato “Dose intercomparison at hadrotherapy centres”, 2017, M.Sc. Thesis,

Universita’ di Napoli Federico II.

[6] https://www.fondazionecnao.it/it/

[7] G. H. Hartmann et al. “Determination of water absorbed dose in a Carbon ion beam

using thimble ionization chambers”, Phys. Med. Biol. 44(5), 1193-1206 (1999).

[8] International Atomic Energy Agency (IAEA), TRS-398: Absorbed Dose

Determination in External Beam Radiotherapy: An International Code of Practice for

Dosimetry based on Standards of Absorbed Dose to Water, V. 12, June 2006.

[9] International Commission on Radiation Units and Measurements (ICRU), Report

24: Determination of absorbed dose in a patient irradiated by beams of X or gamma

rays in radiotherapy procedures, Bethesda (1976).

[10] C. Ma, A. E. Nahum “Effect of size and composition of the central electrode on

the response of cylindrical ionization chambers in high-energy photon and electron

beams”, Phys. Med. Bio 38(2): 267(1993).

[11] http://www.ptw.de – PTW Freiburg – Germany.

[12] https://www.sciencedirect.com/science/article/pii/S0360301605027264

59

[13] G.A.P. Cirrone, et al. “Clinical and Research Activities at the CATANA Facility of

INFN-LNS: From the Conventional Hadrontherapy to the Laser-Driven Approach.”

Frontiers in Oncology 7: 223(2017).

[14] S. Devic, et al. “Reference radiochromic film dosimetry: Review of technical

aspects”, Physica Medica 32(4): 541 – 556(2016)

[15] J.Pence, et al. “The characterization of the Advanced Markus ionization chamber

for use in reference electron dosimetry in the UK”, Phys. Med. Biol. (51), 473(2006)

[16] http://www.teambest.com/CNMC_docs/radPhysics/thimble/CNMCN30013.pdf

[17] A. Mirandola et al. “Dosimetric commisioning and quality assurance of scanned

ion beams at the Italian National Center for Oncological Hadrontherapy”, Med. Phys.

42 (9), 5287-5300 (2015).

[18] R. Castriconi et al. “Dose–response of EBT3 radiochromic films to proton and

Carbon ion clinical beams”, Phys. Med. Bio. (62), (2016).

[19] S. Rossi “The National Centre for Oncological Hadrontherapy (CNAO): Status and

perspectives”, Phys. Med. 31, 333-351(2015).

[20] IBA-International. https://iba-worldwide.com/proton-therapy

[21] C. P. Karger et al. “Dosimetry for ion beam radiotherapy”, Phys. Med. Biol. 55(21),

193-234 (2010).

[22] O. Geithner et al. “Calculation of stopping power ratios for carbon ion dosimetry”,

Phys. Med. Biol. 51(9), 2279–2292 (2006).

[23] D. Sanchez-Parcerisa et al. “Influence of the delta ray production threshold on

water-to-air stopping power ratio calculations for carbon ion beam radiotherapy”,

Phys. Med. Biol. 58(1), 145–158 (2013).

[24] Raystation by Raysearch Laboratories – Treatment Planning System software

used at Centro di Protonterapia di Trento (CPT). https://www.raysearchlabs.com

60

[25] B.R Muir et al. “Beam quality conversion factors for parallel-plate ionization

chambers in MV photon beams”, Medical Physics, Vol.39, No 3

[26] G. Bruggmoser et al. “Determination of recombination and polarity correction

factors for small cylindrical ionization chambers PTW 31021 and PTW 31022 in pulsed

filtered and unfiltered beams”, Z Med Phys. 2018

61

ACKNOWLEDGEMENTS

They say that it is never easy to write acknowledgments, especially at the end of a

thesis work; “they” are right.

First of all, I am very grateful to my advisor Prof. Russo who gave me this great

opportunity, teaching me why medical physics is beautiful; thank you for the trust

you had in me, for the guidance in this path and for all the precious advices.

Thanks to Prof. Mettivier who helped me overcame not only scientific issues but also

bureaucratic ones, which can be even more terrifying.

Thanks to Dr. Sarno whose wise words really helped me in many stressful moments

and Dr. Di Lillo for her scientific advices.

Thanks to my co-supervisor Prof. Vardaci for his curiosity and kind availability.

Thanks to Dr. Cirrone and Dr. Petringa for their precious suggestions about

measurements and Geant4 simulations.

Thanks to Dr. Ciocca and Dr. Mastella, not only for their valuable contribution to this

work but also for their hospitality and help.

Thanks to Dr. Schwarz and Dr. Lorentini for their kindness and their invaluable

assistance; I really appreciated your help and every advice you gave me.

Thanks to Dr. Tarabelli De Fatis and Dr. Liotta for their willingness to help and their

perseverance, especially when last time problems have occurred.

Thanks to Arcangelo Barbato, first to tackle such an intercomparison; thanks for your

precious remote and in person help.

Last, but not least, I wish to thank all the women in the Medical Physics Laboratory

(of whom there is clearly no shortage in this day and age) for their time, support and

understanding during these months; I am so sorry you girls had to bear me rambling

about ionization chambers issues.

July 2nd, 2018

F.G.