2023 Stereotactic Body Radiation Therapy

Stereotactic
Body Radiation
Therapy
Principles and Practices
Yasushi Nagata
Editor
Second Edition
123
Stereotactic Body Radiation Therapy
Yasushi Nagata
Editor
Stereotactic Body Radiation

Therapy
Principles and Practices
Second Edition
Editor
Yasushi Nagata
Department of Radiation Oncology
Hiroshima University
Hiroshima, Japan
ISBN 978-981-99-3977-0 ISBN 978-981-99-3978-7 (eBook)

https://doi.org/10.1007/978-981-99-3978-7
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Preface
The first edition of this book was published in 2015. At that time, stereotactic body
radiation therapy (SBRT) for lung cancer was just going to expand in the world.
New technologies and new indications were on the verge of development. This book
covered basic and clinical information of SBRT.
Eight years after that, various new techniques and new indications were devel-
oped. Intensity-modulated radiotherapy (IMRT) technique became more widely
available for SBRT. Various clinical trials were reported and are now ongoing. The
indications of various organs and oligo-metastases have become more popular
than before.
I am very happy that we can publish the second edition of this book today. This
article represents the most updated basic and clinical information of SBRT. I hope
that this book will be helpful in facilitating clinical and research activities on
SBRT. Finally, I would like to thank all of the authors for their contributions as well
as Springer Japan for their efforts in publishing this book.
Hiroshima, Japan Yasushi Nagata

May 2023
v
Contents
Part I Introduction
1 I ntroduction and History of Stereotactic Body Radiation
Therapy (SBRT)�� 3
Yasushi Nagata
Part II Basic Principles

2 adiobiology of Stereotactic Ablative Radiation Therapy�� 13
R
Chang W. Song, Sun Ha Paek, Mi-Sook Kim, Stephanie Terezakis,
Yoichi Watanabe, and L. Chinsoo Cho
3 hysics of SBRT �� 35
P
Teiji Nishio
4 uality Assurance in SBRT�� 55
Q
Shuichi Ozawa
5 atient Immobilization, IGRT, Respiratory Motion Management �� 69
P
Yu Kumazaki and Igari Mitsunobu
6 Dose Calculation Algorithm�� 83
Satoru Sugimoto, Tatsuya Inoue, and Jun Takatsu
7 Treatment Planning �� 97
Mitsuhiro Nakamura
Part III Clinical Applications

8 Lung: Peripheral�� 113
Masaki Kokubo
9 Lung: Central �� 125
Takafumi Komiyama
vii
viii Contents
10 Lung: Toxicities�� 137

Yukinori Matsuo, Noriko Kishi, Kazuhito Ueki, and Masahiro
Yoneyama
11 iver�� 153
L
Yoshiko Doi
12 Kidney �� 171
Hiroshi Onishi
13 Spine�� 183
Kei Ito and Yujiro Nakajima
14 Oligomets�� 199
Nobuki Imano
15 Other Indications �� 215
Tomoki Kimura
Part IV Development of Machines

16 ero4DRT System and Dynamic Tumor Tracking SBRT�� 233
V
Takashi Mizowaki, Yukinori Matsuo, and Masahiro Hiraoka
17 eal-Time Tumor-Tracking Radiotherapy (RTRT), SyncTraX�� 243
R
Naoki Miyamoto, Norio Katoh, Hiroshi Taguchi, Kentaro Nishioka,
and Hidefumi Aoyama
18 CyberKnife®�� 255
Satoshi Kito
19 Tomotherapy�� 263
Hidetoshi Shimizu
20 R-LINAC: Elekta Unity �� 277
M
Noriyuki Kadoya, Shohei Tanaka, Yoshiyuki Katsuta, Kiyokazu
Sato, Noriyoshi Takahashi, and Keiichi Jingu
21 ViewRay MR-Linac �� 285
Hiroyuki Okamoto, Takahito Chiba, Junichi Kuwahara,
and Hiroshi Igaki
Part V Future Perspectives

22 uture of SBRT with AI (Artificial Intelligence)�� 299
F
Daisuke Kawahara
23 uture of SBRT with Photon and Charged Particles �� 311
F
Tadamasa Yoshitake, Akira Matsunobu, and Yoshiyuki Shioyama
Index�� 323
Part I
Introduction
Chapter 1
Introduction and History of Stereotactic
Body Radiation Therapy (SBRT)
Yasushi Nagata
1.1 Introduction
Intracranial Stereotactic Radiosurgery (SRS) was a new treatment method for brain
tumor introduced in the twentieth century to deliver tight spatial/temporal distribu-
tion using a high precision technique. The clinical experience from intracranial
SRS, together with the technical developments in conventional RT, initiated the
development of Stereotactic Body Radiation Therapy (SBRT) for extracranial
tumors characterized by a very high dose per fraction, delivered in a short time. This
was started at the Swedish Karolinska University hospital in 1991 with tumors in
the liver and lungs by Bromgren and Lax [1–3]. In parallel, this method was devel-
oped in Japan and clinically introduced in 1994 for lung tumors [4–6]. During the
last 5 years of the 1990s, SBRT was introduced in several centers in Europe, Japan,
and the USA. Wulf and Herfarth in Germany reported their clinical results on lung
cancer in 2001, followed by Timmerman in the USA in 2003. In Japan, Japanese
study group of stereotactic body radiation therapy was formed in 1999, and it
expands annually. It then transformed into the Japan 3-D Conformal External Beam
Radiotherapy Group (J-CERG) in 2002 and the Japan High-Precision External-
beam Radiotherapy Group in 2016. The SBRT procedure was approved by the
Japanese government to be covered by the health insurance in 2004. The early
reports had already shown very promising results with regard to local control and
toxicity for the hypofractionation schedules which were adopted with 10–15 Gy/
fraction given in 3–5 fractions during a short time . However, due to the new aspects
introduced in SBRT, clinical experience was initially accumulated at a very slow
rate, and it was only during the last decade that outcome data from several centers
Y. Nagata (*)
Department of Radiation Oncology, Graduate School of Biomedical & Health Sciences,
Hiroshima University, Hiroshima, Japan
e-mail: nagat@hiroshima-u.ac.jp
© The Author(s), under exclusive license to Springer Nature Singapore Pte 3

Ltd. 2023
Y. Nagata (ed.), Stereotactic Body Radiation Therapy,
https://doi.org/10.1007/978-981-99-3978-7_1
4 Y. Nagata
was available to confirm the initial promising results. In this session, the historical
development of SBRT was reviewed.
1.2 Intracranial Radiosurgery
The field of intracranial radiosurgery was mainly developed between 1950 and 1970.
The treatment was named as radiosurgery by Leksell as an alternative to neurosur-
gery [7, 8]. Thereafter, the terminology of stereotactic radiosurgery meant single
high dose with accurate spatial precision. The system named the Gamma Knife is a
system with a metal helmet and multiple holes attached to a capsule of 201 multiple
gamma sources. The Gamma Knife system developed from the original system up to
a modern new system. The new system has an automatic beam shaped modification
with multi-leaf collimators. Metallic ring attached to a patient is currently replaced
with noninvasive plastic mask with the development of cone-beam CT. The radiosur-
gery technique was also possible using a conventional linear accelerator with a three-
dimensional radiosurgery systems. This system included metallic ring to be attached
to a patient and fixation system attached to a couch. The three-dimensional coordi-
nates were essential for SRS. The accuracy of linear accelerator was essential.
1.3 Principles and Methods
To extend the intracranial radiosurgery technology to extracranial tumors, two prob-

lems should be solved. First, most extracranial tumors move with or without respira-
tory motion. With tumor motions, wide ITV margins prevent delivering high dose to
the tumor. The other difficulty is the unknown normal tissue toxicity using single high
dose. Previous experiences with clinical radiotherapy are based on daily 2 Gy radio-
therapy up to 60 or 70 Gy. Therefore, 48–60 Gy in 3–5 fractions are unknown areas.
Therefore, initial SBRT was based on stereotactic coordinates using the
Stereotactic Body Frame. Patients were stored within a plastic frame with three-
dimensional coordinates. After the setup with these coordinates, single high dose
was irradiated with non-coplanar beams.
The other concern is the respiratory tumor movement. To regulate respiratory
movement, various methods were used. Initially, abdominal press techniques or
breath-hold techniques were most popular methods, thereafter, developed into
respiratory gating and chasing methods.
Geometric verification at each treatment is essential for SBRT, it is because sin-
gle dose setup error will consequently make local tumor recurrence. Therefore, AP
and lateral portal verifications using films were essential before each treatment,
which now developed into EPID technology and cone-beam CT technology.
The indications of SBRT expanded from lung cancer, liver cancer, renal cancer,
prostate cancer, adrenal cancer, pancreatic cancer, vertebral bone tumor, lymph
nodal tumors and other indications. The details of clinical application will be pre-
sented in this book [9–68].
1 Introduction and History of Stereotactic Body Radiation Therapy (SBRT) 5
1.4 Dose Fractionation and Normal Tissue Dose Constraints
Even now, the best dose fractionation schedule for lung and liver tumors could not be
determined. Various dose fractionation schedules are used at different countries and at
different institutions by now. The dose constraints for normal tissue are still finalized,
and different dose constraints are used in different clinical trials. Previously in Japan,
50 Gy in 10 fractions, 60 Gy in 8 fractions, 48Gy in 4 fractions were prescribed at the
isocenter. In the USA and Europe, 60 Gy in 3 fractions, 54 Gy in 3, and 48–50 Gy in
4 were prescribed at D95. We must be careful that these doses were prescribed at dif-
ferent points. The normal tissue dose constraints were set by JCOG (Japan Clinical
Oncology Group) first proposed by Dr. Shirato and modified by JCOG1408.
1.5 Terminology
The name of SBRT was introduced by Timmerman in 2002. He originally used

Stereotactic Ablative Radiosurgery for this treatment. However, there were several
oppositions from radiation oncologists because this treatment is completely differ-
ent from radiofrequency ablation (RFA). In 2005, SBRT was used as a code of
radiation therapy in the USA. Extracranial stereotactic radiation therapy (ESRT)
was used in Europe in the late 1990s and pin-pointed radiation therapy was used in
Japan in the late 1990s. In 2010, stereotactic ablative radiotherapy (SABR) was
introduced by Loo et al. It was because the pronunciation of SBRT was difficult.
Currently, the terminology of SBRT and SABR are both used and are confusing.
1.6 Survey of SBRT in Japan and Its Current Status
The Japan 3-D conformal external beam radiotherapy group (J-CERG) developed
into the Japan High-Precision External Beam Radiotherapy Group of the JASTRO
in 2016. J-CERG and the JASTRO group continuously conducted a survey of the
SBRT in Japan since 2006.
Figure 1.1 is the accumulated number of cases for SBRT in Japan. The number
of institutions where SBRT is performed increased from 58 in 2006 to 310 in 2020.
The indications of SBRT were lung cancer (70%), followed by liver cancer (13%),
prostate cancer (6%), head and neck cancer, vertebral bone tumor, oligo-mets, adre-
nal tumor, renal cancer, and others as shown in Fig. 1.2. Grade 5 sequela are listed
in Table 1.1 by the same survey. Radiation pneumonitis was the most common
Grade 5 toxicity followed by pulmonary bleeding, liver damage, radiation esopha-
gitis, and GI bleeding. The frequency of Grade 5 toxicity is 0.2 % on average.
6 Y. Nagata
NSCLC:T1N0M0
Fig. 1.1 Accumulated number of SBRT cases in Japan
Fig. 1.2 Accumulated ɼ

number of major cases for
SBRT as in 2021
Table 1.1 Accumulated Grade 5 sequela of SBRT by 2020 (by 2018, 2016, 2014, 2010, 2008)
1. Radiation pneumonitis 55 (43, 40, 41, 42, 28)
2. Pulmonary bleeding 6 (5, 4, 3, 3, 3)
3. Liver damage 4 (7, 0, 2, 0, 0)
4. Radiation esophagitis 4 (1, 2, 1, 1, 1)
5. GI bleeding 4 (3, 3, 0, 0, 0)
6. Others 3 (4, 3, 6, 5, 4)
76 cases/36,557 total cases = 0.2%
0.2% (0.2%, 0.2%, 0.5%, 0.5%, 0.6%)
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Part II
Basic Principles
Chapter 2
Radiobiology of Stereotactic Ablative
Radiation Therapy
Chang W. Song, Sun Ha Paek, Mi-Sook Kim, Stephanie Terezakis,

Yoichi Watanabe, and L. Chinsoo Cho
2.1 Introduction
High-dose hypofractionated stereotactic body radiotherapy (SBRT) and stereotactic

radiosurgery (SRS) are ablative radiotherapies; they are also referred to collectively
as stereotactic ablative radiotherapy (SABR). The SRS usually refers to a single
treatment of SBRT or SABR. The SABR is a precise and conformal approach that
delivers 15–60 Gy in 1–5 fractions to target tumor volume with a steep dose gradi-
ent and sharp dose falloff to all directions, thereby minimizing damage to the sur-
rounding normal tissues [1]. Whereas conventional multifractionated radiotherapy
with 1.5–2.0 Gy per fraction takes advantage of greater radiosensitivity of actively
dividing cancer cells relative to normal tissues, the conformal SABR dosimetrically
spares the adjacent normal tissues [2]. The biological mechanisms that account for
the high efficacy of SABR, however, have not been firmly established.
It is well known that DNA double-strand breaks followed by chromosome breaks
is the major mechanism by which conventional multifractionated radiotherapy kills
cancer cells. Some investigators have asserted that DNA double-strand breaks is
also the major cell death mechanism in SABR, and that no new radiobiological
C. W. Song (*) · S. Terezakis · Y. Watanabe · L. C. Cho

Department of Radiation Oncology, University of Minnesota Medical School,
Minneapolis, MN, USA
e-mail: songx001@umn.edu; sterezak@umn.edu; watan016@umn.edu; choxx106@umn.edu
S. H. Paek
Department of Neurosurgery, Cancer Research Institute, Hypoxia/Ischemia Disease Institute,
Seoul National University College of Medicine, Seoul, South Korea
e-mail: paeksh@snu.ac.kr
M.-S. Kim
Korean Institute of Radiological & Medical Sciences, Seoul, South Korea
e-mail: mskim@kirams.re.kr

Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_2
14 C. W. Song et al.
mechanism is needed to account for the high efficacy of SABR [3–5]. This view,
however, has been disputed, with a growing body of preclinical and clinical evi-
dence against it [6–18]. The clonogenic cancer cells in tumors are surrounded by the
complex tumor microenvironment (TME), which is composed of a variety of cell
types such as vascular endothelial cells, pericytes, fibroblasts, lymphocytes, and the
extracellular matrix. As cancer cells are in close contact with components of the
TME and, thus, the survival and proliferation of cancer cells are intimately influ-
enced by the TME, it is highly likely that destruction of the TME by high-dose
hypofractionated irradiation such as SABR would significantly affect the fate of the
irradiated cancer cells. It has been unequivocally demonstrated that high-dose radia-
tion per fraction causes severe damage in tumor blood vessels [8, 19–29], thereby
depriving tumor cells of nutrients, including oxygen. Such deteriorations of the
TME are detrimental for the survival of cancer cells and lead to secondary and indi-
rect tumor cell death [11, 13–16, 20, 29]. Furthermore, the vascular destructions and
consequent changes in the TEM caused by SABR have been shown to either improve
or suppress the antitumor immunologic profile [9, 16, 30]. In this chapter, various
radiobiological aspects underlying the high efficacy of SABR are discussed.
2.2 More Than DNA Damage Is Involved in The Cell Death

by High-Dose Hypofractionated Radiotherapy
The number of clonogenic cancer cells in 1–10 g of malignant tumors is as many as

108–1010, which implies that 8–10 logs of cancer cells should be sterilized to control
1–10 g tumors [31]. Figure 2.1 shows the radiation cell survival curve of Walker 256
Fig. 2.1 Radiation

survival curve of 100
clonogenic cells in Walker
256 carcinoma grown 10-1 Walker tumors
subcutaneously in the thigh
of rats. Open circles are the 10-2
Surviving Cell Fraction
mean surviving cell

fractions of 9–12 tumors In vivo tumor
determined immediately 10-3
after irradiation,
representing the cell death 10-4
due to DNA double-strand
breaks [16] 10-5
10-6 In vitro
Oxic cells
10-7
10-8
10 20 30 40 50 60 70
Radiation Dose(Gy)
2 Radiobiology of Stereotactic Ablative Radiation Therapy 15
carcinoma cells grown subcutaneously in the hind legs of rats [16, 19]. Each open
circle is the average of surviving cell fractions in 9–12 tumors determined immedi-
ately after exposure to a single fraction of 2.5–30.0 Gy; cell death determined
immediately after irradiation was assumed to be the cell death via radiation-induced
DNA double-strand breaks. The solid curve, which represents the experimentally
determined cell death, is extended with a dotted line to the 10−8 surviving fraction.
It shows that as much as 70 Gy in a single fraction is needed to reduce the surviving
cell fraction to 10−8, implying that a dose as large as 70 Gy is needed to control 1 g
small tumors if DNA double-strand breaks is only the cause of cell death. It also
indicates that irradiation with 20 Gy or 30 Gy can reduce the cell survival by only
approximately 2.5 logs and 4 logs, respectively, if cells are killed only via DNA
double-strand breaks. Similar results were obtained with other experimental
tumors [16].
These results strongly indicate that if SABR is assumed to kill tumor cells via
DNA double-strand breaks only, SABR with currently used doses (e.g., 15–60 Gy
in a single or a few large dose fractions) would not be able to control human tumors
as small as 1 g. Leith et al. [32] reported that 90 Gy in a single exposure is needed
to control 3 cm diameter brain tumors if the cell death is due to DNA double-strand
breaks only. Fowler et al. [33] also concluded that the radiation doses used in clini-
cal SABR are insufficient to account for the effective tumor control by SABR if
SABR is assumed to kill tumor cells solely via DNA damage. Taken together, one
can conclude that mechanisms other than DNA double-strand breaks are involved in
efficient tumor control by SABR. In this respect, growing evidence strongly sug-
gests that additional cell death secondary to radiation-induced vascular damage sig-
nificantly contributes to the remarkably high efficacy of SABR.
2.3 Effect of High-Dose Hypofractionated Irradiation

on Tumor Vasculatures and TME
Tumor vasculatures are formed initially by angiogenesis, which involves sprouting

microvascular growth from existing arteries or veins induced by vascular endothe-
lial growth factor (VEGF) secreted from the tumor cells and stroma cells [34, 35].
The inner walls of the hastily formed capillary-like tumor blood vessels are com-
posed of a layer of endothelial cells with many gaps between the endothelial cells.
Frequently, the gaps are filled by tumor cells and even pericytes (muscle cells),
forming “mosaic vessels” [8, 16, 36, 37]. Tumor vasculatures also are formed by
vasculogenesis, which involves assembling blood vessels from circulating cells
such as endothelial progenitor cells and from bone marrow-delivered stem-like cells
[37, 38].
The poorly organized endothelial layers of tumor blood vessels are supported by
an incomplete thin layer of basement membranes and loosely bound pericytes.
Architecturally, these tumor blood vessels are irregular in diameter, sharply bent,
tortuous and branched with multiple dead ends. Furthermore, tumor cells often
organize themselves into vascular-like tubes, which are referred to as “vasculogenic
mimicry” and function as canals between blood vessels [39]. Blood flow through
such disorganized vascular networks usually is sluggish and often intermittent, with
varying interval times leading to the development of microscopic and macroscopic
hypoxic regions throughout the tumors.
2.4 Vascular Damages by High-Dose

Hyperfractionated Irradiation
The hastily formed and morphologically immature tumor blood vessels are
extremely vulnerable to ionizing radiation [8, 19–29]. Irradiation of tumors with
5–10 Gy in a single dose causes relatively mild vascular damages, whereas increas-
ing the radiation dose to higher than 10 Gy/fraction induces severe vascular dam-
ages [8]. Figure 2.2a shows the effects of radiation on the functional vascular
volume in Walker tumors in rats [28]. The functional vascular volume began to
decrease immediately after irradiation with 2.5 Gy or 5.0. Gy, reached a nadir in
6–12 h and then recovered to the pre-irradiation level in 24–36 h. The functional
vascular volume after irradiation with 10 Gy also immediately decreased but failed
to recover as was seen with the 2.5–5.0 Gy irradiation. When Walker tumors were
irradiated with 30 Gy in a single dose, the vascular volume decreased to approxi-
mately 20% of the original value in 12 days and then gradually recovered as the
tumors started to regrow (Fig. 2.2b) [27].
In a study with FSaII tumors of C3H mice, blood perfusion (as measure with
Hoechst 33342 staining) decreased to <30% of control 1 day after irradiation with
20 Gy in a single dose (Fig. 2.3a) [15, 16]. The blood perfusion then gradually
recovered although the blood perfusion on day 10 after the irradiation remained at
only approximately 50% of the pre-irradiation value. Importantly, the decrease in
blood flow after irradiation was associated with a marked increase in the expression
of hypoxia-inducible factor (HIF-1α) and its downstream target carbonic anhydrase
9 (CA9), demonstrating that a decline in blood perfusion increases tumor hypoxia
(Fig. 2.3b). Interestingly, pimonidazole staining, a hypoxic cell marker, markedly
decreased for 3 days after 20 Gy irradiation and then significantly increased on day
5 after irradiation. It appeared that the several vascular occlusions soon after irradia-
tion inhibited the delivery of the hypoxic cell markers to hypoxic areas for several
days after irradiation.
The mechanism underlying the decrease in tumor blood flow after high-dose
irradiation is not clear. It was reported that irradiation with doses higher than
8–10 Gy per fraction triggers massive ceramide-mediated apoptosis in endothelial
cells, leading to decrease in the tumor blood flow [24]. Of note, tumor blood flow
begins to decrease soon after high-dose irradiation, prior to significant apoptotic
deaths in the endothelial cells, indicating that the decline in tumor blood flow soon
b
A
Fig. 2.2 (a) Effects of X-irradiation in a single dose on the functional vascular volume in Walker
256 carcinoma cells grown subcutaneously in the thigh of rats. Each data point is the mean ±1 SE
of 14–30 tumors [28]. (b) Walker 256 carcinoma cells grown subcutaneously in the thigh of rats
were irradiation with 30 Gy in a single dose and the tumor volume (A), functional vascular volume
(B), and extravasation rate of plasma protein (vascular permeability) (C) were determined. The
dotted lines are the mean values of 15 control tumors [9]. (c) Effects of X-irradiation on the func-
tional vascular volume in the skin and muscle of Sprague-Dawley rats. The % of control was
obtained and each data point is the mean ± 1 SE of 8–10 rats [26]
Fig. 2.2 (continued)
after irradiation is not necessarily due to the death of endothelial cells. It has been
shown that the permeability of tumor blood vessels significantly increases soon
after irradiation (Fig. 2.2b) [27], which could increase the extravasation of various
circulating macromolecules including plasma proteins, thereby increasing the inter-
stitial fluid pressure in the tumors. Increased interstitial fluid pressure might
mechanically compress the fragile tumor blood vessels, leading to vascular col-
lapse. Brown et al. [40] made a similar conclusion to account for the rapid decrease
in blood flow soon after irradiation with 20 Gy in human brain tumor xenografts
grown in rat brains. When endothelial cells are injured by radiation, the expression
of adhesion molecules on the endothelial cells is elevated, which then increases the
adhesion of leukocytes on the vessel walls, leading to luminal closure. Furthermore,
endothelial damages elicit formation of fibrin and trigger adhesion of leukocytes
and platelets, leading to thrombosis and obliteration of blood perfusion [41]. Despite
the wealth of information on radiation-induced vascular damage in experimental
tumors, little is known about the response of human tumor vasculatures to high dose
per fraction irradiation. It would be reasonable to assume, however, that the vascular
changes that occur in human tumors by SABR would be similar to those in experi-
mental tumors.
The endothelial layers of normal tissue blood vessels are composed of mitoti-
cally inactive endothelial cells, which are well supported by solid basement mem-
branes and outer muscle layers. These well-organized and morphologically matured
blood vessels of normal tissues are far more radioresistant than the more fragile,
immature tumor blood vessels. As shown in Fig. 2.2c, the functional vascular vol-
ume in the skin and muscle of rats markedly increased soon after irradiation with
5–60 Gy and remained elevated up to 12 days postirradiation, which was the time
extent of the study [26]. In this regard, in vitro, the endothelial cells obtained from
normal tissues have been reported to be more radioresistant than the endothelial
cells obtained from tumor vessels [8]. Such differences in the radiosensitivity of
endothelial cells alone, however, may not account for the striking differences in the
response of blood vessels in tumors and normal tissues to high-dose irradiation. The
matured basement membrane, together with the protective and firm outer muscle
layer and secretion of various protective cytokines from the adjacent tissues, might
prevent collapse of the irradiated normal tissue in the blood vessels.
2.5 Indirect Cell Death Due to Vascular Damages
When tumor vasculatures are injured and blood flow is disrupted, the intrinsically
hypoxic TME becomes further hypoxic and nutritionally deprived, leading to deple-
tion of ATP and accumulation of tumor necrosis factor (TNF-α). Tumor cells, par-
ticularly irradiated tumor cells, will be unable to survive in this hypoxic and
nutritionally deprived TME and undergo apoptotic or necrotic death. In 1947,
Lasnitzki [42] reported that, in mouse adenocarcinoma irradiated with 2000–3000
rads (20–30 Gy) in a single exposure, cell death due to vascular damages accounted
for as much as two-thirds of the total cell death. Denekamp [43] reported that one
endothelial cell segment subtends as many as 2000 tumor cells. It should be empha-
sized that blood vessels are serial organs and thus damage in a small segment of
blood vessels will disrupt the blood perfusion through the vessels and affect the
tumor cells along the entire length of the vessels. Therefore, death of one endothe-
lial cell can conceivably affect much more than the 2000 tumor cells lying along the
affected blood vessels. In the 1970s, Clement et al. [19] observed that in Walker
tumors of rats, surviving cell numbers progressively decreased for 2–3 days when
tumors were left in situ after irradiation with 10–20 Gy. The investigators attributed
the additional cell death following the high-dose irradiation to radiation-induced
vascular damage. More recent investigations by Song et al. using FSaII mouse
tumors [14, 15] and human sarcoma HT-1080 xenograft [11] have provided more
detailed insights into the kinetics of indirect and secondary cell death after high-
dose irradiation. As shown in Fig. 2.3c [16], when FSaII tumors were irradiated
with 15 Gy, the cell survival decreased by approximately 1.5 logs when determined
soon after irradiation. The cell survival further decreased by approximately 1.5 log
during the 2 days after 15 Gy irradiation when the tumors were left in situ, which
indicates that the extent of secondary cell death that occurred during 2 days after
15 Gy irradiation was almost equal to the cell death caused by DNA damages.
Murata [44] observed that the clonogenic cell numbers per squamous cell carci-
noma VII (SCCVII) of mice progressively decreased for several days after 30 Gy.
Similar additional cell deaths after high-dose irradiation in various rodent tumors
have been reported by other investigators [45–47]. However, the importance of such
additional cell deaths occurring in several days after high-dose irradiation was
unrealized until SABR became an established modality for cancer treatment in

recent years. Additional cell deaths due to vascular damages have been reported to
play an important role in the response of human tumors to SABR [6, 7, 47]. More
specifically, Kocher [7] reported that 19–33% of cell death was due to necrosis as a
result of vascular damages in human cranial tumors treated with radiosurgery.
Kawahara et al. [48] recently applied the tumor control probability (TCP) model to
investigate the effects of indirect cell death due to low oxygen tension in tumors
caused by vascular damage after irradiation with 15–20 Gy in a single exposure.
Their calculation using an improved cellular automata model showed that the apop-
totic indirect tumor cell death due to depletion of oxygen supply ensuing from the
radiation-induced vascular damages led to a 4% increase in the TCP. Of note, vas-
cular dysfunction would lead to depletion of oxygen as well as nutrients, and that
hypoxia and low glucose supply synergistically kills tumor cells [49]. Palmiero
et al. [50] described the importance of indirect cell death in the response of brain
metastases to SABR. The authors concluded that the high local tumor control rate
following 15–20 Gy irradiation in a single dose was due to indirect cell death as a
result vascular damage although some contribution of antitumor immune response
could not be excluded. Kirkpatrick et al. [6] concluded that the linear quadratic
model is inappropriate to model the effect of high-dose per fraction for human brain
lesions because of the additional cell death via vascular damages after high-dose
irradiation.
Despite the overwhelming preclinical and clinical evidence that indirect cell
death occurs in tumors after high dose per fraction irradiation, some investigators
asserted that the indirect cell deaths due to vascular damage contribute little to the
control of tumors by SABR [51, 52]. For example, Moding et al. [52] reported that
increasing the radiosensitivity of endothelial cells by means of genetic manipulation
increased the tumor growth delay but not the local tumor control after exposure to
high-dose irradiation, while increasing the radiosensitivity of tumor cells increased
the local tumor control by high-dose irradiation. In this regard, it must be realized
that tumor cells are also components of “mosaic vessels” and “vasculogenic mim-
icry,” so that any radiosensitization of tumor cells can also lead to radiosensitization
of tumor vasculatures. It must be emphasized, also, that the structural and functional
Fig. 2.3 (a) (Upper panel). Fluorescent staining for hypoxia (pimonidazole, in green), blood per-
fusion (Hoechst, in blue) and blood vessels (CD31, in red) in FSaII tumors grown subcutaneously
in the thigh of C3H mice (Lower panel). % of positive area for Hoechst staining and pimonidazole
staining ± 1 SE are shown [15]. (b) (Upper panel). Immunohistochemical images of HIF-1α
(magenta), CA9 (white), CD31 (green), and DAPI (blue) in FSaII tumors grown subcutaneously in
the legs of C3H mice. (Lower panel). % of positive area for HIF-1α and CA9 ± 1 SE are shown
[15]. (c) Surviving cell fractions after a single dose of 10–30 Gy in FSaII tumors grown subcutane-
ously in the legs of C3H mice. Geometric means ± 1 SE of 8–12 tumors are shown. (d) Hypoxic
cell fraction (%) in FSaII tumors grown subcutaneously in the thighs of C3H mice after 10, 15, or
20 Gy irradiation. Each data point is the mean ± 1 SE of 7–10 tumors [15]
b
A
B
Fig. 2.3 (continued)

