1250401/fulltext01.pdf · i abstract spatially fractionated radiotherapy, also known as grid...
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Interlaced proton grid therapy: development of aninnovative radiation treatment techniqueThomas Henry
Academic dissertation for the Degree of Doctor of Philosophy in Medical Radiation Physicsat Stockholm University to be publicly defended on Friday 9 November 2018 at 09.00 in CCKLecture Hall, Building R8, Karolinska University Hospital, Solna.
AbstractSpatially fractionated radiotherapy, also known as grid therapy (GRID), has been used for more than a century to try to treatseveral kinds of lesions. Yet, the grid technique remains a relatively unknown and uncommon treatment modality nowadays.Spatially fractionated beams, instead of conventional homogeneous fields, have been used to exploit the experimentalfinding that normal tissue can tolerate higher doses when smaller tissue volumes are irradiated. This increase in tolerancewith reducing beam size is known as the dose-volume effect. Despite the fact that targets were given inhomogeneous dosedistribution, sometimes with some volumes receiving close to no dose, good results in the form of shrinking of bulky tumorshave been observed in palliative treatments. The biological processes responsible for this effect are still under discussion,with several possible causes. However, numerous experiments on mice, rats and pigs have confirmed the existence ofsuch effect, which in turn motivates the present development of grid therapy.While mainly photons have been used in gridtherapy, proton and ion grid therapies are also emerging as potential alternatives. In this work, an innovative form of gridtherapy was proposed. Grids of proton beamlets were interlaced over a target volume with the intention of achieving twomain objectives: (1) to keep the grid pattern (made of adjacent high and low doses) from the skin up to the vicinity of thetarget while (2) delivering nearly homogeneous dose to the target volume. This interlaced proton grid therapy was exploredwith the use of different beam sizes, from conventional sizes deliverable at modern proton facilities, down to millimetersized beams. Other considerations that would prevent its clinical use, such as the variable relative biological effectivenessof protons or the use of cone beam computed tomography, were also evaluated. The overall aim was to assess if, and how,such treatment modality could be applied clinically, from a physics and dosimetry point of view. While it presented severaltheoretical advantages, its potential issues of concern and limitations were also evaluated.
Keywords: proton therapy, grid therapy, spatially fractionated therapy, interlacing.
Stockholm 2018http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-160427
ISBN 978-91-7797-442-0ISBN 978-91-7797-443-7
Department of Physics
Stockholm University, 106 91 Stockholm
INTERLACED PROTON GRID THERAPY: DEVELOPMENT OF ANINNOVATIVE RADIATION TREATMENT TECHNIQUE
Thomas Henry
Interlaced proton grid therapy:development of an innovativeradiation treatment technique
Thomas Henry
©Thomas Henry, Stockholm University 2018 ISBN print 978-91-7797-442-0ISBN PDF 978-91-7797-443-7 Cover picture by PixelAnarchy @ Pixabay, www.pixabay.com Printed in Sweden by Universitetsservice US-AB, Stockholm 2018Distributor: Department of Physics
i
Abstract
Spatially fractionated radiotherapy, also known as grid therapy (GRID), has
been used for more than a century to try to treat several kinds of lesions. Yet,
the grid technique remains a relatively unknown and uncommon treatment
modality nowadays. Spatially fractionated beams, instead of conventional
homogeneous fields, have been used to exploit the experimental finding that
normal tissue can tolerate higher doses when smaller tissue volumes are
irradiated. This increase in tolerance with reducing beam size is known as
the dose-volume effect. Despite the fact that targets were given
inhomogeneous dose distribution, sometimes with some volumes receiving
close to no dose, good results in the form of shrinking of bulky tumors have
been observed in palliative treatments. The biological processes responsible
for this effect are still under discussion, with several possible causes.
However, numerous experiments on mice, rats and pigs have confirmed the
existence of such effect, which in turn motivates the present development of
grid therapy.
While mainly photons have been used in grid therapy, proton and ion
grid therapies are also emerging as potential alternatives.
In this work, an innovative form of grid therapy was proposed. Grids of
proton beamlets were interlaced over a target volume with the intention of
achieving two main objectives: (1) to keep the grid pattern (made of adjacent
high and low doses) from the skin up to the vicinity of the target while (2)
delivering nearly homogeneous dose to the target volume. This interlaced
proton grid therapy was explored with the use of different beam sizes, from
conventional sizes deliverable at modern proton facilities, down to
millimeter sized beams. Other considerations that would prevent its clinical
use, such as the variable relative biological effectiveness of protons or the
use of cone beam computed tomography, were also evaluated.
The overall aim was to assess if, and how, such treatment modality
could be applied clinically, from a physics and dosimetry point of view.
While it presented several theoretical advantages, its potential issues of
concern and limitations were also evaluated. The results from six studies are
here presented and summarized.
ii
iii
Sammanfattning
Oönskad bestrålning av friska vävnader har alltid varit ett bekymmer för
cancerbehandlingar med joniserande strålning då detta kan inducera
oönskade bieffekter. Redan 1909, bara några år efter att strålbehandling hade
börjat användas, var en tysk läkare med namnet Alban Köhler oroad över
strålningsinducerade hudskador som uppkommit i samband med
strålbehandling. Han hade då en ide att ersätta konventionell strålbehandling,
i vilken patienten bestrålas med homogena strålfält, med heterogena strålfält
där vissa regioner skulle få en hög stråldos och vissa regioner inte skulle få
någon stråldos alls. Med detta ville Köhler öka vävnandens tolerans för
joniserande strålning. Detta bestrålningsmönster har även kallats
"schackbräde" eller "rutnät" (grid). Grid-terapi föddes.
Efter att långsamt blivit bortglömt genom åren, återupptäcktes grid-
terapi på nittiotalet som en teknik för att bestråla skrymmande tumörer som
andra konventionella behandlingstekniker misslyckades med att behandla.
Observationer har visat att toleransen mot strålning hos vissa vävnader ökar
när små regioner av dessa vävnader inte bestrålas. I samband med att
strålbehandling med protoner eller tyngre joner blivit allt vanligare kan grid-
terapi utvecklas ytterligare.
Denna avhandling innehåller en omfattande redogörelse av grid-terapins
historia, från att konceptet introducerades 1909 till de senaste experimentella
studierna som använder väldigt finmaskiga bestrålningsmönster med väldigt
små strålar. Därefter beskrivs utvecklingen av en innovativ typ av grid-terapi
som använder sig av sammanflätade protonstrålar. Bakgrunden till behovet
av denna teknik och dess fördelar presenteras. Resultat från sex olika studier
sammanfattas och diskuteras.
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v
List of papers
PAPER I: Proton-grid therapy (PGT): a proof-of-concept study
T. Henry, A. Ureba, A. Valdman & A. Siegbahn,
Technology in Cancer Research & Treatment 16, 749–757
(2017).
PAPER II: Dosimetric Comparison of Plans for Photon- or
Proton-Beam Based Radiosurgery of Liver Metastases
G. Mondlane, M. Gubanski, P.A. Lind, T. Henry, A.
Ureba & A. Siegbahn, International Journal of Particle
Therapy 3, 277–284 (2016).
PAPER III: Robustness of interlaced proton grid therapy plans
against pencil-beam spot position variations
T. Henry & J. Öden, Manuscript
PAPER IV: Development of an interlaced-crossfiring geometry for
proton grid therapy
T. Henry, N. Bassler, A. Ureba, T. Tsubouchi, A.
Valdman & A. Siegbahn, Acta Oncologica 56, 1437–1443
(2017)
PAPER V: Interlaced proton grid therapy: linear energy transfer
and relative biological effectiveness distributions
T. Henry & J. Öden, Submitted to Physica Medica (2018)
PAPER VI: Organ doses from a proton gantry-mounted CBCT
system characterized with MCNP6 and GATE
O. Ardenfors, T. Henry, I. Gudowska, G. Poludniowski &
A. Dasu, Physica Medica 53, 56-61 (2018)
vi
Publication relevant to, but not included in the thesis:
PAPER VII: Quantitative evaluation of potential irradiation
geometries for carbon-ion beam grid therapy
T. Tsubouchi, T.Henry, A. Ureba, N. Bassler & A.
Siegbahn, Medical Physics 45, 1210–1221 (2018).
vii
Author’s contribution
PAPER I: I designed the study, produced and analyzed all the results
and was the main writer of the manuscript.
PAPER II: I took part in reviewing some of the plans included in this
study and helped revising the manuscript.
PAPER III: I designed the study, produced and analyzed all the results
and was the main writer of the manuscript.
PAPER IV: I designed the study, produced and analyzed all the results
and was the main writer of the manuscript.
PAPER V: The paper was a close collaboration between the co-author
and myself. Contribution to the design of the study,
production/analysis of the results and writing of the
manuscript was equally shared between the two of us.
PAPER VI: I took part in all the measurement sessions, scientific
discussions and in the design of the study, and was in charge
of all the GATE-based simulations. I took part in reviewing
the manuscript.
viii
ix
Outline of the thesis
This thesis focuses on exposing the train of thoughts that, over the past four
years, led to the development of the proposed interlaced proton grid
technique in its current state. As such, an extensive historical background
and state-of-the-art of grid therapy is first presented, giving the reader the
scientific bases on which the proposed proton grid therapy grew. In the
second part of this thesis, the studies performed in papers I-VI are
summarized to give an overview of the different aspects of the in-
development treatment modality.
Part of the text found in this thesis originates from my licentiate thesis
that was presented in June 2017. As such, the following chapters, sub-
sections and paragraphs were partially or fully reproduced from the said
licentiate to the present thesis:
The Abstract was partially reused and improved.
The Introduction was reused, improved and updated to provide a better
overview of the entire project.
Chapters 2 and 3 were originally included in the licentiate thesis. Apart from
small modifications, figures 2,8 and 10 were replaced with more instructive
figures and figure 11 was added.
Chapters 4 and 5 are based on sub-sections from the licentiate thesis. Some
parts of said sub-sections were reused, improved, complemented and made
up-to-date with the latest studies.