integrity of tumor blood vessels after high-dose irradiation depends not only on the
radiosensitivity of endothelial cells but also on the entire components of the TME,
including interstitial fluid pressure. Taking all these observations and arguments
together, it would be highly reasonable to conclude that additional tumor cell death
secondary to vascular damages plays an important role, perhaps a major role, in the
response of human tumors to high-dose hypofractionated SABR.
2.6 Immunologic Effects of SABR
SABR acts as a double-edge sword in antitumor immunity: it activates the antitu-

mor immune processes from immune recognition to execution of cell killing by
activated T cells, while at the same time it promotes the immune escape pathways
of tumor cells [30, 53, 54]. Irradiation of tumors not only damages and kills the
clonogenic cancer cells but also affects the components of the TME, including the
radiosensitive immune lymphocytes. When tumors are treated with conventional
multifractionated radiotherapy over prolonged periods, the immune cells that have
infiltrated the tumors are repeatedly assaulted and eliminated. On the other hand,
SABR which is administered only in 1–5 fractions over 1–2 weeks may be less
detrimental to antitumor immune lymphocytes.
The high dose per fraction irradiation used in SABR causes massive tumor cell
deaths, which may be considered to be endogenous tumor vaccination [49, 53, 54].
The tumor cells that are injured by radiation undergo immunogenic cell death (i.e.,
inflammatory necrotic death) characterized by cell surface expression of the protein
calreticulin and release of tumor-associated neoantigens and immune cytokines
such as ATP and HMGB1 (high morbidity group box 1) [49, 53, 54]. These “danger
signals” act on the antigen-presenting cells (APCs), including dendric cells, thereby
leading to maturation and activation of the APCs.
The activated APCs then phagocytize dying tumor cells, migrate to nearby drain-
ing lymph nodes and prime the antigen-specific CD8+ T cells by presenting tumor-
associated antigens (TAAs). The activated CD8+ T cells release IFN-γ, which in turn
promotes the trafficking of the activated CD8+ T cells to tumors. The high-dose
irradiation also increases the expression of class I major histocompatibility mole-
cules (MHC-1) on the tumor cells, which increases the immune recognition of
tumor cells by the cytotoxic CD8+ T cells [52–54]. Two major pathways are known
to play a part in killing the target tumor cells via CD8+ T cells: (1) release of perforin
and granzyme from the activated CD8+ T cells, which leads to tumor cell apoptosis
and (2) engagement of Fas ligand (FasL) on CD8+ T cells with Fas expressed on
tumor cells, thereby triggering apoptosis in the tumor cells [55]. Collectively, it can
be concluded that high-dose hypofractionated irradiation promotes all the antitumor
immune processes—from activation of APCs to the engagement of cytotoxic CD8+
T cells on target tumor cells and killing of the tumor cells.
Conversely, high-dose hypofractionated irradiation has been reported to suppress
antitumor immunity via a variety of immunosuppressive pathways [56–62].
Irradiation-induced vascular damage and the resultant increase in tumor hypoxia

upregulates HIF-α, which may be incriminated for the upregulation of immune sup-
pression after high-dose hypofractionated irradiation. For example, HIF-1α stimu-
lates cancer-associated fibroblasts (CAFs) to release stromal-derived factor-1
(SDF-1) [56–58]. SDF-1, then, promotes the recruitment of immature myeloid cells
into the TME. The recruited myeloid cells either develop into TAMs (tumor-
associated macrophages) or differentiate into myeloid-derived suppressor cells
(MDSCs), which produce transforming growth factor-β (TGF-β). TGF-β is also
produced by CAFs and regulatory T cells (Treg). TGF-β promotes the polarization
of TAMs into immunosuppressive M2 phenotype and also promotes the differentia-
tion of dendric cells into immunosuppressive Treg [58].
The activity of CD8+ T cells following high-dose hypofractionated irradiation is
maintained by interaction of CD28 (primary costimulatory receptor) on the T cells
with CD80/CD86 on the APCs [58–60]. High-dose irradiation has been shown to
upregulate immune checkpoint CTLA-4 (cytotoxic T lymphocytes antigen-4) on
the CD8+ T cells, most likely through upregulation of HIF-1α [53–55]. CTLA-4 on
the activated CD8+ T cells has a greater affinity than CD28 for CD80/CD86 on the
APCs, and the interaction of CTLA-4 with CD80/86 on the APCs disrupts the inter-
action between CD28 and CD80/CD86 leading to inactivation of CD8+ T cells [61–
63]. This finding implies that blocking the immune checkpoint receptor CTLA-4
will render CD8+ T cells to stay active. Indeed, in a number of recent preclinical and
clinical investigations, immunotherapy using anti-CTLA-4 antibodies increased the
CD8+ T cell activity and acted synergistically with SABR [61–63].
Another major immune checkpoint is the PD-1 (programmed cell death protein-
1) on activated CD8+ T cells. When the PD-1 on CD8+ T cells interacts with its ligand
PD-L1 (programmed death ligand-1) on the surface of tumor cells as well as on
other immune cells in the TEM such as MDSCs, macrophages, and dendric cells,
CD8+ T cells undergo functional exhaustion and apoptosis [58–60]. Importantly,
high-dose irradiation markedly upregulates PD-L1 expression on tumor cells and on
other cells in the TME, thereby leading to inactivation of CD8+ T cells [54–56].
Monoclonal antibodies against PD-1 or PD-L1 impede the PD-1/PD-L1 pathway,
thereby preventing the inactivation of CD8+ T cells. Immunotherapy using anti-PD-1
or anti-PD-LI monoclonal antibodies has been shown to be effective for specific
types of tumors and improves the response of these tumors to SABR [64, 65].
The PD-L1 expression on tumor cells has been shown to be mediated by HIF-1α
[66]. It follows, then, that inhibition of HIF-1α will suppress the expression of
PD-L1, and thus it will improve the antitumor immune profile in tumors exposed to
high-dose irradiation. Indeed, in preclinical studies with murine tumors, inhibition
of HIF-1α with small molecules such as metformin effectively suppressed PD-L1
expression in irradiated tumors and led to a greater delay in the growth of radiation-
induced tumors (our unpublished observation). It can be concluded, then, that the
antitumor immunity in heavily irradiated tumors can be elevated by pharmacologi-
cally suppressing the radiation-induced upregulation of HIF-1α.
In conclusion, high-dose irradiation of tumors increases antitumor immunity by
acting like an in situ vaccination. However, high-dose hypofractionated irradiation
can have the opposite effect: it has been shown to suppresses antitumor immunity,
mainly by upregulating HIF-1α. Therefore, at present, it is reasonable to conclude
that the contribution of antitumor immunity is unclear regarding human tumor
response to SABR. Nevertheless, inhibition of HIF-1α activity holds promise as a
potentially effective approach to promote the response of human tumors to
SABR. Furthermore, combinations of HIF-1α inhibition with the conventional
immunotherapy using antibodies against PD-1/PD-L1 pathway or CTLA-4 check-
point may synergistically increase the antitumor immune response after SABR
treatment.
2.7 The 5Rs and Fractionation in SABR
The role of the 5Rs (reoxygenation of hypoxic cells, repair of sublethal radiation
damage, redistribution of cells in cell cycle phases, repopulation of tumor cells,
radiosensitivity of tumor cells) in the response of tumors and normal tissues to con-
ventional multifractionated radiotherapy is well established. In contrast, the role of
the 5Rs in SABR is largely speculative. It is likely that whereas the 5Rs exert little
effect on the response of tumors to a single large dose of SABR, some of the 5Rs
might play a role in fractionated SABR. Due to normal tissue damage, the size of
tumors usually is limited to <3 cm in diameters when SABR is applied in 1 or 2
fractions. Paek et al. [67, 68] reported that 3–4 consecutive daily irradiations at
approximately 8 Gy/fraction could effectively control brain metastases with mean
gross volume of 18 cm3 with acceptable morbidity. It is conceivable that reoxygen-
ation of hypoxic cells and repair of normal tissue damage during the intervals of
fractionations were responsible for the favorable therapeutic ratio in treating the
large tumors.
2.7.1 Reoxygenation of Hypoxic Cells
Varying fractions of clonogenic cells in tumors are radiobiologically hypoxic. In

multifractionated radiotherapy, irradiation of tumors with 1.5–2.0 Gy/fraction pref-
erentially kills oxic cells reducing oxygen consumption. Consequently, oxygen may
diffuse into previously hypoxic areas and reoxygenates the hypoxic cells. One may
wonder whether reoxygenation of hypoxic cells would occur in tumors irradiated
with high-dose irradiation, in which the blood vessels are severely damaged and
thus oxygen supply is diminished. This question was addressed recently in a study
by Song et al. [15], in which the reoxygenation kinetics after irradiation with vari-
ous doses in a single exposure in an experimental murine tumor model [15].
In this study, all the surviving tumor cells were hypoxic immediately after irra-
diation with 10, 15, and 20 Gy due to the death of all oxic cells. The hypoxic cell
fraction, however, progressively decreased during the several days after irradiation,
indicating that reoxygenation of hypoxic cells was occurring (Fig. 2.3d). Importantly,
the rate of reoxygenation was dependent on the dose of radiation: significant reoxy-
genation occurred within 24 h after 15 and 20 Gy irradiation while it occurred from
3 days after 10 Gy irradiation. Nevertheless, the hypoxic cell fraction declined
equally to approximately 50% regardless of the dose applied (i.e., 10–20 Gy) on day
7 postirradiation, then began to rise again thereafter. Of note, despite the prompt
reoxygenation, approximately 50% of surviving tumors were still hypoxic at the
time when the reoxygenation was maximal (i.e., 7 days after irradiation), which was
significantly higher than the 30% hypoxic cell fraction in the control tumors. In a
recent study using a cellular automata model, the optimum interval for two fractions
treatments with 13.5 Gy per fraction was found to be 6 days when the reoxygenation
of hypoxic cells and repopulation of surviving cells were taken into account [69].
2.7.2 Repair of Sublethal Radiation Damage in Tumor Cells
It has been reported that the sublethal radiation damage repair rate is diphasic. The
half-time of the early phase is approximately 0.3 h, while that of the subsequent late
phase is approximately 4 h [70]. Therefore, when tumors are treated with SABR,
which can take >30 min, repair of sublethal damage may start during the radiation
exposure. The magnitude of the repair that occurs during and after irradiation varies
depending on the total dose, dose rate, and tumor type. Furthermore, when exposed
to high-dose irradiation, the hypoxic and acidic TME in the tumors can interfere
with the repair process of sublethal radiation damage.
2.7.3 Redistribution of Cells in Cell Cycle Phase
The cell cycle progression, cell cycle arrest and consequent changes in the distribu-
tion of cells in cell cycle phases (G1, S, G2, and M) are radiation dose-dependent.
After irradiation with modest doses (1–5 Gy), the cell cycle progression is slowed
and cells are transitionally arrested at each cycle phase, but the irradiated cells even-
tually progress to the G2/M phase. Following the G2/M arrest, some cells success-
fully complete mitosis, while other cells undergo mitotic death or mitotic catastrophe.
When tumors are exposed to high-dose irradiation, cells tend to be arrested and
undergo interphase cell death in the cell cycle phase in which the cells are irradi-
ated. When HL-60 cells were irradiated with 20 Gy, for example, almost all cells
died in the cell cycle phases in which the cells were irradiated [71]. This finding
implies that when tumors are irradiated with ablative high-dose irradiation, cell
cycle progression is halted and cells undergo interphase death without redistribution
in cell cycle phases. The resulting increased hypoxia and acidity in the TME due to
vascular destruction can further enhance cell cycle arrest and interphase death fol-
lowing high-dose hypofractionated irradiation.
2.7.4 Repopulation of Tumor Cells
When the surviving cell population is depleted substantially in tumors during the
course of multifractionated radiotherapy, the compensatory repopulation of tumor
cells is triggered starting approximately 3–4 weeks after commencement of the
treatment. As the treatment of tumors with SABR in 1–5 fractions is completed
within 1–2 weeks, which is before significant depletion of tumor cells occurs, the
compensatory repopulation of cells would occur—if it occurs—after the SABR
treatment is completed. The repopulation of tumor cells or recurrence of tumors
after SABR is directly related to revascularization. It has been reported that vascu-
logenesis mediated by HIF-1α, not angiogenesis, is responsible for the regrowth of
tumors receives high-dose irradiation [38].
2.7.5 Radiosensitivity of Tumor Cells
The intrinsic radiosensitivity of a tumor cell varies considerably depending on the

cell type and origin of the cells. The radiosensitivity of tumor cells is an important
factor in the outcome of treatment with conventional multifractionated radiotherapy
with 1.5–2-0 Gy per fraction. The radiosensitivity of tumor cells, however, is rela-
tively less important for indirect cell death caused via vascular damage. The indirect
cell death secondary to vascular damage as well as the cell death due to antitumor
immunity can occur independent of the inherent radiosensitivity and mitotic activity
of tumor cells. Indeed, it has been known that the brain metastases almost equally
respond to SABR regardless of the origin of the tumors.
2.8 The Linear Quadratic Model in SABR
The linear quadratic (LQ) model is a mechanistic model for the calculation of isoef-
fect dose that is based on the assumption that the radiation-induced cell death is
caused by DNA double-strand breaks. The LQ model is widely used in conventional
multifractionated radiotherapy (i.e., 1.5–2.0 Gy per fraction). In light of the increas-
ing evidence that radiation-induced vascular damage and probably anti-immune
response also significantly contribute to tumor cell death when tumors are treated
with high-dose hypofractionated irradiation; however, the validity of the LQ model
for SABR has come into question [6, 12]. Nevertheless, some investigators con-
clude that the LQ model remains useful to estimate the outcome of SABR for some
types of cancers [3–5, 17].
As shown in Fig. 2.4, the radiation cell survival curve based on the LQ model
bends (is nonlinear) downward with the increase in radiation dose. As shown with
the dotted line, cell death due to DNA damage is projected to increase linearly, that
Fig. 2.4 Indirect Cell Death Model: the survival curve of tumor cells in vivo. The red dotted line
indicates cell death due to direct effect on DNA; the blue solid line represents cell death due to
vascular damages. LQ Model: the dotted line indicates the cell death in vitro due to DNA damage;
the solid line represents the cell death calculated with α/β model
is, surviving cell fraction is projected to decrease linearly) indicating that the LQ
model might overestimate the radiation-induced cell death at the high-dose range.
In contrast, the LQ model often has been shown to underestimate the actual clinical
outcome of SABR treatment [9, 17, 72]. The radiation survival curve of tumor cells
in vivo also bends downward with an increase in radiation dose due to the indirect
and additional cell death that results from vascular damage (Fig. 2.4). If there is no
additional cell death in SABR, the LQ model would certainly overestimate the out-
come of SABR. On the other hand, the LQ model would underestimate the outcome
of SABR when the total cell death (direct and indirect cell death) is greater than the
cell death estimated by the LQ model. In some clinical situations, the cell death
estimated by the LQ model may be coincidently similar to the actual total cell death
[17]. Despite the inherent flaws of the LQ model, which overestimates the cell death
caused by DNA damage, the model might approximate the outcome of SABR for
some clinical cases because of the indirect cell death associated with treating tumors
with SABR [72].
2.9 Summary
SABR (i.e., SBRT and SRS) is highly effective to induce local control of various
human tumors because it not only kills tumor cells through DNA damage but also
causes indirect and additional cell death by inducing severe and a long-lasting vas-
cular damage followed by deprivation of oxygen and nutrients in the tumors
(Fig. 2.5). SABR promotes a series of immune stimulating pathways including the
release of tumor antigens from tumor cells and the final effector phase of T-cell-
mediated lysis of target tumor cells. However, concomitantly, immunosuppressive
responses are also evoked after SABR due to an increase in the expression of
HIF-1α, the major immune mediator of immune escape, as a consequence of vascu-
lar damage and ensuing increase in tumor hypoxia.
Fig. 2.5 Biological mechanisms of SART (SBRT/SRS). SART kills tumor cells via DNA double-
strand breaks and via vascular damages. SART also triggers an antitumor immune response,
thereby killing tumor cells and leading to suppression of tumor recurrence and metastases. At the
same time, SART can also elicit anti-immune responses via activation of HIF-1α, leading to
immune escape of tumor cells [16]
The roles of the 5Rs in SABR are dependent on various factors including the
radiation dose per fraction. After high-dose SABR, the vascular damage and the
resultant increase in tumor hypoxia and expression of HIF-1α greatly affect the
repair of sublethal radiation damage and repopulation of the surviving tumor cells.
With increasing radiation doses per fraction, interphase cell death supplants mitotic
catastrophe becoming the prevailing mechanism of cell death. Fractions of the sur-
viving hypoxic tumor cells after SABR are reoxygenated owing to decline in oxy-
gen consumption resulting from the massive death of tumor cells. Despite the
inherent flaws of the LQ model overestimating the cell death caused by DNA dam-
age, the model might approximate the outcome of SABR for some clinical cases by
virtue of the additional cell death due to vascular injury by the high-dose irradiation.
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Chapter 3
Physics of SBRT
Teiji Nishio
3.1 Electromagnetic Wave: X-Rays, Gamma Rays
Electromagnetic waves exhibit wave-particle duality; thus, they carry the properties
of both particles and waves. Photons travel at the speed of light c, and their fre-
quency ν, wavelength λ, and the speed are related as follows:
c [ m / s] = λ ⋅ν = 3.0 × 108. (3.1)

The radiation used in the radiation therapy includes high-energy X-rays and
gamma rays, which are types of electromagnetic waves. Their energy in radiation
therapy is expressed in the unit of MeV. The energy of an electromagnetic wave E
is expressed as follows, including Planck’s constant h:
h⋅c
E [ MeV ] = h ⋅ν =  4.14 × 10 −21 ⋅ν s−1   1.24 × 10 −12 / λ [ m ]. (3.2)
λ
As shown in Fig. 3.1, when matter is irradiated with an incident charged particle,
an electromagnetic wave is released from the outside of the nucleus in the form of
an X-ray, while another wave is released by the nucleus in the form of a gamma ray.
When the incident charged particle is an electron, bremsstrahlung is produced when
the direction of the electron is deflected by the Coulomb force of the nucleus of the
matter during its passage through the matter.
Characteristic X-rays are electromagnetic radiation with a certain energy whose
release corresponds to the filling of an outer-shell electron vacancy produced by the
emission of an inner-shell electron of an atom of matter.
T. Nishio (*)
Medical Physics Laboratory, Division of Health Science, Graduate School of Medicine,
Osaka University, Osaka, Japan
e-mail: nishio@sahs.med.osaka-u.ac.jp

Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_3
36 T. Nishio
Fig. 3.1 Release of X-rays

and gamma rays
3.2 Interactions of Photons with Matter
Interactions of photons with matter depend on the energy of photons. These interac-
tions include the photoelectric effect, Rayleigh and Thomson scattering (coherent
scattering), Compton scattering (incoherent scattering), pair production, and photo-
nuclear reaction. In radiation therapy, transfer of the energy possessed by photons to
matter (i.e., a tumor) is important, that is, this energy should be transferred from
photons to electrons, which are charged particles. Since no energy is given to any
charged particle by coherent scattering, the photoelectric effect, Compton scatter-
ing, and pair production are key interactions of photons with matter in radiation
therapy, as shown in Fig. 3.2.
3.2.1 Photoelectric Effect
The photoelectric effect is a reaction involving the loss of energy that is caused
when photons of relatively low energy are absorbed by matter and bound electrons
of atoms or molecules in that matter are released. The maximum kinetic energy Ee
that is carried by an electron is expressed as follows:
Ee ≤ E − W , E = h ⋅ν . (3.3)
Here, W is the work function. Indeed, it is the minimum energy required to
remove an electron from the binding of an atom or a molecule in the matter.
The energy of a photon absorbed by the matter excites an atom. Subsequently,
the excited atom returns to its stable ground state by ejecting an Auger electron and
an X-ray. Figure 3.3 shows the results of the mass attenuation coefficients μm = μ/ρ
for water, silver, and lead, and the cross section as a function of the energy of the
incident photon in the photoelectric effect [1]. The term ρ is the density and μ indi-
cates the attenuation coefficient. The photoelectric effect tends to emit inner-shell
electrons (K-, L-, and M-shell), which are bound at a higher level of energy.
Furthermore, it causes a physical phenomenon in which an atom made unstable by
absorption of the energy of a photon releases a high level of energy each time;
3 Physics of SBRT 37
Fig. 3.2 Interactions of incident photons with matter
Fig. 3.3 Mass attenuation coefficient and cross section as functions of the energy of the incident
photon in the photoelectric effect [1]
however, with a smaller number of reactions. Therefore, the cross section of the
photoelectric effect shows changes in a stepwise manner according to the bound
energies of electrons, as presented in Fig. 3.3.
The cross section of the photoelectric effect is approximately inversely propor-
tional to the 3.5th power of energy of the incident photon, proportional to the fifth
power of the atomic number of the matter, and proportional to the 3.5th power of the
effective atomic number of the matter.
38 T. Nishio
3.2.2 Compton Scattering
Compton scattering is a scattering phenomenon between a photon and an electron

that is caused when the energy of the incident photon is considerably higher than the
bound energy of the electron. Part of the energy of the incident photon is transferred
to the electron, which uses it to travel, while the scattered photon loses energy.
When the energy of the incident photon is extremely lower than the mass energy of
the electron, the incident photon hardly loses energy by scattering with an electron;
this phenomenon is called Thomson scattering. This scattering phenomenon can be
neglected for photons with energy on the order of MeV, as used in the radiation
therapy.
As represented in Fig. 3.4, the law of conservation of momentum and energy in
Compton scattering yields
Ein 2 ⋅ Ein ⋅ γ ⋅ cos2 φ

E= , Ee = ,
1 + γ ⋅ (1 − cos θ ) (1 + γ ) − γ 2 ⋅ cos2 φ
2
(3.4)
θ  Ein
cot   = (1 + γ ) ⋅ tan φ , γ = ,
e ⋅c
2
2
  m
where Ein is the energy of the incident photon, E is the energy of the scattered
photon, θ is the scattering angle of the scattered photon, Ee is the kinetic energy of
the recoil electron, and ϕ is the scattering angle of the recoil electron. The quantity
of me ⋅ c2 ≃ 0.511[MeV] is the rest mass energy of an electron. A recoil electron
receives the maximum energy by Compton scattering when the scattering angle of
the recoil electron ϕ = 0(θ = π). Subsequently, Eq. (3.4) can be used to write
2 ⋅γ
Ee ≤ Ee (φ = 0 ) = Ein ⋅ . (3.5)
1+ 2 ⋅γ
The edge of the energy spectrum of a recoil electron with the maximum recoil
energy is called the Compton edge. The difference between the wavelength of an
incident photon and that of a scattered photon depends on the scattering angle θ;
however, it does not depend on the energy of the incident photon or scattered photon.
Fig. 3.4 The Compton

scattering
The differential cross section of Compton scattering per unit of solid angle is
expressed by the Klein-Nishina formula as follows:
dσ comp ( Ein )
= re 2 ⋅
(1 + cos θ )
2
dΩ 2 {1 + γ ⋅ (1 − cos θ )}
2
 (1 − cosθ )
2

× 1 + γ 2 ⋅ , (3.6)

 (1 + cos θ )
2
⋅ {1 + γ ⋅ (1 − cos θ )} 

e2
re =  2.818 × 10 −13 [ cm ] , (3.7)
me ⋅ c 2
where re is the classical electron radius. Figure 3.5 shows the calculated differential
cross section of the Compton scattering for every angle of a scattered photon as a
function of the energy of the incident photon using Eqs. (3.6) and (3.7). The red
lines represent the cases of incident photons with energy in the range of 1–100 keV,
while the blue lines indicate those in the range of 1–10 MeV. In addition, the pos-
sibility of causing forward scattering increases when the energy of the incident pho-
ton becomes higher. This possibility is extremely high, and Compton scattering
tends to deposit energy of the incident photon forward for energy on the order of
MeV (the blue line in the figure), as used in the radiation therapy.
The total cross section of the Compton scattering σcomp is expressed by integrat-
ing the differential cross section of the Compton scattering, as expressed in Eq.
(3.6), with the total solid angle. The integral calculation result is presented as
follows:
4 ⋅π
σ comp ( Ein ) = ∫ ( dσ
0
comp ( Ein ) / dΩ ) dΩ
1 + γ  2 ⋅ (1 + γ ) 1 
 2 ⋅ − ⋅ ln (1 + 2 ⋅ γ ) 
= 2 ⋅ π ⋅ re 2 ⋅ 
γ  1 + 2 ⋅ γ γ  . (3.8)
 1 1+ 3⋅γ 
+ ⋅ ln (1 + 2 ⋅ γ ) − 
 2 ⋅ γ (1 + 2 ⋅ γ ) 
2
When the total cross section of the Compton scattering is divided into the cross
section of the Compton scattered photon σs and the cross section of the recoil elec-
tron σa, then
σ comp ( Ein ) = σ s ( Ein ) + σ a ( Ein ) , (3.9)

40 T. Nishio
Fig. 3.5 Differential cross section of the Compton scattering for every angle of a scattered photon
as a function of the energy of the incident photon
4 ⋅π
σ s ( Ein ) = ∫ {1 + γ ⋅ (1 − cosθ )} ⋅ ( dσ ( Ein ) / dΩ ) d Ω
−1
comp
0
(3.10)
1
= π ⋅ re ⋅  3 ⋅ ln (1 + 2 ⋅ γ ) +
2
(
2 ⋅ (1 + γ ) ⋅ 2 ⋅ γ 2 − 2 ⋅ γ − 1
+
) 8 ⋅γ 2 
.
γ ( ) ( )
2 3
γ 2
⋅ 1 + 2 ⋅ γ 3 ⋅ 1 + 2 ⋅ γ 
 
Figure 3.6 shows the calculated total cross section of the Compton scattering and
those of the Compton scattered photon and recoil electron as a function of the
energy of the incident photon, which were determined using Eqs. (3.8)–(3.10),
respectively. In addition, the Compton scattering decreases as the energy of the
incident photon increases.
Fig. 3.6 Cross section of the Compton scattering as a function of the energy of the incident photon
3.2.3 Pair Production
Pair production is the phenomenon of the creation of a pair of an electron and a

positron when an incident photon passes through a nearby atomic nucleus. Therefore,
pair production does not occur in a vacuum. This phenomenon requires the energy
of an incident photon to be greater than the total mass energy of an electron and a
positron. In addition, the mass energy of an electron is the same as that of a positron.
The total kinetic energy of an electron and that of a positron after pair production
are expressed by the following equation because the recoil energy of an atom can be
ignored in pair production.
E+ + E− = Ein − 2 ⋅ me ⋅ c 2 = Ein − 1.022 [ MeV ] , (3.11)
where E− and E+ are the kinetic energies of an electron and a positron, respec-
tively. The energy of an incident photon is equally divided between an electron and
a positron when the energy of the incident photon is low, whereas an unequal divi-
sion of energy occurs when the energy of the incident photon is high.
When the energy of an incident photon is smaller than the threshold energy
1.022 MeV, the cross section of pair production is zero; however, it is proportional
to the energy of an incident photon when the energy of the incident photon is greater
42 T. Nishio
than the threshold value. When the energy of an incident photon is high, the cross
section slowly increases; in addition, it is proportional to lnEin and the second power
of the atomic number of the matter.
3.3 Photon Flux in Matter
When a photon enters matter, the photon flux decreases by five interactions in mat-
ter, including the photoelectric effect, Thomson scattering, Compton scattering, pair
production, and photonuclear reaction. Figure 3.7 shows a schematic of the photon
flux passing through matter. The relational equation is expressed as follows:
I out = I in ⋅ exp ( − µ ⋅ d ) , (3.12)
where d is the thickness of matter, Iin is the incident photon flux, Iout is the photon
flux after passing through the matter, and μ is the linear attenuation coefficient.
Fig. 3.7 Schematic of the photon flux passing through matter