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xi
Contents
Abstract ................................................................................................ i
Sammanfattning ................................................................................. iii
List of papers ....................................................................................... v
Author’s contribution ....................................................................... vii
Outline of the thesis ........................................................................... ix
Contents .............................................................................................. xi
Abbreviations ................................................................................... xiii
1. Introduction ............................................................................... 15
2. Grid Therapy ............................................................................. 19
2.1. The history of grid therapy ........................................................... 19
2.2. Radiobiological basis of grid therapy: the dose-volume effect ..... 21
2.3. Contemporary grid therapy ........................................................... 23
2.4. Experimental grid therapy with µm- and mm-wide beamlets ....... 25
3. Towards the development of an interlaced proton grid
therapy ............................................................................................... 29
3.1. Objectives and questions to be answered ...................................... 29
3.2. Grid geometries and irradiation setups ......................................... 30
4. Using conventional beam sizes: a first step ............................. 33
4.1. Establishing the potential with commercial treatment planning
systems ...................................................................................................... 33
4.2. Going further: planning clinically realistic grid plans .................. 34
4.3. Impact of spot position uncertainties ............................................ 36
4.4. Discussion ..................................................................................... 37
5. Proton grid therapy with small beamlets ................................ 41
5.1. Establishing the potential through Monte Carlo simulations ........ 41
xii
5.2. A motorized collimator design to produce millimeter-wide
beamlets .................................................................................................... 42
5.3. Discussion ..................................................................................... 45
6. Clinical challenges: RBE and CBCT imaging ........................ 47
6.1. RBE considerations ....................................................................... 47
6.2. The use of CBCT imaging ............................................................ 48
6.3. Discussion ..................................................................................... 50
7. General discussion and concluding remarks .......................... 53
8. Summary of papers ................................................................... 55
Acknowledgments ............................................................................. 57
References .......................................................................................... 59
xiii
Abbreviations
BEV Beam’s eye view
CBCT Cone beam computed tomography
C-T-C Center-to-center
DVH Dose-volume histogram
ED50 Effective dose 50
FWHM Full width at half maximum
IMPT Intensity-modulated proton therapy
IMRT Intensity-modulated radiation therapy
LET Linear energy transfer
MC Monte Carlo
MCS Multiple Coulomb scattering
MRT Microbeam radiation therapy
NTCP Normal tissue complication probability
OAR Organ at risk
PTV Planning target volume
PVDR Peak-to-valley dose ratio
QUANTEC Quantitative analyses of normal tissue effects in the clinic
RBE Relative biological effectiveness
SBRT Stereotactic body radiation therapy
SFUD Single field uniform dose
xiv
SOBP Spread-out Bragg peak
TCP Tumor control probability
TPS Treatment planning system
VMAT Volumetric modulated arc therapy
VPDR Valley-to-peak dose ratio
Chapter 1. Introduction
15
1. Introduction
For almost 120 years, from the discovery of x rays in 1895 by Wilhelm
Röntgen until now, ionizing radiations have been used as a regular modality
to treat cancerous tumors and other lesions. In search for the best treatment
outcome, new treatment modalities, machines and particle types have since
been introduced into the clinic.
As knowledge was gained over the years, more effort was put on
reducing the toxicity of radiotherapy treatments to the skin and healthy
tissues beneath it and around the lesion. Techniques using broad radiation
beams like intensity-modulated radiation therapy (IMRT), volumetric
modulated arc therapy (VMAT) with photons or intensity-modulated proton
therapy (IMPT) with protons, where the target is irradiated with beams
incident from several directions to lower the normal tissue dose, were
developed. In parallel, temporal dose fractionation i.e. whether the dose
should be given in several fractions over time or in a single fraction
(radiosurgery), has become the standard of care. Radiotherapy as a whole
has been greatly focusing on protecting the surrounding healthy tissues while
delivering a clinically relevant dose to the targeted tumor.
In proton therapy, the special dosimetric characteristics of charged
particles are exploited. As charged particles, protons interact through
numerous collisions with the atomic electrons of the medium in which they
are propagating, slowly reducing their speed. As a consequence, the slower
the particles become, the higher their probability of interaction with the
medium, increasing the energy locally deposited. This will result in a high
energy being deposited as the protons are completely stopped, known as the
Bragg peak. Furthermore, in addition to slowing down, protons experience
multiple elastic interactions with the positively charged atomic nuclei in the
medium, leading to these protons being deflected from their initial path and
scattered in the medium. This is known as multiple Coulomb scattering
(MCS). Finally, a proton can also undergo non-elastic collisions with the
said atomic nuclei, during which the proton is absorbed by the nucleus,
leading to the potential ejection of numerous particles: secondary protons
(which can have a small impact on the spatial dose distribution of the beam),
deuterons and heavier ions (which deposit all their energy locally due to
their small range and energy) and neutrons, which are very penetrating and
16
should therefore be given a special care as they can deposit energy far from
the interaction point.
In radiotherapy, the limited range of the protons (and more generally
heavy ions) is therefore used to improve dose conformity to the target and
consequently the outcome of radiotherapy treatments. From single field
uniform dose treatments (SFUD) and IMPT, where targets are given
homogeneous doses, to proton stereotactic body radiation therapy (proton
SBRT or proton radiosurgery) where high inhomogeneous doses are allowed
in the targeted volumes, proton therapy has greatly developed. It is worth
mentioning also that protons and other heavier charged particles have been
known for many years to have a different relative biological effectiveness
(RBE) compared to conventionally used photons (Durante and Paganetti,
2016). While a constant RBE value of 1.1 has been assumed for protons,
studies pointing towards the existence of a variable RBE have been
conducted in the past years (Paganetti, 2014).
One form of therapy that was developed to allow the further reduction
of the toxicity to normal tissue is the so-called grid therapy. In grid therapy,
narrow beams are arranged in a chess-board pattern leading to a spatial
fractionation of the beams, with parts of tissue left unirradiated in between
the beams. The idea of spatially fractionating the beams to increase the
healthy tissue tolerance to the treatment is not new (Köhler, 1909; Laissue et
al., 2012). The method has been abandoned and then rediscovered several
times since its introduction. It came back some years ago as an option to
treat bulky tumors for which there were no other treatment options available
(Huhn et al., 2006; Kaiser et al., 2013; Mohiuddin et al., 2015, 1999, 1990;
Neuner et al., 2012; Peñagarícano et al., 2010).
The motivation for using small beams in place of regular broad,
homogeneous fields directly comes from the experimental observation that
normal tissue can tolerate a higher dose if the radiation dose is deposited in a
small volume. This finding is known as the dose-volume effect and has been
mainly observed on skin and spinal cord in several animal experiments (Bijl
et al., 2002; Hopewell and Trott, 2000).
Historically, only photons have been used in grid therapy. The spatial
fractionation of the beams has been obtained with the use of perforated
collimators attached directly on the treatment head. However, the arrival of
more recent techniques such as proton and heavy-ion therapies opened a new
door for grid therapy. Because of the interesting depth-dose characteristics of
charged particles in the human body, a new proton or ion grid therapy has
emerged.
Chapter 1. Introduction
17
Until recently, most research and treatments using grid therapy had
been conducted using only one incident grid, itself consisting of numerous
micro-, mini- or centimeter-wide beams. Using such irradiation geometry,
not only the normal tissue but also the target receives a spatially fractionated
dose, i.e. some parts of the tumor/lesion receive very high doses (peak doses)
and some parts receive low doses (valley doses). Some attempts have been
made to deliver a nearly homogeneous dose to the target using only one
incident grid (Dilmanian et al., 2015; Zlobinskaya et al., 2013). This resulted
in the loss of the grid pattern of the dose distribution (made of consecutive
peaks and valleys of dose, theoretically responsible for the improved
tolerance of the tissue) already a few centimeters in depth beneath the skin,
i.e. a high and nearly homogeneous dose could already be observed several
centimeters before the target. This could be of importance since most
radiation necrosis in normal tissues seem to appear in the high dose regions,
near the target (Lawrence et al., 2010).
In this work an innovative grid method using proton beams was
proposed. The main objectives were the following: (1) to maintain the grid
pattern of the dose distribution, made of alternating high and low doses, in
the normal tissue up to the direct vicinity of the target, and (2) to deliver a
rather homogeneous dose to the target (with a high minimum dose). To do
so, grids of proton beamlets incident from several directions were interlaced
over the targeted volume.
This grid geometry, along with the use of proton beams, is anticipated
to produce desirable dosimetric results in terms of target volume dose
coverage and normal tissue sparing. In return, this would make the proposed
grid therapy a potential strong candidate as a new modality for curative
treatments, and not just palliative last-chance attempts.
This thesis summarizes the development of such interlaced proton grid
therapy, from the very first proof-of-concept study using conventional
proton beam sizes available at any modern proton facility, to the latest
advancements. Along the way, different beam sizes were explored, down to
millimeter sized beamlets, and more clinical concerns such as the impact of
variable RBE on the clinical validity of grid plans or the use of cone beam
computed tomography (CBCT) and its implication were considered. All of
which to achieve a unique goal: develop the proposed technique to,
eventually, make it closer to a clinical application and relevant as a stand-
alone treatment modality.
18
Chapter 2. Grid Therapy
19
2. Grid Therapy
2.1. The history of grid therapy
The history of grid therapy can be traced back to 1909 (Köhler, 1909;
Laissue et al., 2012), when Dr. Alban Köhler, a German physician, proposed
to attach an iron wire net with 1 mm-square holes to a radiation source,
pushed to the patient’s skin, with the aim of irradiating this latter with small,
separated beams. The suggested irradiation method was expected to increase
the maximum tolerated skin dose manyfold and therefore, achieve a better
skin sparing (Köhler, 1909). He tested this grid setup in 1912 on several
patients, irradiating the skin with up to approximately 60 Gy, and observed
the healing of skin necrosis in several weeks.
Figure 1. Schematic illustration of a typical grid with circular holes arranged in a
hexagonal pattern.
In 1933, Dr. Liberson, from the U.S Marine Hospital of New York City,
revived the concept of grid therapy and published a new study, without any
apparent knowledge of Köhler’s work (Liberson, 1933). In this paper,
Liberson explored different possible geometries for a perforated screen
(Figure 1), trying out squared, oval or round perforations, comprising one-
quarter, one-half or two-thirds of the total screen area. Similar to Köhler, his
main concern was the skin protection. Skin reactions were commonly
observed at the time of orthovoltage x ray therapy. He finally opted for a
1.5-2 mm-thick lead sheet, perforated with 2 to 8 mm circular holes in
diameter, comprising half of the total screen area. Liberson then applied his
grid technique on small animals, mice and rabbits, but also on a few human
2.1. The history of grid therapy
20
cases (mostly inoperable head & neck, lung, esophagus and bone cases) and
noticed an increased skin tolerance when using his perforated screen. He did
not however study other organs and focused on the skin toxicity.