The linear attenuation coefficient μ represents the amount of decrease per unit
length in matter. It can approximate the total value of the linear attenuation coeffi-
cient of the photoelectric effect μphot, Compton scattering μcomp, and pair production
μpair in the case of an incident photon with an energy in the order of MeV, as used in
the radiation therapy.
µ ( E ) = ∑µi ( E )  µ phot ( E ) + µcomp ( E ) + µ pair ( E ) . (3.13)

i
The relationship between the linear attenuation coefficient μ and cross section σ
for interactions of photons in matter is expressed by μ = n ⋅ σ, where n is the number
density of the matter. In addition, the number density can be expressed by
n = ρ ⋅ NA/A, where A is the mass number, NA is Avogadro’s constant, and ρ is the
density. Consequently, the linear attenuation coefficient is expressed as
NA
µ (E)  ρ ⋅ ⋅ (σ photo ( E ) + Z ⋅ σ comp ( E ) + σ pair ( E ) ) , (3.14)
A
where σphoto, σcomp, and σpair are the reaction cross section of the photoelectric
effect, Compton scattering, and pair production, respectively.
Figure 3.8 shows the mass attenuation coefficient μm, which is calculated by
dividing the linear attenuation coefficient μ by the density ρ, for each interaction as
a function of the energy of the incident photon in water [1]. It can be observed that
the Compton scattering is a dominant interaction in the energy of X-rays used in the
radiation therapy. The photoelectric effect and Compton scattering can occur nearly
equally in the energy range of X-rays of approximately 10–100 keV, as used in the
diagnostic radiation. Pair production is dominant in the case of extremely high
energy ranges.
Interactions of incident photons with matter cannot be described only by a
simple model of attenuation of those photons because the energy and spatial dis-
tributions of photons actually change in matter. For example, some incident pho-
tons become scattered photons, which are scattered forward after the Compton
scattering, and incident photons, including the scattered photons; undergo new
interactions, particularly in the energy range used in the radiation therapy.
Therefore, the photon flux upon entering matter does not follow a simple exponen-
tial attenuation. Interactions of photons with a real matter are extremely compli-
cated; thus, the energy of the photon, its direction, mass attenuation coefficient of
all energy, and the photon flux at a point in the matter should be considered as
parameters of those interactions.
44 T. Nishio
Fig. 3.8 Mass attenuation coefficient of water for each interaction as a function of the energy of
the incident photon [1]
3.4 Energy Deposition by Incident Photons to Matter
An incident photon deposits kinetic energy Ee on an electron by interactions, such

as the photoelectric effect, Compton scattering, and pair production, and the elec-
tron deposits the energy on matter while passing through it, as shown in Fig. 3.9.
The stopping power is defined as the energy loss per length along the electron’s
track, which is expressed as −dE/dx[MeV/cm]. The mass-stopping power;
−dE/ρ ⋅ dx[MeV ⋅ cm2/g] is obtained by dividing the stopping power by the density
of the matter.
An energy relational equation with a special relativity is used to express the elec-
tron velocity while passing through the matter as follows:
me ⋅ c 2 1
= Ee + me ⋅ c 2 . ⇒ β = 1 − , (3.15)
(1 + E )
2
1− β 2
e / me ⋅ c 2
where c is the speed of light; β = υ/c; and e and me indicate the electron charge and
rest mass, respectively. Moreover, me ⋅ c2 is the electron rest mass energy; its value
Fig. 3.9 Schematic of the

energy deposition by an
incident photon to matter
is 0.511 MeV. The electron velocity is greater than 50% of the speed of light when
the kinetic energy of the electron is only 0.08 MeV.
Moreover, the mass-stopping power in the electron energy (electron kinetic
energy) range, which should be considered in the radiation therapy, can be divided
into terms of ionization and radiation losses.
dEe  dEe   dEe 

− = −  +−  , (3.16)
ρ ⋅ dx  ρ ⋅ dx col  ρ ⋅ dx rad
where the first and second terms represent the ionization and radiation losses,
respectively.
The ionization loss is calculated using the Bethe-Bloch formula, which describes
the stopping power as follows:
 dEe  2 ⋅ π ⋅ me ⋅ c 2 2 Z
−  = ⋅ re ⋅ N A ⋅
 ρ ⋅ dx col β 2
A
  2 ⋅ m ⋅ c2 ⋅ E ⋅ β 2  
ln  e e
(
 + 1− β 2 ) 
 
×  (
1− β ⋅ I
2
)
2



,
(3.17)

( ) ( )
2
1
− 2 ⋅ 1 − β − 1 + β ⋅ ln 2 + ⋅ 1 − 1 − β
2 2 2

 8 
where I is the mean excitation potential energy. Furthermore, I for water is

75.0 eV. The ionization loss is in proportional to the atomic number of the matter
and inversely proportional to the electron energy. Similarly, the radiation loss is
expressed as follows:
 dEe  Ee + me ⋅ c 2
α
Z2 

⋅ 4 ⋅ ln 
(
 2 ⋅ Ee + me ⋅ c 2 )  − 4  ,
−  = ⋅ ⋅ ⋅ ⋅
2
r N  (3.18)
 ρ ⋅ dx rad β2
e A
A  me ⋅ c 2  3
   
where α is the fine-structure constant.

46 T. Nishio
e2 1
α= . (3.19)
⋅ c 137
The radiation loss is in proportional to the second power of the atomic number of
the matter and to the electron energy if it is sufficiently greater than the electron rest
mass energy. When the ionization and radiation losses are equal, the electron energy
is called the critical energy Ec, which is approximated as follows:
 dEe   dEe  800

−  = −  . ⇒ Ee = Ec  [ MeV]. (3.20)
 ρ ⋅ dx col  ρ ⋅ dx rad Z + 1.2
According to Eq. (20), the critical energy for water is approximately 92 MeV.
Figure 3.10 demonstrates the calculated electron-stopping power in water using
Eqs. (3.15)–(3.19). The radiation loses the electron-stopping power predominantly
in the energy range used in the radiation therapy. The distance over which the elec-
tron energy becomes 1/e owing to the loss of approximately all of its energy is
called the radiation length Lrad. The radiation length of water is approximately 36 cm.
Fig. 3.10 Mass-stopping power for water as a function of the electron energy
The mass of an electron is extremely small, which is only approximately 1/1800

that of a proton. Because an electron has a negative elementary electric charge, it is
scattered markedly by the Coulomb scattering in matter. In addition, an electron is
scattered many times; this effect is called multiple Coulomb scattering. The multi-
ple Coulomb scattering is expressed as
Z2 d
θe2 ∝ ⋅ , (3.21)
β 2 Lrad
where 〈θe2〉 denotes the mean square angle of an electron. This formula shows
that electron scattering in matter is proportional to the second power of the atomic
number and thickness of the matter, whereas it is inversely proportional to the sec-
ond power of the electron velocity and radiation length of the matter. Because the
speed of the recoil electron that is produced by the Compton scattering with X-rays
used in the radiation therapy is approximately that of light in the range of kinetic
energy of the recoil electron, the ratio of change of the scattering angle is small,
approximately 10%.
The range of an electron in matter Re ⋅ ρ can be calculated by integrating the
reciprocal of mass-stopping power with electron energy from E0 to zero, as follows:
0 −1
 dEe 
Re ⋅ ρ = ∫  −  dEe g / cm 2  . (3.22)
E0 
ρ ⋅ dx col
However, the actual stopping positions of electrons significantly diverge because

while electrons pass through the matter, the multiple Coulomb scattering changes
their directions in a complicated manner. Therefore, electron path lengths in matter
can be calculated using Eq. (3.22).
The energy deposition by electrons to matter, which occurs when X-rays used in
the radiation therapy irradiate matter, is approximately entirely owing to energy
losses of recoil electrons by the Compton scattering. In addition, dose kernel KX is
formed by the energy losses of recoil electrons owing to the Compton scattering at
a point in matter.
 dσ photo dσ comp dσ pair   dσ comp   dσ a 

KX = KX  , ,   KX    KX  . (3.23)
 dΩ dΩ dΩ   dΩ   dΩ 
The shape of dose kernel KX depends on the differential cross sections of recoil
electrons following the Klein-Nishina formula, as presented in Eq. (3.6). Figure 3.11
demonstrates that the shape of dose kernel KX is elongated forward in the case of
incident photons or X-rays with a high energy. In a low-density matter, the shape of
dose kernel KX expands on the basis of its similarity depending on the lung density
48 T. Nishio
Fig. 3.11 Schematic of shapes of dose kernels in various situations
in the radiation therapy, whereas the shape in an inhomogeneous matter is formed

in a boundary region between the high- and the low-density area corresponding to
the area between the mediastinum and lungs because of shape changes under vari-
ous conditions, such as the incident energy and matter density. Dose distribution is
provided by convoluting the dose kernel KX within the spatial region inside the mat-
ter that is irradiated by X-rays used in the radiation therapy, as presented in Fig. 3.12.
Fig. 3.12 An example of

the dose distribution of
X-rays used in the
radiation therapy
3.5 Energy Spectrum and Dose Distribution of Therapeutic

X-Rays from a Linear Accelerator (Linac)
A linear accelerator (Linac) is used in the X-ray therapy, including stereotactic body
radiation therapy (SBRT) for the lungs and liver. Bremsstrahlung X-rays are pro-
duced by the phenomenon of bremsstrahlung, which occurs when MeV-energy
electrons accelerated by a Linac irradiate a metallic target. Figure 3.13 shows the
calculated mass-stopping power for a tungsten (chemical symbol W) target as a
function of the electron energy. Compared with water, as shown in Fig. 3.10, the
ratio of bremsstrahlung, which is the radiation loss in the mass-stopping power, is
larger for electrons with an MeV-order energy, as used in the radiation therapy. The
critical energy for water is approximately 92 MeV, whereas that of tungsten is small
and approximately 10 MeV.
Energy spectra of bremsstrahlung X-rays using a Linac are formed by not only
the incident energy of electrons to the target but also the material of the target or a
flattening filter and their optical arrangement. Therefore, shapes of the energy spec-
tra differ among Linac manufacturers. Typical energy spectra of X-rays of a Linac
are shown in Fig. 3.14 [2].
50 T. Nishio
Fig. 3.13 Mass-stopping power for tungsten as a function of the electron energy
Fig. 3.14 X-ray energy spectra of Linac [2]

Figure 3.15 shows the product of the energy spectrum of a 6-MV X-ray produced
by a Varian Linac and the mass attenuation coefficient for each energy. The value
expresses the occupancies for each interaction in the energy spectrum of 6-MV
X-rays of the Linac. Figure 3.16 shows the dose kernel with the 6-MV X-ray energy
spectrum of Varian Linac. Dose kernels in homogeneity (water) and inhomogeneity
(water / low density substance (30% of water density)) were calculated using the
Monte Carlo simulation code: Electron Gamma Shower version 5.0 (EGS5) [3]. In
addition, Fig. 3.17 demonstrates the dose distribution of seven irradiation fields
with gantry angles of 5, 50, 135, 175, 220, 280, and 325 degrees in water-tank type
lung phantom for lung SBRT [4], calculated using EGS5. The simulation using
EGS5 was performed considering photons of 1.3 × 109, a calculation grid size of
1 mm, photon cut-off energy of 10 keV, and electron cut-off energy of 200 keV. These
simulation data were provided by a medical physicist, S. Kito at the Radiation
Physics Section, Tokyo Metropolitan Cancer and Infectious Diseases Center
Komagome Hospital.
Fig. 3.15 Occupancies for each interaction in the 6-MV X-ray energy spectrum of Linac
52 T. Nishio
Fig. 3.16 Dose kernel with the 6-MV X-ray energy spectrum of Linac calculated using EGS5
(left: in water, right: in water / low-density substance)
Fig. 3.17 Dose distribution of seven irradiation fields for lung SBRT calculated using EGS5
54 T. Nishio
References
1. NIST/XCOM, http://physics.nist.gov/PhysRefData/Xcom/html/xcom1.html
2. Sheikh-Bagheri D, Rogers DWO. Monte Carlo calculation of nine megavoltage photon beam
spectra using the BEAM code. Med Phys. 2002;29(3):391–402.
3. Hirayama H, Namito Y, Beilajew AF, Wilderman SJ, Nelson WR. The EGS5 Code System.
Report SLAC-R-730 and KEK Report 2005-8; 2005.
4. Nishio T, Shirato H, Ishikawa M, Miyabe Y, Kito S, Narita Y, Onimaru R, Ishikura S, Ito Y,
Hiraoka M. Design, development of water tank-type lung phantom and dosimetric verification
in institutions participating in a phase I study of stereotactic body radiation therapy in patients
with T2N0M0 non-small cell lung cancer: Japan Clinical Oncology Group trial (JCOG0702).
J Radiat Res. 2014;55(3):600–7.
Chapter 4
Quality Assurance in SBRT
Shuichi Ozawa
4.1 Introduction
SBRT is a technique to irradiate small, localized tumors in the body by using mul-
tiple or rotational beams to improve local control and reduce adverse events to sur-
rounding organs. SBRT aims to deliver a larger dose in a shorter period than
conventional radiotherapy and requires a high degree of precision in the irradiation
position [1].
As with other radiotherapy techniques, SBRT has both clinical and physical
aspects. As mentioned above, SBRT administers large doses in small fractions and
minimizes damage to surrounding normal tissue by concentrating high doses on the
planned target volume (PTV) with a steep dose gradient. Therefore, dose accuracy
and dose conformity to the PTV are important, and dose accuracy to the tumor loca-
tion in SBRT requires well-developed treatment planning, patient immobilization,
respiratory motion management, and target localization based on image-guided
radiation therapy (IGRT).
According to the guideline on SBRT by Japanese Society for Radiation Oncology
(JASTRO), SBRT is specifically defined as satisfying the following conditions [2]:
1. Irradiation of a small field with a larger dose in a shorter period than conven-
tional radiotherapy using a linear accelerator (including a microtron) in a three-
dimensional manner from multiple directions by means of fixed multi-radiation
with 5–10 fields or multi-orbit rotational irradiation.
2. The deviation of the treatment isocenter position (target localization accuracy)
for each treatment session should be kept within 5 mm. Confirm at each treat-
ment session that the target localization accuracy to the treatment isocenter (i.e.,
S. Ozawa (*)
Hiroshima High-Precision Radiotherapy Cancer Center, Hiroshima, Japan
e-mail: ozawa@hiprac.jp

Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_4
56 S. Ozawa
the movement of the radiation isocenter at each irradiation session, excluding

internal organ movements, relative to the radiation isocenter put in the treatment
plan) is within 5 mm.
3. Immobilize the patient’s movement by using a body frame or body shell. The
fixed frames or body shells are used not only to immobilize the patient, but also
irradiation is performed by synchronizing or tracking the physiological
respiratory movement or internal movement of organs, and accuracy control is
performed for any misalignment during treatment.
The mission of QA is to safely implement SBRT with the above features. To
achieve this mission, physics QA has an important role that includes routine opera-
tions to control the quality of radiotherapy treatment at each facility in accordance
with guidelines published by the Japanese Society of Radiation Oncology and other
related societies [3–5], as well as independent verification through third-party eval-
uations. Typical examples of third-party evaluations include QA activities in multi-
center clinical trials. While the QA guidelines published to date have focused on
facility-based physics QA (which form the basis for physics QA in clinical trials),
guidelines for physics QA in clinical trials have also been published [6–8].
4.2 Physics QA in SBRT
For stereotactic radiotherapy, the AAPM TG-142 and 198 report also sets stricter
tolerances than for conventional techniques [9, 10]. Of particular importance in
these recommendations is to confirm the agreement between imaging coordinates
and treatment coordinates; SBRT is often delivered in five or fewer dose fractions,
and even a single geometric error can result in a dose error of 20% or more.
There are two types of physical QA in radiotherapy: routine QA to control the
quality of radiotherapy treatment at each facility in accordance with guidelines pub-
lished by the related societies; and QA to ensure the quality of clinical trials in
which multiple facilities participate to establish a standard of care. Two types of
guidelines exist. While the physics QA guidelines published to date have focused
primarily on facility-based physics QA (which also form the basis for physics QA
in clinical trials), the American Association of Physicists in Medicine (AAPM) pub-
lished in 2018 a guideline, TASK GROUP 113: Guidance for the Physics Aspects of
Clinical Trials (TG113) provides guidance on physics QA in clinical trials.
4.2.1 Staffing and Equipment
In the context of radiotherapy quality control, appropriate staffing is the first issue
that facilities should address to ensure the safe delivery of radiotherapy, though it is
not only for SBRT. The clinical team and facility management need to understand
4 Quality Assurance in SBRT 57
their roles and responsibilities before implementing SBRT. Human staffing and
associated equipment specifically refer to adequate staffing and coverage, appropri-
ate equipment to support the treatment process, appropriate equipment for QC, clear
operational procedures that define duties and appropriate work hours for all staff to
perform their tasks safely, and documentation that is rooted in transparency and
process analysis. Facility directors should not provide SBRT before these personnel
arrangements and related equipment are in place in the radiation therapy department.
In particular, relevant equipment required for SBRT includes the following [4]:
1. Radiation detectors suitable for small irradiation fields.
2. Reference class electrometer suitable for low current measurements.
3. An E2E phantom suitable for verification of the accuracy of SBRT
4. QC equipment capable of performing isocenter tests (i.e., Winston-Lutz tests)
for IGRT and beam alignment verification.
4.2.2 Facility-Based Physics QA
4.2.2.1 Commissioning
The following items must be implemented in the commissioning procedure espe-

cially for SBRT:
1. Treatment delivery machine (linac)
2. Immobilization devices
3. Supportive systems for imaging and patient motion management
4. Radiotherapy treatment planning system (RTPS)
Establish a facility policy for SBRT at the time of commissioning. This policy
should clarify the workflow of SBRT implementation and the minimum usable field
size for treatment planning, as well as the data at the time of commissioning that
will serve as the baseline for the SBRT and equipment QA programs. These QA
programs must be clearly communicated within the department prior to clinical
implementation of SBRT. To this end, work with other team members to develop
standard operating procedures (SOPs) for major steps through the entire treatment
process.
4.2.2.2 Simulation
The purpose of simulation in SBRT is threefold. They are to create a patient immo-
bilization device, determine how to manage tumor motion, and obtain 3D anatomi-
cal imaging data necessary for treatment planning and image-guided therapy. The
priority for patient immobilization is reproducibility of patient positioning. In deter-
mining how to manage tumor motion, measurement of the length of tumor
58 S. Ozawa
movement is important. The Guidelines for Respiratory Motion Management in

Radiation Therapy Respiratory Motion by JASTRO [11], as discussed below, also
address the use of a 10-mm movement as a standard, and considering the interplay
effects of IMRT/VMAT can be negligible [12–14].
4.2.2.3 Planning
It is recommended to use a calculation grid size of 2 mm or less, but not more than
3 mm. [TG101, MPPG.9.a]. For very small targets, a calculation grid size of 1 mm
may be necessary [MPPG.9.a]. Since the calculation accuracy of small irradiation
fields is an issue in SBRT treatment planning, care should be taken in handling the
output factors of small irradiation fields when commissioning the treatment plan-
ning system. Particular attention should be paid to the calculation accuracy of irra-
diation fields smaller than 2 × 2 cm2 because of the large variation among facilities
less than this field size [15]. For actual measurements, refer to various guidelines,
use the correct detector, and use correction coefficients. For dose calculation algo-
rithms, commissioning of dose models for treatment planning systems should
include all aspects described in the AAPM Medical Physics Practice Guideline 5,14
but should also include evaluation of multimodality image fusion accuracy, clini-
cally appropriate small-field dose calculations (using cone, IrisTM, or MLC fields
if in range), calculation accuracy with respect to couch attenuation and its effect on
surface dose,12 and additional validation tests depending on the specific SRS-SBRT
irradiation technique and scope of clinical service, such as heterogeneity correction.
It should be noted that the pencil beam dose algorithm is not suitable for extracra-
nial SRS-SBRT applications where the beam path traverses significant tissue het-
erogeneity, such as the lung, liver dome, and nasopharynx treatment sites. In the
commissioning for inhomogeneity correction on RTPS, verification by measurement-
based verification with heterogeneity phantoms are common, but the verification of
the CT value to density conversion table registered in the RTPS has also been
reported [16].
4.2.2.4 RMM
The Japanese Guidelines for Respiratory Motion Management in that the respira-
tory management is necessary for lung cancer, liver cancer, or renal cancer with a
respiratory motion more than 10 mm [11]. When the movement exceeds 10 mm,
measures should be taken to reduce it to 10 mm or less. In other words, respiratory
motion managements are not needed the movement of 10 mm or less, so if the
movement is within 10 mm, there is less possibility to give a clinical impact even
when the patient treated with VMAT [12–14].
4.2.2.5 IGRT
Image Guided Radiotherapy (IGRT) is defined as the radiotherapy that uses image
guidance in various procedures, including acquisition of patient imaging data, treat-
ment planning, patient setup, and target location before and during treatment. IGRT
for SBRT is used to determine the therapeutic target. For a minimum requirements
of IGRT QA in SBRT, AAPM MMPG-AAPM MMPG-9.a for SRS-SBRT is a good
reference [4].
4.2.2.6 Third Parity Evaluation
Once the facility-based commissioning and QA Program are completed, patient

treatments are finally able to start. However, if it is possible, the third-party evalua-
tions are recommended before starting the clinical program. In addition to the inves-
tigation of the output of the linear accelerator, it is also recommended to undergo
end-to-end third-party evaluation, including phantom irradiation and so on [16–19].
4.2.3 Multifacility-Based Physics QA
4.2.3.1 Physical QA in Clinical Trials
Unlike QA performed on a one facility basis, the objective of QA performed at

multiple sites is to ensure that equivalent quality control is performed among the
various treatment modalities. Furthermore, it needs to be performed using the same
methods in different modalities. Therefore, the same QA items with the same toler-
ances are very difficult to be performed for multifacility-based QA as well as
facility-based QA. The items to be performed for multi-facility are comprehensive
items for each QA category, and a third-party evaluation is performed to ensure that
there are no major errors, using the same tools and with the same acceptable values.
Therefore, it should be noted that the number of QA items to be implemented is
small and the tolerance values tend to be larger. Third-party evaluation is only an
additional evaluation, and the fact that they have been evaluated by a third party
should not be a reason to omit QA in the facility.
Clinical trials that are quality assured by the multifacility-based physics QA can
minimize the variations in treatment plans and delivery doses to the patients. In the
radiotherapy-related clinical trials that have been conducted, secondary analyses
have demonstrated that the degree of protocol adherence in treatment planning has
an impact on overall survival [20]. This result shows that minimizing treatment vari-
ability among facilities through standardization of treatment protocols and
multifacility-based physics QA will reduce variation in the quality of radiation ther-
apy and improve outcomes. In recent years, attempts have been made to harmonize
internationally the methods of QA and OAR contouring of clinical trials [21, 22].
The Radiation Therapy Study Group of the Japan Clinical Oncology Group (JCOG
60 S. Ozawa
RTSG) has conducted several clinical trials on SBRT so far and the Medical Physics
WG (MPWG) has conducted physics QA activities in each trial [23–26]. As an
example of multi-facility physics QA in SBRT clinical trials, Credentialing at
JCOG1408 [27, 28] is discussed in this section.
4.2.3.1.1 Credentialing
Accreditation to verify performance of specific processes of SBRT by each facility

to demonstrate their ability to accurately plan and treat patients based on the proto-
col is fundamental when the facility join the clinical trial. To verifies that the institu-
tion is capable of submitting the required datasets to the QA center is verified during
the credentialing process.
The first step toward efficient implementation of the physical QA necessary to
ensure the quality of radiation therapy is to standardize the names of the ROI
(Region of Interests) and the names of the dose indexes (D95%, V20 Gy, etc.)
derived from the DVH (Dose Volume Histogram) used in the protocol. The AAPM
TG-263 for standardizing nomenclatures in radiation oncology [29] and TG-113 for
standardizing the names of ROIs used in treatment planning [30] were useful to
achieve the above goals in the treatment planning benchmark test (Dummy Run
with delineation exercise). It ensures that the specific delineation and dose guide-
lines for a given trial are properly understood by all facilities.
The list of Credentialing items that must be performed at participating sites in the
JCOG1408 clinical trial is summarized in Table 4.1.
1. Physical and technical questionnaire survey on SBRT implementation methods:
This needs to be answered by facilities not only at the time of initial credential-
ing, but also each time when additional credentialing is conducted, equipment
such as linac is changed or added, algorithms are changed, or delivery technique
for SBRT are changed.
2. Dose calculation audit for small fields: Rather than based on the measurements,
calculated point doses by small fields are compared with the multi-facility aver-
Table 4.1 List of credentialing items required to be performed at participating sites in JCOG1408
clinical trials
IMRT/
Item 3D-CRT VMAT
1. Questionnaire survey on physical and technical aspects of Required
SBRT implementation
2. Calculation audit for small field comparing with multi- Required
institutional average
3. Mailing audit of IGRT by the original IGRT phantom Required
4. Dummy run of treatment planning using two sample cases Required Required
5. Mailing audit using the original phantom for IMRT/VMAT Not Required
required
6. Questionnaire survey respiratory motion management for Not Required
moving target required
age dataset categorized by each linac type and energy as shown in Fig. 4.1.
Calculated value in the unit of cGy/MU of small field from 10 × 10 cm2 down to
2 × 2 cm2 at 5 cm depth and 10 cm depth on RTPS are compared with multi-
facility average. It needs to be conducted for all energies and dose calculation
algorithms that are planned to be used for the case for this clinical trial.
3. IGRT mailing audit using the original phantom shown in Fig. 4.2: since this is an
end-to-end test, it should be conducted again when the CT scanner for treatment
JCOG RTSG/MPWG
Calculated value (cGy/MU) on RTPS of small field
collected from participating facilities.
Facility A Facility B
TrueBeam (6X) TrueBeam (6X)
Facility C Facility D
TrueBeam (6X) TrueBeam (6X)
Multi-facility average (cGy/MU) for TrueBeam (6X)
Compare
New participating facility with TrueBeam (6X)

Submit the calculated values of output (cGy/MU) for small
field on RTPS
Fig. 4.1 Workflow of calculation audit for small field comparing with multi-facility average
RTQA2
films
Dummy Target
Fig. 4.2 Outside view (left) and CT image (left) of the IGRT audit phantom
62 S. Ozawa
planning or the treatment planning system are replaced. It is not necessary to

implement this item for all the energy planned to be used in SBRT, but only the
most frequent one. But this IGRT mailing audit must be repeated when the plan-
ning device is replaced.
4. Dummy run of treatment planning using a standardized sample case: Required
for both 3D-CRT and IMRT/VMAT; not required by 3D-CRT technique if the
facility use only IMRT/VAMT technique to the case of this clinical trial. Use the
same sets of CT images and ROIs at all facilities to confirm that treatment plan-
ning is possible in compliance with the protocol (Fig. 4.3).
5. Mailing audit of the dose calculation by using original phantom for IMRT/
VMAT [18]: To be performed only by the facility to use IMRT/VMAT technique
for the clinical trial. Note that this QA item is common to other JCOG clinical
trials that allow IMRT. Figure 4.4 shows the workflow of the IMRT/VMAT mail-
ing audit by JCOG RTSG/MPWG.
6. Questionnaire survey on respiratory motion management: To be conducted only
the facilities that use IMRT/VMAT technique to make sure the technique of
respiratory motion management follows the guideline [11] . The repeat imple-
mentation of this credentialing item is necessary when the device or technique
for respiratory motion management on planning or CT simulation are changed.
It is also necessary to redo this credentialing item when replacing a linear accel-
erator, but it is not necessary when replacing only a treatment planning device.
No deviation Major deviation
PTV, GTV PTV, GTV
Fig. 4.3 Sample of the dummy run planning with no deviation (left) and major deviation (right).
Upper figures show the dose distribution of axial images and the lower shows the Beams Eye View
with PTV. The plan with major deviation has lower conformity and higher lung dose
JCOG RTSG/MPWG
Participating Facility
Simulation phantom (left) with internal

structure of C-shaped target volume.
Dose delivery phantom (right) with glass
dosimeters and films.
Scan the simulation phantom by CT and

treatment planning based on the protocol.
Irradiate the dose delivery phantom.
Analyze glass dosimeters and films in the

phantom.
Fig. 4.4 Workflow of IMRT mailing audit by JCOG RTSG/MPWG
4.2.3.1.2 Individual Case Review
During a clinical trial, parts or all of the patients’ treatment datasets will be requested
for a prospective or retrospective evaluation by a panel of specialists in order to
confirm the registered patients received the radiation therapy as the protocol. On a
case-by-case basis, this process will cover sources of variation in each facility. In
JCOG1408, submission of the following materials is mandatory for all regis-
tered cases.
1. Copies of the diagnostic images in DICOM format that provide the basis for the
indication of protocol treatment.
2. DICOM RT Dose of total dose of all beams, DICOM RT Structure of all con-
touring information, DICOM RT Plan of the treatment planning information
summary, and DICOM file of CT image set used in dose calculation.
3. Screen capture of DVH screen including PTV and organs at risk: JPEG or PDF
format, and DVH checklist specified form for JCOG 1408 with a list of dose
indices for each ROI including target and OARs.
4. Copy of the treatment record routinely used at the hospital should be submitted.
These should include the treatment date, treatment machine name, beam name
(the beam name should be consistent with the treatment plan), delivered MU
value, cumulative dose, and the name of the physicist or technologist and the
physician in charge of treatment.
64 S. Ozawa
4.2.3.2 Secondary Analysis
The purpose of the clinical trial is to evaluate the end points described in the proto-
col. The secondary analyses would include evaluation of treatment and physics QA
data analysis to unveil how QA is linked to clinical outcomes. The importance of
protocol compliance in clinical trials and its impact on endpoints was reported in a
meta-analysis of the TROG 02.02 trial (a phase III trial evaluating the efficacy of
concurrent Cisplatin + Tirapazamine (TPZ) in chemoradiation of locally advanced
head and neck cancer) [20]. The results of a secondary analysis evaluating the
impact of protocol compliance showed a 2-year survival rate of 50% in the group
with significant deviations, which was clearly a poor outcome compared to 70% in
the protocol-compliant group. These results indicate that the quality of radiotherapy
has a significant impact on clinical outcomes.
Credentialing is a prerequisite for ensuring that participating institutions have
own adequate quality control structure. Furthermore, the procedures to efficiently
implement the physical QA are necessary to ensure the quality of radiotherapy
include standardizing the names of the ROI used by participating facilities in treat-
ment planning and the names of the dose indices; such as D95% and V20Gy [29, 30].
The JCOG1408 trial also standardized ROI nomenclature for target volumes and
critical organs, which has led to the collection of high-quality data that can be used
for subsequent secondary analyses.
Other secondary analyses have reported that IMRT reduced lung organ inflam-
mation predominantly compared to 3DCRT in the RTOG 0617 advanced lung can-
cer phase III trial[ref]. No dose-response analysis has yet been reported showing
IMRT to be superior to 3DCRT in clinical trials of SBRT in the lung. On the other
hand, in a treatment planning study of liver SBRT, the mean dose of the liver minus
GTV (liver-GTV) was found to be significantly lower for VMAT compared with
3D-CRT [31].
4.3 Perspective of Physics QA for SBRT
The next challenge for SBRT is Adaptive Radiation Therapy (ART) [32]: ART
requires real-time imaging, for which MRI-guided devices are expanding. ART
requires instantaneous plan modifications based on real-time images. For instanta-
neous plan modifications, an auto-contouring function is essential, and this is being
developed to include an Artificial Intelligence (AI) [33]. Several manufacturers
have already released products for auto-planning, but in SBRT, where VMAT is
becoming the basis for implementation, the efficiency of patient-specific QA is
likely to be the key to widespread use [34, 35].
Flash therapy is also considered to the effective for SBRT. Clinical application
has recently started, especially in proton therapy, and is expected to reduce damage
to OAR and enhancement of biological effects on the target, but there are many
issues to be addressed for widespread use and is still in the research phase [36, 37].
Adapting FLASH to SBRT would require even stricter standards for irradiation
positioning accuracy. To meet this, the current QA strategy is not sufficient, and a
new QA strategy is needed.
4.4 Conclusion
The biological effect of SBRT dose fractionation is very high, more than twice that
of conventional fractionation methods. In addition, because the number of fraction
is small, delivery errors are not averaged out, so more stringent QA is required than
with conventional treatments. To implement SBRT safely, continuing education of
medical staff are essential. There are two types of QA: those conducted on a facility-
by-facility basis and those conducted across multi-facilities. The latter is called an
independent. However, few institutions have yet conducted third-party evaluations
specific to SBRT, which accept any facilities. Credentialing in clinical trials can be
very helpful and facilities to start new SBRT programs may better to request assis-
tance from facilities participating in clinical trials.
SBRT technology is advancing, and in recent years it has become possible to
perform real-time motion tracking and to monitor organ motion with MRI. On the
other hand, real-time adaptive radiation therapy will require automated segmenta-
tions, automated treatment planning, and efficient patient-specific QA for each.
Moreover, ff FLASH therapy with ultra-high dose rate beams is adapted to SBRT in
the future, new QA strategies will be required because the tumor movement man-
agement such as respiratory motion will be more demanding.
It is not only for SBRT, but the development of QA techniques is vital to ensure
the quality of advanced radiation therapy. We must continue to develop QA strate-
gies to keep the quality of medical care.
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Chapter 5
Patient Immobilization, IGRT, Respiratory
Motion Management
Yu Kumazaki and Igari Mitsunobu
5.1 Image-Guided Radiation Therapy (IGRT)
5.1.1 Objective of IGRT
IGRT aims to improve clinical outcomes of radiotherapy and reduce side effects on
normal tissues by enabling precise irradiation of a target. In a narrow sense, it is a
matching technique that measures the amount of patient position displacement dur-
ing treatment based on two-dimensional (2D) images in two or more directions,
three-dimensional (3D) volume images, or 3D patient body surface information,
and reproduces the patient position relative to the treatment beam determined in the
radiation treatment plan to the extent possible. In a broad sense, it includes image-
based radiotherapy which uses computed tomography (CT), magnetic resonance
imaging (MRI), positron emission tomography (PET), ultrasound (US), and other
medical imaging modalities to accurately define the target and risk organs during
treatment planning, as well as diagnostic imaging and evaluation of the efficacy of
radiotherapy. For stereotactic body radiotherapy (SBRT), which has become popu-
lar in recent years, IGRT technology is used to increase the dose concentration on
the target and reduce the dose to normal organs surrounding the target by irradiating
beams with steep dose gradients from multiple directions. If a patient’s position
relative to the treatment beam is wrong, it may result not only in an insufficient dose
delivered to the target but also in serious damage to normal tissues. Although IGRT
Y. Kumazaki (*)
Radiation Oncology, International Medical Center, Saitama Medical University,
Saitama, Japan
e-mail: kumazaki@saitama-med.ac.jp
I. Mitsunobu
Radiation Oncology, Saitama Medical University, Saitama, Japan
e-mail: migari@saitama-med.ac.jp

Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_5
70 Y. Kumazaki and I. Mitsunobu
improves the accuracy of irradiation to the target, irradiation position error cannot
be reduced to zero even with IGRT. The margin to compensate for irradiation posi-
tion error should be set correctly based on an understanding of the characteristics of
each device and method of use. However, if the margin is increased, the advantages
of high-precision radiotherapy are lost. Therefore, it is important to safely reduce
the margin to compensate for irradiation position error in order for IGRT to be
effective. In addition to correcting irradiation position errors, IGRT also plays an
important role in identifying the shapes and changes in shape of organs, such as
target and risk organs, and in performing adaptive radiotherapy (ART) [1]. With
ART, the irradiation plan is modified according to the patient’s condition during the
irradiation period and can be categorized as online ART and offline ART [2]. The
former modifies the radiation treatment plan for each irradiation according to the
patient’s condition at the time of irradiation while taking into account irradiation
which has already occurred, while the latter modifies the plan prior to the next round
of irradiation. In recent years, online ART has become more accessible with the
advent of MR-Linac and gantry-based linear accelerators that can perform online
ART [3–5].
5.1.2 Uncertainties in IGRT
Radiotherapy requires the treatment beam isocenter to be aligned with the irradia-
tion center position determined in the treatment plan. However, given the difficulty
of reproducing the irradiation center position perfectly, some uncertainty exists in
this position. The irradiation center, or isocenter, is the reference point in three
dimensions that connects the three coordinate systems of the patient, the imaging
device, and the irradiation device. Uncertainty of the irradiation center position as
determined in the treatment plan can be broadly divided into geometric position
uncertainty associated with machines (e.g., gantry, collimator, treatment couch, and
imaging devices) and patient positioning uncertainty (e.g., skin marks, patient
motion, and organ motion). For the former, it is necessary to minimize the error by
performing quality assurance (QA) and quality control (QC) of radiotherapy equip-
ment, including imaging devices. For the latter, an appropriate target volume in
accordance with ICRU report 50, 62, and 91 should be determined based on the
irradiation method, patient immobilization method, patient positioning method, and
method of respiratory motion management [6–8]. In particular, ICRU report 62
defines the internal margin (IM) and setup margin (SM) in order to guarantee the
irradiation position by compensating for organ movement relative to the treatment
beam and uncertainty of patient position. IM and SM are generally added together
to provide the margin to the planning target volume (PTV). IM is a margin that
compensates for organ motion relative to a stationary skeleton as physiological
movements (e.g., respiration, pulsation, and intestinal peristalsis), as well as changes
in clinical target volume size, shape, and position. SM is a margin that compensates
for patient positioning errors during setup (just before irradiation) and during
5 Patient Immobilization, IGRT, Respiratory Motion Management 71
irradiation. IM and SM can be divided into those that occur inter-fractionally (per
irradiation) and those that occur intra-fractionally (during irradiation). If SM and
IM can be reduced, the dose and volume to normal tissues can be reduced and the
dose to tumors can be increased. Unlike the conventional margin setting for PTV, in
IGRT, it is necessary to set a margin calculated based on data such as the residual
difference between the planned position and the final patient position and patient
movement during treatment, and the margin must not be reduced without evidence.
The irradiation position error can be divided into systematic error and random
error. Systematic errors translate the beam profile and random errors blur the beam
profile (Fig. 5.1). The effect of the random error on the profile can be obtained by
integrating the probability distribution of the irradiation position error with the orig-
inal beam profile, which is referred to as the blurring effect [9]. Random errors in
irradiation position of a few millimeters have a small effect on the dose distribution,
but systematic errors have a large effect. Therefore, it is important to use IGRT to
reduce systematic errors in irradiation position errors.
5.1.3 IGRT Devices and Methods
In recent years, IGRT devices have been attached to linear accelerators, making it
easier to determine the patient’s irradiation position through image position match-
ing. Figure 5.2 [10, 11] shows the illustration of various IGRT devices. The IGRT
device is installed in the same room as the irradiation system, and its imaging sys-
tem must be capable of acquiring images to measure patient position displacement
based on the skeleton, metal markers, organ contours, and 3D patient body surface
information. 2D images using a gantry-mounted kV/MV imager and 3D images
using cone-beam CT are commonly used. Ceiling- and floor-mounted kV image
devices that can acquire fluoroscopic images from two or more directions have also
Fig. 5.1 Influence of irradiation position error on beam profile

Fig. 5.2 Illustration of various IGRT devices. Images are cited from each vendor’s website and
provided by each vendor. 1. TrueBeam (Varia Varian Medical Systems, Palo Alto CA, USA), 2.
Versa HD (Elekta AB, Stockholm, Sweden), 3. CyberKnife (Accuray, Inc., Sunnyvale, CA), 4.
Radixact (Accuray, Inc., Sunnyvale, CA. USA), 5. Catalyst (Elekta AB, Stockholm, Sweden), 6.
AlignRT [10] (Vision RT, London, UK), 7. ExacTrac Dynamic (Brainlab AG, Germany), 8.
SyncTrax [11] (SHIMADZU Co., Kyoto, Japan), 9. Clarity (Elekta AB, Stockholm, Sweden)
been introduced [12, 13]. There are also methods of patient positioning using medi-
cal images that do not use X-rays, such as the use of an US device for the prostate
gland [14], the attachment of an infrared marker to the patient’s body surface to
measure the patient’s position based on the marker position [15], and the use of a
CCD camera to obtain body surface information by shining a laser on the body
surface and using the distortion of the laser beam [16]. These devices can obtain
patient position information in real time. However, since they only provide location
information on the body surface, accuracy of the target location may be lower when
the target is located far from the body surface. There are also devices that receive
signals from the global positioning system (GPS) inserted into the target outside the
body to obtain 3D location information [17].
2D-kV/MV imaging is applicable when irradiating a site where the relative posi-
tional relationship between bone and target remains unchanged and allows for
quicker patient positioning compared to other IGRT systems. Usually, frontal and
lateral images of the patient are acquired to determine the irradiation position three-
dimensionally. However, image matching with 2D-kV/MV images only matches
the bone structure and does not confirm the target location. Bone matching has limi-
tations when the relative position of the bone and target changes, and IM compen-
sates for the shift of the target relative to the bone. In general, gantry-mounted
image devices require more time for image matching than ceiling- or floor-mounted
kV imagers, which are installed independently of the gantry because they must be
moved to the gantry angle for image acquisition. Therefore, in many cases, position
matching occurs only before irradiation. On the other hand, ceiling- and floor-
mounted kV imager systems are installed independently of the gantry and are not
dependent on the gantry angle and can be position-matched between beams.
Especially in SBRT, which makes extensive use of non-coplanar beams, systematic
errors can be reduced by performing position matching between beams and making
corrections. In addition, MV-X-ray images acquired by the Electronic Portal
Imaging Device (EPID) attached to the linear accelerator are used for linacgraphy,
which includes irradiation field information to confirm the irradiation position.
Furthermore, cine images can be acquired to allow real-time confirmation of the
beam passing through the body during irradiation. The cine images are also used to
monitor dose distribution in the body and are useful not only for in vivo dosimetry
to determine patient misalignment and anatomical changes during irradiation, but
also for detecting interplay effects in SBRT in the lung region [18, 19]. 3D image
matching by cone-beam CT (CBCT) allows the location of organs (soft tissues) in
the body to be determined, and target size and body shape changes to be confirmed.
IGRT plays an important role in ART, especially in the head and neck region, where
irradiation causes significant target and body shape changes. Furthermore, the
acquired CBCT images are fed back to the treatment planning system for off-line
image registration, which has the advantage of enabling evaluation of the irradiated
dose distribution. The CBCT system is indispensable for online ART which has
been introduced into clinical practice in recent years because ART is performed
using CBCT images. While the image quality does not need to be as high as that of
diagnostic images, it must be high enough to allow adequate deformable registra-
tion for ART. However, if the image cannot be reconstructed by respiratory phase at
the site of respiratory motion, the image will include all respiratory phases.
Since the image quality of CBCT images is inferior to that of CT systems used
in diagnostic fields, it is sometimes difficult to accurately determine the target con-
tour; marker matching using fiducial markers is also performed. Especially in
ground-glass opacity lung cancer, it may be difficult to visualize with CBCT. In
such cases, the marker can be placed in or near the target for indirect target location
matching. Since it is important that the positional relationship between the marker
and the target does not change between treatment planning and irradiation, a treat-
ment planning CT should be taken several days after the marker is implanted in the
body to minimize misalignment of the gold marker. In particular, when performing
respiratory gating irradiation or dynamic tracking irradiation based on a marker
inserted in the lung, it should be confirmed before irradiation that the relative posi-
tions of the target, and the marker have not changed from the planned positions
because gold markers are easily misaligned. In addition, when a gold marker is
implanted in a location other than the lungs, a CT scan for treatment planning should
be taken several days after implantation. In some cases of CT-guided marker place-
ment in the liver, there have been reports of marker migration due to the placement
of markers in the hepatic vein [20]. In position matching using fiducial markers,
position correction of 6D (3 axes of translation and 3 axes of rotation) is
theoretically possible when three or more gold markers are implanted. However,
when the markers are near each other, a slight misalignment of the markers relative
to the rotation axis can cause a large rotation position error. Thus, it is important to
confirm beforehand that there are no issues with the metal marker position in the
beams eye view at the angle to be image-matched.
5.2 Patient Immobilization
5.2.1 Objective of Patient Immobilization
The purpose of patient immobilization in radiotherapy is to reproduce the patient’s