One year later, in 1934, Dr. Wilhelm Haring performed his own study
of grid therapy (Haring, 1934). The grid he used consisted of a 25x25 cm2
large and 3 mm-thick lead sheet, perforated with 3 mm holes in diameter and
comprising half of the total screen area, much like Liberson’s perforated
screen. With the use of this grid, he irradiated a total of 20 patients, mainly
lung and stomach carcinomas and one case of pelvis sarcoma. He was able
to deliver approximately 5 Gy to the skin without noticing any important
unexpected effects. However, Haring remained relatively vague on the
outcome of the treated cases, providing only details on the evolution of the
skin. He simply mentioned that in the pelvis case, no further growth of the
tumor was observed after irradiation.
Dr. Hirsch Marks, in 1950, reported three cases of grid treatments
(Marks, 1950). The grids employed were made of 3 mm-thick lead-rubber
sheets, perforated with 0.25 cm2 to 4 cm2 squared holes (depending on the
grid used) comprising 40% of the total screen area. The three patients
presented with either vulva mass, suprapubic mass or tongue carcinoma.
After grid irradiations of 184, 210 and 212 Gy over 35, 18 and 20 treatment
days respectively, there was no clinical evidence of remaining disease for
any of the treated cases.
Finally, in 1953, in his book titled X-Ray Sieve Therapy in Cancer: A
Connective Tissue Problem, Dr. Benjamin Jolles provided an extensive study
of grid therapy, focusing on the radiobiology of the connective tissue, the
irradiated tissues and their neighborhood (Jolles, 1953). He notably
emphasized the protective role of the normal tissue and its part in the
repairing of irradiated adjacent tissues which could explain the results
witnessed with grid therapy. In the last chapter of his book, Jolles presented
detailed information on grid treatments for a total of 56 patients, which most
of the other authors failed to provide, focusing only on the evolution of the
skin after treatment and not on the treatment itself. The treated patients were
separated in two groups: the “accessible tumors” group, comprising 36
patients (12 skin, 3 anus, 5 vulva, 7 breast, 9 lymph nodes in neck and
groins) and the “deep-seated tumors” group containing 20 patients (8
carcinoma in uterus and ovary, 2 lung, 7 bowel, 3 miscellaneous). From
these study cases, Jolles reported remarkable results for many patients, some
with very advanced diseases that would have only been offered very limited
or no palliative care with conventional therapy at that time. In the first
patient group, the response to treatment for the skin cases was excellent
Chapter 2. Grid Therapy
21
while the treatments of the anus and vulva cancers provided a high degree of
palliation. However, the response of lymph nodes of neck and breast cancers
was poor. In the second group of patients (the deep-seated tumors), the
overall response was “fairly good”, with a degree of palliation way above
anything conventional therapy would have offered. For this second group,
Jolles emphasized that the curative value of the treatment had still to be
demonstrated, but concluded that grid therapy had proved to be useful in
some difficult cases which could be successfully irradiated without any risk
of skin necrosis.
2.2. Radiobiological basis of grid therapy: the dose-
volume effect
The rationale for using small and spatially-fractionated radiation beams to
achieve a higher normal tissue sparing is directly related to the dose-volume
effect, which has been historically described for single beam irradiations
(Hopewell and Trott, 2000).
Experiments on animals, including rats (Bijl et al., 2006, 2003, 2002,
Hopewell et al., 1987, 1986; Laissue et al., 2013; van der Kogel, 1993; Van
Luijk et al., 2005), pigs (Hopewell et al., 1986; van den Aardweg et al.,
1995; van der Kogel, 1993), monkeys (Schultheiss et al., 1994) and dogs
(Powers et al., 1998) have showed that the tolerance of the organs studied
(mainly skin and spinal cord) to radiation greatly increases with a decreasing
beam size (Figure 2). In the case of rat spinal cord irradiation, a steep rise in
the effective dose 50 (ED50), i.e. the dose required to expect a particular
endpoint to occur in 50% of the irradiated animals, was observed for
beamlets smaller than 8 mm when looking at the paralysis in fore or hind
limbs, or both, be it with photons (Hopewell et al., 1987; van der Kogel,
1993) or protons (Bijl et al., 2002, refered to as "Present study" in Figure 2).
In studies of the pig skin, similar results were observed for beamlets which
were 9 mm-wide and smaller when the acute reaction moist desquamation
and late dermal thinning endpoints were considered.
2.2. Radiobiological basis of grid therapy: the dose-volume effect
22
Figure 2. Effective dose 50 (ED50) (Gy) for the limb paralysis endpoint as a
function of irradiated spinal cord length in rats, using photons (Hopewell et al.,
1987; van der Kogel, 1993) or protons (Bijl et al., 2002, "present study") (reprinted
from Bijl et al., 2002 with permission from Elsevier).
The reason why the tolerance of the normal tissue increases when the
irradiated volume becomes smaller is still to-date not fully understood. But
several hypotheses have been proposed to explain the dose-volume effect.
Migration of unirradiated cells to irradiated volumes to repair the
radiation damage was suggested already in 1953 by Jolles as stated
previously (Jolles, 1953). Since then, other studies have explored this
process (Hopewell and Trott, 2000; Shirato et al., 1995; Withers et al.,
1988). The undamaged cells are believed to be able to migrate a short
distance (~2 mm) from the unirradiated to the irradiated volumes and
contribute to the repair of the locally damaged cells.
Furthermore, while a “classical” bystander effect has been observed and
described extensively, even for grid therapy (Asur et al., 2015), for which a
decrease in the survival of unexposed cells next to irradiated cells was
witnessed, some evidence seems to point towards the existence of another
type of bystander effect (described as type III in Mackonis et al., 2007). In
this case, communication between cells receiving a high dose and close cells
receiving a low dose is thought to lead to an increased survival of the heavily
irradiated cells. In grid therapy, this could occur when cells in the peak
region (high dose) are more efficiently repaired if the neighboring cells in
the valley region (low dose) are undamaged.
Chapter 2. Grid Therapy
23
2.3. Contemporary grid therapy
After the Second World War, the development of high-energy (MV) and
Cobalt-60 treatment units marked an important turn in the history of grid
therapy. With the new devices then available, the dose to the skin was
reduced due to the buildup effect of dose for high (1-20 MV) energy
photons. The concept of grid therapy was slowly abandoned and the number
of patients treated was greatly reduced.
Grid therapy has however resurfaced in the last three decades: it has
been occasionally performed at few clinics around the world as an attempt to
shrink bulky tumors that other treatment modalities failed to treat, with
impressive results (Huhn et al., 2006; Kaiser et al., 2013; Mohiuddin et al.,
2015, 1999, 1990; Neuner et al., 2012; Peñagarícano et al., 2010). It has
mainly been used for head-and-neck, thoracic and abdominal cancers, most
of the time in combination with other treatment modalities.
Figure 3. Photograph of a grid collimator used clinically (reprinted from Zwicker et
al., 2004 with permission from Elsevier).
Beam sizes of approximately 1 cm at the patient skin have been produced
with the help of collimators attached to a photon unit gantry head (Figure 3).
Only a single incident grid has normally been used, leading to an
inhomogeneous dose being delivered in the targeted volume, similar to what
can be observed in some brachytherapy treatments (Figure 4). But despite
the fact that some parts of the tumor are receiving very low doses, significant
reduction in the size of these bulky tumors has been observed (Figure 5).
2.3. Contemporary grid therapy
24
Figure 4. (a) Beam’s eye view (BEV) of one multileaf collimator strip over the
target breast in a patient with locally advanced breast cancer; (b) dosimetric profile
of spatially fractionated GRID radiotherapy beamlets in BEV. (reprinted from
Neuner et al., 2012 with permission from Elsevier)
Figure 5. Neck nodes from primary squamous cell cancer of the oropharynx. (Left)
Before and (Right) after a 15 Gy grid irradiation (reprinted from Mohiuddin et al.,
1999 with permission from Elsevier).
Chapter 2. Grid Therapy
25
In Figure 6, a typical grid lateral dose profile, with the associated grid-
specific parameters, is depicted. The characteristic succession of high doses
(peaks) and low doses (valleys) is shown, as well as the center-to-center (c-t-
c) distance separating each beam contained in the grid. This particular
example was Monte Carlo generated with 2 mm-wide proton beams, full
width at half maximum (FWHM), with a c-t-c distance of 4 mm.
Figure 6. Illustration of a typical grid lateral dose profile with 2 mm-wide (FWHM)
115 MeV monoenergetic proton beamlets and a c-t-c distance of 4 mm in water. The
profile was taken at the water tank entrance. (Monte Carlo simulation with the code
TOPAS).
2.4. Experimental grid therapy with µm- and mm-wide
beamlets
Another form of photon grid therapy which has been studied for the last
three decades is the so-called microbeam radiation therapy (MRT)
(Blattmann et al., 2005; Bouchet et al., 2013, 2010, Bräuer-Krisch et al.,
2010, 2005; Crosbie et al., 2010; Dilmanian et al., 2007, 2006, 2002; Grotzer
et al., 2015; Laissue et al., 2013; Serduc et al., 2010, 2009, 2008; Slatkin et
al., 1992; Smilowitz et al., 2006; Van Der Sanden et al., 2010). In MRT,
grids containing quasi-parallel photon beamlets produced by a synchrotron
accelerator with widths in the micrometer range (typically 25-100 µm) are
used. The beamlets comprised in the grid are usually spaced with distances
2.4. Experimental grid therapy with µm- and mm-wide beamlets
26
of 100-400 µm (Figure 7) and peak entrance doses up to 10 000 Gy have
been investigated. MRT is an extreme case where the dose-volume effect is
exploited maximally, with extremely small beamlets to greatly increase the
radiation tolerance of the underlying tissues.
Figure 7. Horizontal section of the cerebellum of a piglet 15 months after irradiation
with a skin entrance dose of 300 Gy. Some cells and their nuclei directly in the path
of microbeams were destroyed. There was no tissue destruction present, nor were
there signs of hemorrhage. The paths of the microbeams appear in the section as
thin, white horizontal parallel stripes, which are more easily visible in the insert.
Beam width 27 µm, spacing 210 µm. (reprinted from Blattmann et al., 2005 with
permission from Elsevier)
Even though only a small volume of the target receives high doses of
radiation, good tumor control has been reported after MRT (Dilmanian et al.,
2003; Laissue et al., 1998; Miura et al., 2006). Preferential damage seems to
occur to the tumor microvasculature when irradiating with microbeams. This
process has been shown mainly for rat brain tumors (Bouchet et al., 2013,
2010). In these studies, a differential effect of the microbeams on the tumor
vasculature has been observed, leading to increased blood vessel
permeability and to tumor hypoxia. However, no such effects were detected
in the normal brain vasculature.
Most MRT studies have been focusing on rat and mouse brain tissues,
with few additional data on the spinal cord and skin. Experiments on pigs are
currently ongoing, while the first clinical trials are in preparation (Bräuer-
Krisch et al., 2015; Schültke et al., 2017).
With the recent developments in proton and heavy-ion therapy a new
kind of grid therapy has been suggested. In proton and ion grid therapy, the
Chapter 2. Grid Therapy
27
special dose characteristics of charged particles are taken advantage of. With
their limited range, a conformal dose distribution on the distal edge of the
target volume can be produced. Furthermore, with the right c-t-c distance
between the beams and due to multiple Coulomb scattering of the charged
particles in the medium, the initially spatially fractionated beamlets will
overlap at a certain depth and produce a nearly homogeneous dose
distribution over the target as depicted in Figure 8. Proton and ion grid
therapies have mostly been explored with the use of minibeams, i.e.
beamlets with widths in the order of 0.3-0.7 mm (Dilmanian et al., 2015,
2012; Lee et al., 2016; Peucelle et al., 2015; Prezado et al., 2017; Prezado
and Fois, 2013) and sometimes microbeams (Kłodowska et al., 2015;
Zlobinskaya et al., 2013). A recent work also explored the use of
conventional, non-collimated proton beam sizes in a clinical grid application
(Gao et al., 2018). Overall, only few studies have been published so far, but
it is a growing field of research that has shown great potential for future
clinical applications.
Figure 8. Example of the dose pattern produced by a single grid irradiation in water
with 2 mm-wide (FWHM) 115 MeV monoenergetic proton beamlets and a c-t-c
distance of 4 mm (Monte Carlo simulation using the code TOPAS).
2.4. Experimental grid therapy with µm- and mm-wide beamlets
28
Chapter 3. Towards the development of an interlaced proton grid therapy
29
3. Towards the development of an
interlaced proton grid therapy
3.1. Objectives and questions to be answered
Several major differences in how grid therapy can be delivered can be
identified when studying retrospectively the history of grid therapy, from the
very first attempts in the beginning of the 20th century until today’s research
on this topic. With grid therapy, the dose distributions produced inside the
irradiated target volume can be of two different types:
Type 1: The beamlets are well separated throughout the irradiated
volume and the target, producing the grid pattern of the dose
distribution (“peaks” of high doses and “valleys” of lower doses) in
the normal tissue and in the targeted volume as well.
Type 2: The beamlets are well separated at the entrance but overlap
in depth due to scattering in the volume, creating a nearly
homogeneous dose distribution in the target but also several
centimeters in front of it.
In this project, these two approaches were merged to create an improved
approach for grid therapy. The objectives for the suggested approach were
the following:
1. To maintain the grid pattern of the dose distribution (peaks and
valleys) in the normal tissue from the entrance all the way to the
direct vicinity (< 1 cm) of the target, in order to keep the normal
tissue toxicity as low as possible for all organs, and not only for the
skin.
2. To deliver a nearly homogeneous dose to the targeted volume to
achieve a high tumor control probability (TCP).
To fulfill these objectives, an improved grid geometry was suggested.
By interlacing grids of proton beamlets over a target volume, a dose
distribution similar to what can be obtained with conventional proton
therapy inside a target volume can be achieved. Outside of the target volume
however, a well-defined grid pattern in the dose distribution can still be
preserved in the normal tissue down to the direct vicinity of the target. The
3.2. Grid geometries and irradiation setups
30
interlaced geometry has been used before (Dilmanian et al., 2012, 2006;
Lomax and Schaer, 2012; Prezado and Fois, 2013; Serduc et al., 2010) but
with different objectives and/or particle types. Prezado and Fois, 2013
presented results with proton beamlets. In their study, proton beamlets with
an energy of 1 GeV were used to irradiate a volume with the proposed
geometry but due to the high kinetic energy of the protons, the beamlets
propagated way beyond the target. The Bragg-peaks were therefore located
outside of the body. A similar grid irradiation with proton beams as used in
this thesis was presented in the abstract from Lomax and Schaer, 2012. Only
very limited information about the planning strategies being, however,
provided.
The work presented here aimed to use this improved grid geometry and
prove its potential usefullness for radiotherapy treatments. To do so, several
questions had to be answered:
1. Is it possible to deliver this kind of grid irradiation with currently
available proton beams at modern proton facilities with the help of a
commercial treatment planning system (TPS)? (Paper I)
2. How do these interlaced grid irradiations compare with conventional
photon and proton treatments? (Papers II & V)
3. How robust are these irradiations against spot position uncertainties,
considering the precision required for interlacing the beams? (Paper
III)
4. What kind of interlaced grid irradiations could be produced with
smaller beamlets, to exploit the dose-volume effect even further
(Paper IV), and how can one produce these small beamlets at
existing proton facilities?
5. What are the clinical implications of such irradiation modality with
focus on the RBE (Paper V) and the use of CBCT imaging? (Paper
VI)
3.2. Grid geometries and irradiation setups
Two types of grid were evaluated in this work:
A 1-D grid consisting of parallel planar beamlets as pictured in
Figure 9.a
A 2-D grid comprising parallel circular beamlets (Figure 9.b)
Chapter 3. Towards the development of an interlaced proton grid therapy
31
Figure 9. Schematic illustration of (a) a 1-D and (b) a 2-D grid. The center-to-center
(c-t-c) distance between the beamlets is shown for both cases.
Both of these grid types could be used depending on the
situation/objective/studied case. The 2-D grid type offers a higher normal
tissue protection, due to the spatial fractionation of the beamlets in two
dimensions, leaving a higher volume of non-irradiated tissue in-between the
beamlets. However, the 1-D grid type offers higher dose coverage of a
target, due to a larger volume being irradiated by one single grid.
To create a nearly homogeneous dose distribution inside the targeted
volume, the grids were interlaced as described previously and illustrated in
Figure 10. With this setup, one can arrange the beam grids to interlace over
the target. Due to multiple Coulomb scattering in the medium through which
the protons are transported, the elemental beamlets contained in the grids
will overlap in the targeted volume, which will produce a nearly
homogeneous dose.
Intrinsically, interlacing two opposing 1-D grids might be enough to
produce sufficient dose coverage inside a specific target volume. Adding two
additional opposed 1-D grids (2x2 opposing 1-D grids) will increase the total
target dose, while decreasing the peak and valley doses outside of the target.
However, when using 2-D grids, 2x2 opposing grids seem to be mandatory
to achieve reasonable dose coverage of the target volume.
Sometimes, the use of opposing grid angles is not possible, due to e.g.
the close proximity of a sensitive organ to the targeted volume. In that case,
another grid irradiation geometry can be used: 2 non-opposing 1-D grids, in
which the two grids are interlaced without the need to be opposing (Figure
11), allowing for a better sparing of the tissues located beyond the distal
edge of the different beams.
The c-t-c distance between the beamlets inside a single grid can also be
adapted. Intuitively, when the c-t-c distance is increased, a decrease in the
valley dose is obtained. However, obtaining good dose coverage of the
3.2. Grid geometries and irradiation setups
32
irradiated target with a large c-t-c distance will be challenging, due to a
reduced number of beamlets contributing to the total dose inside the target.
Figure 10. Illustration of the interlacing of 2x2 opposing 2-D grids inside a cubic
target volume, each grid containing 9 beamlets.
Figure 11. Illustration of the interlacing of 2 non-opposing 1-D grids.
Chapter 4. Using conventional beam sizes: a first step
33
4. Using conventional beam sizes: a first
step
While small beamlets in the µm- and mm-range seem to be more
advantageous for tissue sparing according to studies focusing on the dose-
volume effect (see 2.2), “larger” beamlets could still be beneficial compared
to the broad fields used in conventional proton therapy. Indeed, modern
photon grid therapy treatments have shown that good results in terms of
shrinking of bulky tumors and skin toxicity could still be achieved with
spatially fractionated beams with sizes of approximately 1 cm at the patient
skin (Huhn et al., 2006; Kaiser et al., 2013; Mohiuddin et al., 2015, 1999,
1990; Neuner et al., 2012; Peñagarícano et al., 2010).
At a modern proton facility center such as The Skandion Clinic in
Uppsala, proton beams with approximate widths of 7-15 mm FWHM,
depending on the energy, can be produced. For beamlets of these sizes, a
small but not insignificant dose-volume effect could be expected (as
observed in animal experiments, see 2.2).
In that regard, it appeared that exploring the interlaced proton grid
therapy presented in this work with these relatively large beamlets was an
evident first step serving as a proof-of-concept, before digging into the use
of mm-wide beamlets. A notable therapeutic advantage can still potentially
be achieved, and working with beams that do not require any kind of
collimation is a tremendous practical advantage, the spatial fractionation of
the beams being accomplished by pencil beam scanning.
4.1. Establishing the potential with commercial treatment
planning systems
The first study of this thesis work then focused on the possibility to carry out
interlaced grid therapy treatments using grids containing beamlets currently
available at a modern proton therapy center, with the grid geometries
described in 3.2 (Paper I). To do so, the TPS Eclipse Protons (Varian
Medical Systems, Palo Alto, USA) was used to replan two patients that were
previously treated with conventional photon therapy at Karolinska
4.2. Going further: planning clinically realistic grid plans
34
University Hospital in Stockholm for liver or rectal cancer. The patients
were replanned using the suggested interlaced proton grid therapy with
either 1-D or 2-D grids.
The results of this proof-of-concept study showed that it was possible to
irradiate the targeted disease (here the planning target volume, PTV) with a
high and nearly homogeneous dose, while preserving the grid pattern of the
dose distribution down to the vicinity of the target. When normalizing the
minimum target dose to 100%, the valley dose in the normal tissue was
approximately 5-20%, depending on the depth considered. The peak doses
ranged from approximately 50 to 120%. Even in the neighborhood of the
PTV (2 cm in front), a peak-to-valley dose ratio (PVDR) of 5 could still be
observed. The target dose ranged from 100% to 120-140% depending on the
grid geometry used.
This work demonstrated the potential of such proton grid therapy from a
dosimetric point of view. In this study, only already clinically available tools
were used, showing that the interlaced proton grid therapy technique
described in this paper is potentially achievable without overcoming
important technical issues.
As a comparison, more conventional proton therapy techniques (proton
radiosurgery) on the liver cancer case were investigated in Paper II. In this
study, ten patients diagnosed with liver metastasis and treated with SBRT at
Karolinska University Hospital were replanned using IMPT with the same
dose objectives set to the targets as in the photon SBRT plans. Patient no. 1
in this Paper II is the patient used for grid planning in Paper I. While similar
doses could be delivered to the PTV, a clear improvement regarding the
sparing of the organs at risk was noticed when using IMPT instead of photon
SBRT. Comparison of photon SBRT, proton SBRT and proton grid plans
can be found in Figure 12. With grid therapy, and based on the dose-volume
effect, our hypothesis is that an even greater normal tissue sparing could be
achieved compared to the studied IMPT radiosurgery.
4.2. Going further: planning clinically realistic grid plans
As stated, the work presented in Paper I served as a proof-of-concept for the
presented grid geometries, using regular proton beam sizes. In that sense, the
focus was put on fulfilling the objectives set previously, i.e. a nearly
homogeneous PTV dose in combination with a well-defined grid pattern in
the normal tissue. However, the different organs at risk (OARs) were given
no particular considerations, making these liver and rectal proton grid plans
probably clinically unrealistic.
Chapter 4. Using conventional beam sizes: a first step
35
Figure 12. Comparison of (a) conventional photon therapy (SBRT), (b) interlaced
proton grid and (c) proton radiosurgery (SBRT) plans on a liver cancer case.
This aspect was studied later on in the project, when looking at RBE for
interlaced proton grid therapy (Paper V). While a full report of the impact of
RBE on conventional and proton grid plans can be found in section 6.1, the
focus here will be on the comparison between conventional and grid plans
with a constant RBE of 1.1.
For this study, the TPS Raystation (RaySearch Laboratories AB,
Stockholm, Sweden) was used to replan five patients, each presenting tumor
volumes in a different location (esophagus, lung, liver, prostate and anus).
The same grid geometries as previously described were used. For
comparison, conventional IMPT plans were also produced. This resulted in a
total of five plans for each patient (one IMPT + four grid). To make both the
IMPT and grid plans clinically relevant, dose objectives to the different
OARs were set according to suitable sources (Emami, 2013; Marks et al.,
2010; Muirhead et al., 2016). Plan optimization was done on the PTV and
OARs.
An example of dose distributions for a conventional IMPT plan using
two fields (200° & 270°) and a grid plan (2x2 opposing 2-D grids, with grid
angles 20°, 110°, 200° & 290°) is presented in Figure 13. Of the 20 grid
plans computed, 18 fulfilled all the clinical goals set for the OARs and the
PTV. The failure of the 2 remaining grid plans was due to the close
proximity of the duodenum in the liver case that would not allow the use of
certain grid geometries. In terms of average doses to the OARs, most of the
passing grid plans were very comparable to the conventional IMPT plans.
4.3. Impact of spot position uncertainties
36
Figure 13. 2-D dose distributions of (a) a conventional two field proton plan, and (b) a 2x2
opposing 2-D proton grid plan, for a lung case.
4.3. Impact of spot position uncertainties
Eventually, this second study confirmed that producing interlaced proton
grid plans that are clinically relevant, with respect to clinical goals to the
OARs and the PTV, is possible with regular beam sizes available at modern
proton centers. However, there are still numerous limitations and questions
that need to be addressed.
The most evident one is the precision in spot delivery. Indeed, all the
presented plans, either with Eclipse or Raystation, assumed perfectly
positioned spots at the desired positions. However, it is commonly accepted
that during quality assurance of proton beams, a tolerance of < 1 mm
(sometimes < 2 mm) is allowed. What would then be the impact of small
mispositionings (within tolerance) of the spots for interlaced proton grid
plans? The interlacing of the beams is of course a central point of the
technique presented here. It is therefore crucial to understand the
consequences of an imperfect interlacing as a result of variability in spot
positioning. It will most likely give rise to local cold and hot spots in the
targeted volume due to a potential overlap of the beams in this latter.
To quantify these effects, a study was performed (Paper III). The idea
was to use the scripting capabilities of Raystation to introduce an uncertainty
in the spot positioning. The grid plans described in section 4.2 were in fact
created using a Python script in Raystation to position the spots. The same
patients and grid plans were reused. A script was created to include a
random error in the X and Y spot positions after the initial plan had been
optimized, based on a Gaussian probability distribution with σ= 0.5 mm and
cut-offs at ± 1 mm. Then, this new grid plan’s dose with slightly out-of-
position spots was recalculated without any optimization process. Dose
statistics and dose-volume histograms (DVHs) were recorded. This was done
Chapter 4. Using conventional beam sizes: a first step
37
30 times for each plan to study the average impact of such spot positioning
errors on all the 18 goal-fulfilling grid plans from the previous study.
Preliminary results have shown that, in the case of small variations in the
positions of the spots, the PTV dose coverage could be slightly altered and
doses could go below and above the clinically accepted dose thresholds
(96% of the PTV should receive 95-107% of the prescribed dose), while
OARs doses would remain almost identical and below limits for most cases.
The observed trend was that the introduction of an imperfect interlacing led
to the occurrence of localized hot and cold spots inside and in the close
vicinity of the PTV. Of the 540 plans computed with spot position
variations, 341 failed the clinical goals set for the PTV. An underdosage of
this latter was observed in 216 plans while an overdosage was seen in 33
plans. The remaining 92 plans presented both an underdosage and an
overdosage of the PTV. However, while the recorded doses of interest were
indeed out of clinically accepted boundaries, they remained very close to
these clinical goals, opening the door for potential robust planning. Also, the
grid geometry played an important role in the success of the plans, with the
2x2 opposing 1-D grid geometry delivering the best PTV dose homogeneity
and highest passing rate of all geometries, while the 2x2 opposing 2-D grid
geometry was the less efficient in terms of dose coverage and passing rate.
4.4. Discussion
The studies discussed in this chapter present a proof-of-feasibility of
interlaced proton grid therapy using beam sizes producible by any modern
proton beam line. The validity of such treatment modality was explored with
the use of treatment planning systems only, and has to be further explored in
a more applied way. Indeed, delivering interlaced proton grid plans will give
rise to additional issues and limitations that have not been evaluated yet in
the TPS.
The concern of spot mispositioning has already been touched on in 4.3,
but could now be assessed for real irradiations. The idea would be to deliver
actual proton grid plans in a phantom at The Skandion Clinic and, similarly,
to recalculate the plan’s dose distribution using the spot positions recorded
after irradiation in the system’s log files. This could be done on a daily basis
to evaluate the average deviation to the original plan, and would provide a
preliminary indication whether or not interlaced proton grid treatments could
be safely delivered at this specific center, on a dosimetric level exclusively.
4.4. Discussion
38
Another obvious issue one may encounter when delivering proton grid
plans is organ motion. For most grid geometries used throughout this entire
thesis (namely the 2 opposing & non-opposing 1-D and 2x2 opposing 2-D
grids), some volumes within the PTV are mainly irradiated by only one
beam (see Figure 10). In the case of organ motion, it is then very likely that
one or more beams could end up being misplaced compared to the planned
spot positions, leading to local hot and cold spots, or even completely
unirradiated small volumes in an extreme case. What would then be the
consequence of such altered dose distributions on the validity of the
treatment plan, for the OARs of course, but more specifically its curative
value? As it was previously observed (section 2.3), current clinical grid
treatments using photons are purposely delivering very heterogeneous doses
in the targeted volume, with some parts receiving very little or close to no
dose. But these treatments are usually followed by more conventional
irradiations. Therefore, if interlaced proton grid therapy is to be evaluated as
a stand-alone treatment modality, as it is the long-term objective here, the
organ motion problem must be addressed. It is uncertain what the best
solution would be, but it definitely requires additional studies. One
workaround would be to first limit proton grid experiments to brain-type
irradiations. There, organ motion seems to be minimal (Enzmann and Pelc,
1992). Moreover, with the help of high precision stereotactic frames, which
can be found in Gamma Knife treatments for example (Heck et al., 2007),
good accuracy in the positioning, within < 1 mm, could potentially be
achieved.
Another concern for interlaced proton grid therapy is range uncertainty.
However, this concern is not expected to be more significant for proton grid
than for, e.g., IMPT. Indeed, the exact same beamline and beam data are
used in the two modalities, the only difference being the beam arrangement.
Therefore, range uncertainty should be dealt with in proton grid as it is in
IMPT. Furthermore, taking advantage of the robust optimization approaches
developed for IMPT, one could spend extra effort on assessing the variable
spot position issue discussed previously. One could think of a special grid
robust planning where tighter PTV doses objectives would be set in order to
prevent any failure of the plans. Also, as the grid geometry used seems to
have a significant impact on the overall passing rate of the plans, extra
attention could be given to choosing the right geometry for the right
situation. Sometimes, as it was the case with the liver patient studied here,
the patient’s geometry and locations of certain OARs prevent the use of
some grid angles/geometries, otherwise exceeding the dose constraints set
for said OARs. A compromise might have to be found in search for the best
Chapter 4. Using conventional beam sizes: a first step
39
option; unless, of course, a small dose-volume effect can still be proved for
these rather large pencil beams, in which case the number of possible grid
geometries and angles for such difficult cases might not be decreased.
Finally, few words should be said about dosimetry. If experimental
interlaced proton grid plans are to be delivered in a phantom as suggested
earlier, they will have to be somehow evaluated. Checking the spot positions
should be fairly easy with existing tools: log files from the system, film
measurements, 2D scintillators etc. However, dose homogeneity in the PTV
has to be verified as well, and one should not only rely on the correct spot
positions to assume that interlacing was done properly. This could prove to
be rather cumbersome. 3D detectors like gels or organic scintillators could
be used but these detectors are prone to quenching, which would add another
issue to solve. 2D arrays of ionization chambers are also an option but they
provide only limited spatial information due to their quite low resolution. A
good compromise/solution has to be found and will be explored in future
works.
4.4. Discussion
40
Chapter 5. Proton grid therapy with small beamlets
41
5. Proton grid therapy with small beamlets
The use of small proton beamlets would theoretically enable a better
exploitation of the dose-volume effect, and might therefore prove to be a
better choice to achieve a higher protection of the sensitive tissues. However,
there are additional concerns with smaller beamlets that need to be
evaluated, such as altered dosimetric properties compared with broad beams,
and the need for extra collimation to create these small beamlets.
5.1. Establishing the potential through Monte Carlo
simulations
To determine if what was presented with “large” beams would be possible to
achieve with beamlets which are smaller than those used clinically today, i.e.
beamlets with widths in the range 1-3 mm FWHM, a Monte Carlo study was
performed (Paper IV).
The aim of this specific study was to perform a simple interlaced proton
grid irradiation of a small cubic target at the center of a water tank, with the
same grid geometries proposed in section 3.2, and the same dose objectives
as previously stated: well defined grid pattern outside of the irradiated
volume and homogeneous dose distribution inside. An extensive focus was
put on assessing the impact of the beamlet width and the c-t-c distance on
the final dose distribution. The Geant4-based MC code TOPAS was used
(Perl et al., 2012).
Also, efforts were made in identifying and establishing the additional
parameters required to characterize grid therapy. There were four parameters
in total: the c-t-c distance, the initial beamlet width and the peak dose, all of
which were discussed previously, but more importantly the valley-to-peak
dose ratio (VPDR). Until now, all grid studies reported the “quality” of the
grid as the peak-to-valley dose ratio. However, this ratio appears to be
numerically unstable and divergent with very low valley doses. Hence, from
this point onwards, the use of the VPDR, that equals 0 for a perfect grid with
no valley dose, and 1 for homogeneously distributed dose, was preferred and
seems to have been adopted by other research groups (Gao et al., 2018).
The results of this study showed that with the optimal c-t-c distances, a
high and nearly homogeneous target dose could be achieved, with a standard
5.2. A motorized collimator design to produce millimeter-wide beamlets
42
deviation of less than ± 5% in all cases (Figure 14). Furthermore, outside of
the target, the grid pattern of the dose distribution could still be maintained
in the normal tissue, with peak doses more than twice as high as the valley
doses in the direct vicinity of the target (1 cm).
Hence, the use of small proton beamlets in the millimeter range is
compatible with the dosimetric objectives set in section 3.1. What was
observed with larger proton beams seems to be reproducible with smaller
beamlets, for a very simple case. The dose distributions obtained with these
beam grids, containing mm-wide beamlets, however need to be further
evaluated for clinically more realistic and complex cases. Tools are under
development with this aim, and are further discussed in section 5.3.
Figure 14. Example of 2x2 opposing 1-D grids interlacing in a cubic target with 2
mm-wide beams and a c-t-c distance of 7 mm (Monte Carlo simulation with the
code TOPAS).
5.2. A motorized collimator design to produce
millimeter-wide beamlets
The production of mm-wide proton beamlets at current proton facilities
could be cumbersome. Such centers are usually equipped with commercial
Chapter 5. Proton grid therapy with small beamlets
43
proton treatment solutions that are designed to better fit clinical
requirements. Unfortunately, the use of small beamlets is not a priority.
Therefore, collimation of the already producible beams seems mandatory.
That poses an extra challenge when working with proton beams, and
more specifically proton beams delivered with pencil beam scanning. Since
the beam can move in the two dimensions perpendicular to the beam
propagation direction, three possible ways of collimating such beams were
identified:
1. The easy way is to make the beam fixed, and move the table
instead to create the spatial fractionation. Then, a collimator
with a simple hole in the middle and with the desired size and
shape can be inserted in the nozzle’s holder (Figure 15 left).
2. A more advanced solution would be to attach a collimator to the
nozzle’s holder with holes already arranged in a grid pattern,
with the desired size and c-t-c distance between them. (Figure
15 middle).
3. Finally, the most advanced solution would be to have a small
collimator that can move in two dimensions, accordingly to the
beam’s position. (Figure 15 right).
Figure 15. Different grid-oriented collimation options for proton pencil beam
scanning.
In these three options the holes could of course be of any shape: circular for
example, to obtain a 2-D grid, or elongated, to have a 1-D grid.
While it is definitely the easiest solution for research purposes, option 1
is not really clinically applicable as it would require numerous small table
movements with high precision. Option 2 is the go-to solution for the vast
majority of grid-focused research groups nowadays. It ensures a good
positioning of the beams thanks to high precision capabilities in industrial
5.2. A motorized collimator design to produce millimeter-wide beamlets
44
manufacturing, and remains quite easy to use. However, it lacks
customization possibilities: the c-t-c distance, the size and position of the
holes and the total number of holes are fixed. Thus, even the slightest change
of one of these parameters requires the manufacturing of a new similar
collimator. The price of such pieces to have some flexibility in the grid
geometry could then add up quickly. Also, since the collimator as a whole is
fixed in the nozzle’s holder, the interlacing between e.g. two opposing
beams would have to be done using small table movements.
It was consequently decided that option 3 was the most suitable for the
current needs and applications. A motorized collimator, capable of moving
in two dimensions, was therefore designed.
The system is made of the following parts (Figure 16):
- Two pairs of motor + linear guide, each producing linear motion in
one dimension (1)
- One linear support to distribute the weight over several points (2)
- A cylindrical brass collimator (3)
- A mounting frame to hold all the different pieces together and
designed to mount the system on the Skandion Clinic’s IBA nozzle
(4)
Figure 16. 3D model of the designed motorized collimator.
This collimator system was recently manufactured, and preliminary
studies evaluating the induced activity in the collimator after proton
irradiations were performed. Testing and irradiation measurements at The
Chapter 5. Proton grid therapy with small beamlets
45
Skandion Clinic are planned for the near future to prove the concept and
assess the efficiency of such system.
5.3. Discussion
Determining what would be possible to do with smaller beamlets than those
currently delivered at modern proton centers was the natural evolution of this
project. Indeed, all observations of the dose-volume effect point towards the
increase of tolerance of tissues to radiation beams with decreasing size of
said beams (see 2.2).
While studies on micro- and minibeams are currently being conducted
by several research groups (see 2.4), it appeared unreasonable to evaluate if
interlacing such beams would result in advantageous dose statistics, in
regards to the objectives set for this work (see chapter 3). The technical
requirements to properly interlace such small beams seemed too
cumbersome to imagine an easy and efficient clinical application. It was
therefore decided that beamlets in the order of 1-3 mm FWHM were more
suitable, as they could still be considered as small beams compared to
regular clinical proton beams, while being technically less difficult to
produce.
In the first study, Monte Carlo simulations were used to assess if the
grid geometries and objectives used in the previous evaluation with “broad”
beams could still be achieved with these millimeter beamlets. While it
provided encouraging results, valuable information and permitted the
establishment of a few grid-specific but important parameters, this study
remained however fairly simple with respect to the geometry - the irradiation
of a cubic target in a cubic water phantom. Unfortunately, studying more
complex irradiation cases, for example on patient CT data instead of simple
Monte Carlo geometries, requires additional parameters and greatly
increases the computation time. One cannot easily and quickly find the
optimal spot positions/spot weights for a complex case, and blindly tuning
these parameters by hand until a satisfying solution is found is not an
efficient way to proceed. Therefore, an in-house Monte Carlo-based and
grid-oriented optimizer tool is currently under development within our
research group and will be presented in a near future. With this tool,
simulating grid irradiations with Monte Carlo-generated beamlets on any
kind of geometry, including patient CT data, will be possible. This will be of
great help to evaluate the potential applications on a whole variety of clinical
cases of interlaced proton grid therapy using small beams.
5.3. Discussion
46
The issue of correct spot positioning has been discussed in the previous
chapter, but it will definitely be different when working with small beamlets.
If the described collimator is to be used to produce these beamlets then the
accuracy in the spot positioning will no longer depend on the accuracy in the
beam delivery position, but rather on the correct positioning of the
collimator itself. Thanks to the linear guide units used in the presented
prototype, this can theoretically be achieved with a fairly good accuracy
(0.04 mm) and repeatability (± 0.01 mm). Therefore, with a correct
calibration of the system (i.e. an accurate determination of the isocenter
position for the collimator), good accuracy in the collimator’s movements
should supposedly be reached. However, if this system is to be used on a
rotational proton gantry as it is currently planned, one will also have to
evaluate the variation of mechanical isocenter position with different gantry
angles. Indeed, a slight variation of e.g. 1 mm between two opposing gantry
angles could have a considerable impact on the overall quality of the
interlacing. While this mechanical variation is usually compensated for the
proton beam with the magnets, one will also have to think about calibrating
the collimator position to match the beam’s isocenter.
Nevertheless, one question remains: what are the biological
implications of using spatially fractionated beams? The lack of data for an
extended range of parameters (beam size, c-t-c distance, peak dose, valley
dose, tissue type, fractionation scheme) is preventing a clear understanding
of all the consequences of using such unconventional beam arrangements.
As it was seen with the use of small beamlets (Paper IV), the peak dose in
the normal tissue is sometimes higher than the actual target dose, depending
on the grid type, beam size and c-t-c distance. What would then be the
outcome for the normal tissue of such high but very localized doses? One
could be tempted to generalize observations of the dose-volume effect for
certain tissue types in animals (Figure 2) to all tissue types in humans,
concluding that the tolerance of the healthy tissue will be tremendously
increased considering the beams sizes used (1-3 mm). This, of course,
represents a most-likely incorrect over-simplification. Clinical reports from
simple grid irradiations from the past three decades seem to be pointing
towards the existence of a dose-volume effect in some human tissues as well.
But substantial efforts still have to be made on the radiobiological side to
fully understand the extent of this effect, and how to use it to our advantage.
Chapter 6. Clinical challenges: RBE and CBCT imaging
47
6. Clinical challenges: RBE and CBCT
imaging
The suggested interlaced proton grid technique is still at a very early stage of
development, and it is of course highly unclear how it could be transferred to
the clinic. However, to ensure that the best treatment option is proposed, one
has to think beforehand of all the underlying implications of using the
interlaced grid geometry.
6.1. RBE considerations
One issue that has to be evaluated before clinical application is directly
linked to the use of proton beams. Indeed, the use of charged particles adds
several physical and biological challenges as compared to radiotherapy with
photon beams. The correct management of the different relative biological
effectiveness (RBE) is one of them.
So far, conventional clinical proton treatments have been planned using
a constant RBE of 1.1. However, a large number of in vitro studies are
pointing towards the existence of a variable RBE, depending on the dose,
linear energy transfer (LET), tissue type and more (Paganetti, 2014).
Variable RBE is therefore an issue that can lead to increased normal tissue
dose and, as such, has to be addressed. This is of course true for regular
IMPT plans, but for proton grid as well, where the fractionation of the beams
usually leads to high doses being delivered in each single beam, and could
therefore result in an even higher increase in the normal tissue dose. Hence,
a study of the differences between dose, LET and RBE-weighted dose
distributions and their consequences for conventional and grid plans was
required.
This was performed in Paper V. The method used in this study has
already been partially described in section 4.2, when comparing clinically
relevant conventional and grid plans. The same set of patients and plans
were considered here, i.e. five patients, one IMPT plan and four grid plans
per patient.
RBE-weighted dose distributions for these plans were calculated using
the method described previously by Ödén et al. (Ödén et al., 2017b, 2017a).
6.2. The use of CBCT imaging
48
In summary, dose-averaged LET was computed on voxel level for the 20
plans (assuming a constant 1.1 RBE) using RayStation v4.6 experimental
Monte Carlo engine. Then, RBE-weighted dose distributions were calculated
following two variable RBE models (McNamara et al., 2015; Wedenberg et
al., 2013). The newly created plans taking into account variable RBE were
then compared, examining fulfillment of clinical goals for the PTV and
different OARs.
Of the 50 variable RBE plans evaluated (five patients, five plans for
each patient and two RBE models), only 15 passed the clinical goals set for
the different structures: 2 IMPT plans and 13 grid plans. Most passing plans
were for a single patient, the esophagus case, where both IMPT plans with
the two models and all the 8 grid plans were accepted. One can also note that
the five remaining passing plans were achieved with grid irradiations for the
liver and prostate case, while the respective IMPT plans failed for both
models considered.
Interestingly enough, despite the different beam arrangements between
IMPT and grid plans, results when considering variable RBE models were
very similar between the two techniques. Most plans were rejected due to the
failure of the same clinical goals: genitalia DRBE,5% for the anus case, bladder
V80 Gy (RBE) for the prostate case, duodenum DRBE,0.1cc for the liver case and
esophagus DRBE,0.1cc for the lung case.
Overall, this study showed that compared to IMPT, the use of spatially
fractionated beams does not seem to add extra difficulties when considering
variable RBE models. However, this does not mean that it is not
problematic, as it remains an issue that has to be addressed, just as it should
be in regular proton therapy.
6.2. The use of CBCT imaging
Another issue that has to be evaluated is the use of CBCT imaging. Indeed,
interlacing proton beams will most likely require high precision in motion
management (as touched briefly in section 4.4) and in positioning of the
patient. For this latter, the use of imaging will most probably be mandatory.
Modern proton therapy facilities can be equipped with CBCT systems
that are often custom made, and which could benefit the suggested proton
grid therapy for positioning purposes.
The aim in proton grid therapy is to give as low dose as possible to the
healthy tissues in between the beams (valley dose, see chapter 2). But
performing CBCT could result in a bath of potentially non-negligible dose
Chapter 6. Clinical challenges: RBE and CBCT imaging
49
over an important volume, therefore increasing the valley dose (and by
extension the valley-to-peak dose ratio), and consequently hypothetically
reducing the benefit expected from the dose-volume effect in terms of tissue
tolerance. But to which extent? Also, due to the lack of radiobiological data,
it is very uncertain what kind of fractionation regimen would the proposed
interlaced proton grid therapy benefit the most. As a consequence, one has to
be prepared to any possibility, including treatment courses spanning over
several weeks. In this case, the use of daily CBCT does not seem implausible
and poses extra challenges due to the increased dose burden of using such
imaging modality on a daily basis. This issue then required an extensive
study of the doses delivered by such CBCT system. This was done in Paper
VI.
In this work, doses to specific organs in an anthropomorphic phantom
delivered by the proton gantry-mounted CBCT system at The Skandion
Clinic in Uppsala were evaluated by means of two Monte Carlo codes,
MCNP6 (Goorley et al., 2016) and Geant4-based GATE (Jan et al., 2004).
To do so, the CBCT system was first modelled in the MC codes using
measurements of depth-dose profiles in water and lateral profiles in air.
Then, those two models were validated against absolute dose measurements
in a CTDI phantom. Finally, the validated models were used to evaluate
doses delivered by this specific CBCT system to organs in an
anthropomorphic phantom (PBU-60, Kyoto Kagaku, Kyoto, Japan),
following irradiation from three protocols (head, thorax (Figure 17) and
pelvis) and different scan modes (full 360° scan, anterior 190° scan,
posterior 190° scan). The cumulative doses from weekly and daily imaging
were also calculated.
Figure 17. Example of simulated energy deposition in the anthropomorphic
phantom for a 360° scan of the thorax (GATE).
6.3. Discussion
50
The average doses from a 360° scan to the organs located inside the
irradiation field for the three protocols (head, thorax, pelvis) ranged between
6-8 mGy, 15-17 mGy and 24-54 mGy, respectively. For daily imaging,
based on a 30-day treatment course, this resulted in doses ranging between
0.2-1.6 Gy, depending on the organ and protocol. The highest organ dose for
daily imaging was achieved on the femoral heads (1.6 Gy).
In comparison, with the same total mAs, anterior 190° scans delivered
doses 24% higher in average, while the posterior 190° scans showed a 37%
decrease. This could be due, as a first rough explanation, to the locations of
the organs evaluated, most of them sitting on the anterior side of the body
(eyes, thyroid, breasts, heart). For more centrally located organs (brain,
lungs, prostate) the difference was negligible. The trend was even inverted
for posterior organs (rectum).
This study would then suggest the use of posterior 190° scans for
clinical routine if, and only if, image quality can be preserved. The impact of
those scans on proton grid plans will be discussed in the following section.
6.3. Discussion
As it was shown in chapter 4, interlaced proton grid therapy is potentially
already applicable using conventional beam sizes. Nonetheless, one has to be
careful when using protons and spatially fractionated beams. The two studies
summarized in this chapter do not aim to blindly support an implementation
of the interlaced proton grid technique, but represent more of an attempt to
anticipate any issue that would come with its clinical application, if/when
this point is reached in the future.
In that regard, assessing the impact of RBE on the quality of the grid
plans, as compared to IMPT plans, was an important step. As it was
observed, considering variable RBE in proton grid plans did not seem to
introduce additional difficulties in comparison with the reference IMPT
plans, despite very different LET distributions. However, one should be
aware of several limitations of such studies.
First of all, results presented here and in Paper V are based on a couple
variable RBE models. As the name suggests, models use observations to
develop a relation between input parameters and observed effects. In the
case of interest for us here, the RBE models are based on in vitro data, as
they attempt to establish a connection between quantities such as LET, the
sensitivity of the tissue to fractionation expressed as the ratio of the
parameters of the LQ model for cell survival - the α/β ratio, dose and more,
Chapter 6. Clinical challenges: RBE and CBCT imaging
51
and the observed enhanced biological effect of charged particles. Can it be
assumed that these in vitro data-based models are a perfect representation of
in vivo effects? Probably not, but they nonetheless certainly provide an
interesting first guess, and should be dealt with as such: an approximation.
In that regard, some results should be handled carefully. For example, a
result in Paper V states that for the liver case, only a grid plan passed all the
clinical goals for the OARs when considering both variable RBE models,
while the IMPT and other grid plans failed. However, a closer look at the
numbers reveals that the IMPT plan was rejected due to the failure of
DRBE,0.1cc ≤ 24 Gy for the duodenum with a value of 24.5 Gy (RBE), while
the passing grid plan was accepted with a value of 23.6 Gy (RBE), both with
the McNamara model. Considering the model-based approach, is such a
minor difference really significant and enough to draw a pass/fail
conclusion?
Another question also remains: what could be done? Taking into
account variable RBE seems to lead to the same observations, independently
of whether grid or conventional plans are considered. However, it does not
mean that this impact is inexistent or negligible. If the variable RBE issue
proves to be as problematic as it seems according to the models used, it has
to be addressed. And that is where grid and conventional proton modalities
could be set apart. For IMPT plans, one solution already explored (Ödén et
al., 2017a) could be to re-optimize plans based on the LET distribution, and
aim for homogeneous RBE in the PTV instead of homogeneous physical
dose. But for grid it might be different. If radiobiological data support the
claim that using spatially fractionated beams allows for a better tolerance of
the normal tissue to radiation, one might seriously consider to take
advantage of this enhanced protection of healthy tissues to increase the target
dose. This would in turn lead to increased doses per fraction, or even very
high doses in a single fraction. Yet, some variable RBE models predict a
decreased RBE with increasing dose (McNamara et al., 2015; Wedenberg et
al., 2013). Would the variable RBE issue still be as significant then? Or
would the observed trend be inversed? Optimizing grid plans to better fit the
RBE variations could prove to be quite different from IMPT plans. Needless
to say, additional radiobiological data for grid and the dose-volume effect
are needed to better understand all the implications of using spatially
fractionated beams.
Regarding the CBCT-related dose considerations, the application will
most probably be more straightforward, although it will also require
additional data.
6.3. Discussion
52
Results presented in Paper VI showed that the use of CBCT imaging
could result in significant doses delivered to large volumes, especially in the
case of a daily use. For interlaced proton grid therapy, this would then result
in a slight increase of the peak and valley doses. Will it have any impact on
the overall protection of normal tissue? Since in a given volume/organ, the
irradiation from such imaging modality is relatively homogeneous, the
valley-to-peak dose ratio should theoretically change when including CBCT
imaging. Additionally, in the attempt to understand the origin of the dose-
volume effect, it has been hypothesized that the valley dose could have a
large impact on the observed effect, larger than the influence of the actual
ratio between valley and peak doses (see 2.2). In that case, increasing the
valley dose through CBCT imaging might reduce the benefits obtained from
the dose-volume effect.
Looking at an example from Paper VI, with the prostate case and the 2
opposing 1-D grid geometry, the valley dose in the femoral heads is around
10 Gy, for a 39 fractions/78 Gy treatment. However, the study in Paper VI
showed that the average dose to these organs after a single CBCT irradiation
could be above 53 mGy. For a 39 fractions treatment, that would result in a
total average dose to the femoral heads of above 2 Gy. For the valley dose,
this would then correspond to a 20% increase, potentially worsening the
outcome of said grid treatment for this organ. Unfortunately, the full extent
of such outcome cannot be quantified with our current knowledge of the
dose-volume effect. The lack of radiobiological data is, again, preventing the
proposed interlaced proton grid therapy to advance a step further and at this
point, one can only guess the consequences that a higher valley dose could
have.
In conclusion, using CBCT imaging for interlaced proton grid therapy
might prove to be complex in certain situations. Of course one could debate
if a treatment course spanning over 30-40 days is really realistic for this type
of treatment, but only further studies will be able to answer these questions.
In the meantime, one should be aware of the potential consequences of such
imaging modality and its use on a daily basis, and be prepared to adjust the
way interlaced proton grid plans are delivered to reach an optimal treatment
solution.
Chapter 7. General discussion and concluding remarks
53
7. General discussion and concluding
remarks
Despite the fact that grid therapy has been proposed in the last century and
used for decades, it still remains unknown to the vast majority of
physicians/physicists working in cancer-related facilities. Important
differences with conventional treatment modalities in terms of dose
distributions (dose coverage of the PTV) or technical applicability might be
reasons why it still appears as peculiar. While modern radiotherapy usually
dictates homogeneous irradiation of the targeted volume to achieve the
highest tumor control probability (TCP) while keeping the normal tissue
complication probability (NTCP) as low as possible, the lack of
experimental data does not allow a clear understanding of what would be the
TCP of a grid treatment delivering very heterogeneous dose in a PTV for
example.
Yet, the grid technique presents numerous potential advantages that
cannot be overlooked, especially in terms of normal tissue sparing.
Consequently, the interest in grid therapy has tremendously grown in the
past few years. However, most research in the field still focus on delivering
very heterogeneous doses to the targeted volume, sometimes with setups that
would require important additional efforts to be clinically achievable.
In this work a different approach to grid therapy was therefore
proposed. Delivering doses to the PTV that are similar to conventional
treatments in terms of coverage to achieve similar TCP is a key point to help
bringing grid therapy closer to the clinic and change the way it is regarded
by clinicians. To have a chance of application, grid therapy needs to be
developed to the point where it would be seen as a solid and safe alternative
to conventional modalities, with undeniable advantages.
This thesis aimed to do just that: develop another form of grid therapy
to get closer to a realistic approach that could be accepted in the clinic. This
was achieved by exploring the use of interlaced proton grids. The interlacing
permits homogeneous irradiation of a specific volume, in the case of an
ideal, or close to ideal, interlacing. Also, while it would have been attractive
to use micrometer beams, it was shown that very interesting results could be
achieved using usual beam sizes, without unsurmountable technical
difficulties. Smaller beam sizes, and how to produce them, were also studied,
to take advantage of the discussed dose-volume effect.
54
But, this thesis should also be taken as it really is: the first steps of an
unconventional modality’s development, almost from square one. In that
sense, while some aspects like physics and dosimetry have been partially
covered or discussed, the amount of remaining unknown variables is large.
Radiobiological data for different beam sizes, different c-t-c distances, with
different valley doses, different peak doses, different tissue types and more
are still very much needed to understand the limits of such technique, and
what would be a safe but efficient application. Some technical difficulties
also need to be addressed and, as it was seen with the RBE considerations,
going further into the development of this interlaced proton grid therapy
usually brings additional issues and questions to be answered.
In addition, it should not be forgotten that the majority of the results
presented in this work were produced using tools such as Monte Carlo codes
and treatment planning systems. These tools are based on models developed
to quickly mimic and approximate realistic interactions/observations. While
they provide valuable results in first-approach studies as it was conducted
here, one could argue about their validity for more sensitive applications.
One evident example would be the production of interlaced proton grid plans
intended for actual treatments. To provide the best grid plans possible extra
optimization objectives might be needed on top of regular PTV dose
coverage and OARs dose constraints: the minimization of the valley dose
and of the VPDR in healthy tissues. However, they directly rely on the
correct modeling of the beam’s lateral scattering in a patient volume, and are
therefore dependent on the model used in the TPS. In that case, are the
current models sufficient for this application or does interlaced proton grid
therapy require additional models? This will have to be evaluated as well.
But, one should not be afraid of the difficulties to come, as this
innovative modality has the potential, on paper, to improve the quality of
certain treatments compared to what can be done currently. Its concept was
proven, and now needs to be further developed. This has to be done on a
scientific level of course, but spreading the word on this research area and
making it widely available is just as important to insure a growing interest
and a potential increased brain-power dedicated to this topic.
Chapter 8. Summary of papers
55
8. Summary of papers
In Paper I, a study of what could be currently done with available beam sizes
at a modern proton center facility was conducted. Two patients previously
treated with photon therapy at Karolinska University Hospital for a liver and
a rectum irradiation were replanned using a commercial proton treatment
planning system with the suggested grid therapy method. Doses inside and
outside the target were studied as a proof-of-concept study, to evaluate if
grid therapy could be technically feasible today, using beams in the
centimeter range currently employed at The Skandion Clinic for example.
Data for one of the two patients, using more conventional radiation therapy
techniques, can be found in Paper II for comparison. In this paper, 10
patients with liver metastasis treated with conventional photon therapy were
replanned using broad-beam proton therapy with the same dose objectives.
In Paper III, the impact of spot position uncertainty on the quality of the
interlaced proton grid plans was assessed. A robustness analysis was
performed in a treatment planning system where numerous proton grid plans
were produced assuming an imperfect spot positioning, with realistic
variations. The effect on target dose coverage and organs at risk constraints
fulfilments were then assessed.
In Paper IV, a Monte Carlo study was performed to obtain dosimetric
characteristics of small proton beamlets in the 0.5-3 millimeters (FWHM)
range and determine which beam width could potentially be the most
advantageous for grid therapy. The doses produced by such beamlets were
then used to produce a virtual grid irradiation were a cubic target at the
center of a water tank was irradiated with interlaced proton grids, using
different grid parameters.
In Paper V, a comparison between interlaced proton grid and IMPT plans
was performed, taking into account a fixed RBE of 1.1 and two variable
RBE models. Dose, LET and RBE-weighted dose distributions were
evaluated, as well as dose-volume histograms.
In Paper VI, a study of the organ doses induced by a proton-gantry based
CBCT system was achieved. The CBCT system was modelled using two
56
Monte Carlo codes. Those two models were then used to evaluate doses
delivered to an anthropomorphic phantom using different scanning protocols
(Head/Thorax/Pelvis, Full/Short scan). Doses delivered in case of
single/weekly or daily imaging were also calculated.
Acknowledgments
57
Acknowledgments
First and foremost, I would like to thank my supervisors, Irena Gudowska
and Iuliana Toma-Dasu for all their help, scientific input, guidance and
support over the years. Your words and advices have really helped me to
always look forward in my projects and become a better scientist. Thank you
also for giving me the opportunity to teach and supervise research projects.
These experiences made me realize that my will to teach and help others was
stronger than I first imagined.
To all my co-authors: thank you for your help, feedback and all the
interesting discussions. Albert Siegbahn is acknowledged for initiating this
project. I would like to extend special thanks to Ana Ureba, Jakob Öden,
Oscar Ardenfors and Niels Bassler. To Ana, thanks for all your very
valuable help and all the discussions that we have had. You made this
project grow with your advices and your never-ending joy and motivation. It
was always a pleasure to have a talk with you, be it scientific or not. To
Jakob, thanks for accepting to get on board of the grid train with me. I am
really proud of the two papers we have achieved together and I would not
have been able to do it without you. I hope there will be me more. Thanks
for being a great office mate and the best “Vindicated” singer in the world.
You are always welcome for an apéro in France with Oscar. To Oscar,
world record holder for fastest accepted publication, thanks for your help
and the discussions from the very beginning. I am proud of what we have
accomplished with our paper, and hopefully there will be more to come.
With all the problems that we encountered, all the sweat, I learned a lot.
Finally playing “Simply the best” was definitely rewarding. Thank you also
to you and Jakob for the help and support you gave me during the less
enjoyable moments of these four years. To Niels, here’s to all the small
discussions that we have had and that taught me a lot. You definitely made
me a better researcher, and I hope that we will be able to continue working
together in the future.
To my mentor Bo Nilsson: thank you for your help and guidance. Our
discussions always helped me go forward.
To Emely “Mormor” Kjellsson Lindblom: thank you for everything, the
laughter therapy, all the help, support, advices and all the things that you did
58
for me and more. I do not know what the outcome of all this would have
been if you had not been there for me. It was always reassuring to know I
had someone I could rely on, no matter the problem or the time. Thanks
again for everything, and I hope you will make good use of all the extra
years of lifetime you deservedly earned!
To all my friends at MSF: Ana, Emely, Gracinda, Hamza, Helena, Jakob,
Marta, Oscar & Toshiro - thanks for all the discussions, laughs, help, good
vibes, dinners, nights outs and all the traveling around the world, karaokes
and more. These four years as a PhD student have been amazing thanks to all
of you.
To Mona and Mariann: thanks for all the administrative and overall help
for a lot of things!
To all my friends in Sweden, France, all over Europe, Canada, USA, Japan
and everybody I had the chance to meet through conferences, workshops,
projects, seminars, study visits and more: thanks for all the good memories.
All of you have become very dear friends. We met through science all over
the world but you have become a lot more than coworkers or colleagues to
me.
Finally, to my family: thank you for the unconditional support you have
given me throughout the years, no matter where my studies took me –
another city, the USA or Sweden. Although I would not have expected 10
years ago to achieve a PhD, you have made it possible.
References
59
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