body position at the time of treatment planning during irradiation in order to match
the treatment beam as closely as possible to the irradiation center determined at the
time of planning and to reduce the uncertainty of the irradiation position with
respect to the patient. In addition to reproducibility of the patient’s position imme-
diately prior to treatment, accuracy of patient immobilization is required to maintain
the patient’s position in order to reduce patient movement during irradiation. This is
generally evaluated as the difference in skeletal position where there is little move-
ment due to respiration and other factors. Recent radiation therapy systems are
increasingly equipped with a couch capable of 6-axis correction. However, since it
is not possible to correct for twisted patient positioning, it is still important to set up
the patient with good reproducibility of patient positioning.
5.2.2 Immobilization Devices
In SBRT, the treatment time is longer than in conventional therapy because an ultra-
high dose is delivered for each irradiation, and the treatment time is even longer in
cases for which respiratory gating irradiation is used. Therefore, immobilization
devices that can hold the patient in a stable position for a long period of time are
necessary to achieve high irradiation position accuracy. Because the accuracy and
reproducibility of patient positioning in SBRT are not sufficient with conventional
immobilization methods, “Body Frames” for SBRT were used before the introduc-
tion of image-guided technology, and a combination of this box-shaped device and
vacuum bags was widely used for immobilization. The vacuum bag can be flexibly
shaped to fit the patient’s body shape, allowing for a good reproduction of the
patient’s position at the time of treatment planning. Several patient immobilization
devices for SBRT have been available from various manufacturers, and some of
these devices have the capability of abdominal compression to control respiratory
motion (Table 5.1). Patient positioning combined with image-guidance technology
is now the mainstream, and the best immobilization device should be selected based
on the patient positioning and irradiation methods used at each facility.
Table 5.1 List of immobilization devices for SBRT

Immobilization devices Manufacturers
Stereotactic Body Frame/Body Fix Elekta AB, Stockholm, Sweden
kVue™ SBRT DoseMax™ Solution Qfix, Avondale, PA, USA
SBRT Solution Orfit Industries Nv, Wijnegem, Belgium
Body Pro-LokTM System CIVCO, Orange City, IA, USA
Esform Body Support system ENN-3000 Engineering System, Matsumoto, Japan
Vac-Loc CIVCO, Orange City, IA, USA
Blue BAG Elekta AB, Stockholm, Sweden
ESFORM Engineering System, Matsumoto, Japan
VacQfix™ Qfix, Avondale, PA, USA
Table 5.2 Reports on patient positioning accuracy with immobilization devices

Immobilization Setup accuracy [mm]
Reference device Site IGRT A-P L-R S-I
Wulf et al. [21] SBF Lung/Liver/Spine Port film 2.2 3.9 3.5
Guckenberger BodyFIX Lung CBCT 2.6 ± 1.1 1.8 ± 2.0 3.2 ± 2.1
et al. [22] (Elekta)
Kosj et al. [23] BodyFIX Spine ExacTRAC 0.77 ± 0.6 0.64 ± 0.4 0.57 ± 0.4
(Elekta)/ (0.03–2.26) (0.05–1.57) (0.01–1.33)
Head-shoulder
mask (CIVCO)
Foster et al. SBF with Lung CBCT 0.58 ± 1.75 0.08 ± 1.31 0.36 ± 1.29
[24] Vacuum pillow (compressed)
Lung 0.25 ± 1.25 0.05 ± 0.90 0.03 ± 1.24
(uncompressed)
Liver 0.17 ± 0.82 0.08 ± 1.07 0.13 ± 1.62
Prostate 0.46 ± 1.26 −0.28 ± 1.42 0.73 ± 1.65
Spine −0.10 ± 1.04 0.06 ± 1.05 0.38 ± 1.23
Ueda et al. [25] BodyFIX Lung CBCT 3.0 5.1 3.5
(Elekta)
BF (CIVCO) 4.8 4.6 5.4
Hansen et al. SBF + Vacuum Lung/Liver – 3 2 4
[26] cushion
Jan-Jakob et al. w/o frame Lung CBCT 0.6 0.2 0.6
[27] (arm/knee
support)
5.2.3 Setup Accuracy Using Immobilization Devices
Various reports have evaluated the accuracy of patient positioning with immobiliza-
tion devices in SBRT, as summarized in Table 5.2. While patient positioning accu-
racy improves with the use of immobilization devices, it is known that in sites
associated with respiratory motion, such as the lungs and liver, there is a baseline
shift in which the tumor position is displaced by several millimeters relative to the
bone structure when the tumor is positioned with respect to a bone structure such as
the vertebral body [21, 22]. Therefore, there are limits to patient positioning based
only on the patient’s bone structure as a surrogate. The combination of patient posi-
tioning with patient fixation devices and image-guidance techniques is now becom-
ing the standard, and the appropriate use of these multiple techniques enables SBRT
to be performed with even higher radiation positioning accuracy [22–25, 27].
5.2.4 Influence on Dose Distribution
Dose changes are caused by components that reside outside the patient’s body, such
as treatment beds and immobilization devices. Patient immobilization devices are
required to restrain patient movement in order to maintain the patient’s position, and
it is also important that the immobilization devices be made of low-absorption
materials so that the radiation treatment beam passing through them does not sig-
nificantly affect the dose distribution. Components that are in close contact or prox-
imity to the patient behave like a bolus and increase the patient’s skin dose, while
components that are located away from the patient behave primarily as attenuators
or scatterers and reduce the dose to the target, potentially altering the dose distribu-
tion. In recent years, carbon fiber couch tops are commonly used for newly intro-
duced treatment devices, replacing the previously used gut-type couches. In
addition, rotational irradiation is increasingly being employed in place of fixed irra-
diation, in which the gantry is stopped, and the proportion of the dose that passes
through the patient’s dorsal bed to the patient increases [28]. When the target is
located near the patient’s dorsal body surface, it may cause more pronounced skin
toxicity due to the high dose being delivered in close proximity to the treatment bed
or immobilization device [29]. If the dose distribution is created ignoring the pres-
ence of couches and fixation devices, skin doses will be underestimated; therefore,
treatment planning should take into account dose changes caused by these devices.
Even if the treatment plan accounts for attenuation caused by the couch and immo-
bilization device, the dose distribution will change if their position relative to the
patient changes during irradiation. This problem can be solved by using an index
bar so that the patient and couch are uniformly positioned during each irradiation.
5.3 Respiratory Motion Management
5.3.1 Objective of Respiratory Motion Management
The purpose of patient respiratory motion management (RPM) is to determine the

extent of respiratory motion of the target under reproducible respiration and to pro-
vide the patient with radiation therapy using clinically optimal irradiation
techniques. In the lungs and liver, which are the targets of SBRT, the target tumors
are constantly moving as the patient breathes. Without knowing the range of respira-
tory motion of the target, an appropriate irradiation field cannot be set for the target
location to be within the irradiation field. The clinically optimal irradiation tech-
nique should be selected and the appropriate IM should be set after evaluating respi-
ratory motion. If the target size is small, the irradiation range to account for
respiratory motion is clinically acceptable. However, if the target size is somewhat
large, the irradiation range to be expanded is too large to be clinically acceptable for
SBRT, which delivers a large dose at a time, and respiratory synchronized irradia-
tion or dynamic tracking irradiation is selected. Respiratory synchronized irradia-
tion and dynamic tracking irradiation are also selected when the target size is small
but risk organs are located near the target and the irradiation field cannot be
expanded. Thus, RPM is important because the appropriate irradiation technique for
the patient depends on the amount of respiratory motion of the target. In addition,
because treatment planning is based on the patient’s respiratory status at the time the
respiratory motion is assessed, respiratory management is necessary to ensure
reproducible breathing.
5.3.2 RPM Methods
Respiratory motion countermeasures should be taken against organ motion due to

respiration, which is the largest contributor to IM in the thorax and abdomen. As
with patient positioning, respiratory motion requires consideration of the inter-
fractional reproducibility of respiratory status and intra-fractional retention of respi-
ratory status during irradiation. Respiratory motion is particularly large near the
diaphragm, and the irradiation volume becomes too large to be clinically acceptable
without countermeasures to reduce IM, especially when performing
SBRT. Countermeasures include methods to reduce the range of respiratory motion
(abdominal compression method, respiratory learning method, breath-hold method)
and methods to reduce the range of irradiation by taking respiratory motion into
account (respiratory synchronization method, dynamic tracking method) [30]. The
following list provides a summary of RPM methods that have been implemented in
many facilities.
(a) Oxygen inhalation method: Keep breathing shallow or facilitate breath holding
by allowing the patient to inhale oxygen. Oxygen inhalation alone may not be
an effective RPM and is used in combination with other methods.
(b) Abdominal compression method: Abdominal compression of the patient’s
abdomen using a compression plate, band, or body shell to reduce the range of
respiratory movement by forcibly inhibiting diaphragmatic movement. In this
method, the amount and direction of respiratory motion of the target change
depending on the degree of abdominal compression, so it is important to repro-
duce the abdominal compression at the time of treatment planning CT during

irradiation.
(c) Respiratory learning method: This method corrects the patient’s irregular respi-
ratory state with a metronome or voice guidance, which reduces uncertainty in
the range of respiratory motion. The patient’s understanding and cooperation
are necessary, and sufficient explanation should be provided in advance.
(d) Breath-hold method: This method includes active breathing control and self-
breathing hold using two-point thoracoabdominal respiratory monitoring. The
method reduces IM by acquiring CT images during breath-hold and irradiating
at the same breath-hold phase during irradiation. Since reproducibility of the
patient’s breath-hold position is important, the patient is allowed to monitor the
respiratory waveform to improve the reproducibility of the breath-hold position.
(e) Respiratory gating method: This method involves irradiation of the patient only
in the respiratory phase determined at the time of treatment planning while
monitoring respiration using infrared reflective markers placed on the patient’s
body surface. The method reduces ITV compared to irradiation in all respira-
tory phases. Since respiratory gating irradiation may not work if the patient’s
breathing is unstable or irregular, prior visual or auditory coaching may help to
resolve these problems.
(f) Real-time tracking method: This method predicts the target position and tracks
irradiation while monitoring markers on the body surface by constructing a
position correlation model that relates the movement of infrared reflective
markers attached to the patient’s body surface to the position of targets inside
the body or fiducial markers inserted into the body. If the tumor cannot be rec-
ognized with kV X-ray images, tracking irradiation is performed using a fidu-
cial marker placed in or around the target as a surrogate. The change in the
positional relationship between the target and the marker during each respira-
tory phase corresponds to the ITV.
5.3.3 Evaluation of RPM
In the treatment of tumors located in areas with respiratory motion, such as the
lungs, it is necessary to evaluate IM appropriately and set margins according to the
irradiation method. X-ray fluoroscopy, CT, cine-MRI, and US systems are used to
assess the extent of respiratory motion of the tumor prior to treatment, but here we
describe respiratory motion assessment with CT, the most commonly used method.
There are four major imaging methods for IM evaluation in conventional CT: (1)
long scan time CT under free expiration, (2) CT with maximal expiration/inspira-
tion stop, (3) prospective four-dimensional (4D) CT, and (4) retrospective
4DCT. However, there are issues with CT volume data for respiratory assessment
obtained using the above four methods. In method (1), time-consuming CT imaging
per cross-section is used to image the range of target motion, but the position and
shape of the target in each respiratory phase cannot be determined. In addition,
voxels in areas where the probability of tumor presence is low may have low CT
values, obscuring the boundaries around the target and making it difficult to estab-
lish an accurate IM. In method (2), images are taken during the patient’s expiration/
inspiration stoppage, but the respiratory state is not always the same as that during
free breathing and may not reproduce the tumor position during expiration/inspira-
tion during free breathing. Furthermore, IM may be underestimated when the target
motion is curved (Fig. 5.3). In method (3), CT imaging is performed in synchrony
with a specific respiratory phase while monitoring the patient’s respiratory wave-
form. In method (4), CT imaging is performed under free breathing, and images are
sorted by respiratory phase for image reconstruction. Methods (3) and (4) tend to
produce artifacts during image reconstruction because the projection data for image
reconstruction are data for a certain range of respiratory phases. In Fig. 5.4, the
patient’s respiratory state is not constant, causing blurring and image discontinuities
around the target and diaphragm due to respiratory phase error. Therefore, it is dif-
ficult to accurately assess respiratory motion of the target using conventional 4DCT
imaging methods. The 320-row multidetector 4DCT is expected to solve the above
issues by eliminating temporal errors to the extent possible and acquiring volume
data in time series [31, 32]. This device has already been used in the diagnostic
radiology field and is expected to be useful in the radiation therapy field. In the dose
distribution created by the combination of beams that irradiate a part of the target,
such as IMRT, it is possible that a high-dose portion and a low-dose portion are
generated in the target due to the shift of the target and irradiation area, which is
known as the interplay effect. If this error is a random error, its effect will be aver-
aged out as the number of irradiations increases, but the effect may become appar-
ent in SBRT with a few irradiation fractions.
Fig. 5.3 Comparison of combined expiratory and inspiratory images and combined total respira-
tory phase
Fig. 5.4 Presence of respiratory phase error by 4DCT imaging
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Chapter 6
Dose Calculation Algorithm
Satoru Sugimoto, Tatsuya Inoue, and Jun Takatsu
Stereotactic body radiation therapy (SBRT) is a technique that provides high radia-
tion doses with a steep dose gradient between a target volume and surrounding
normal tissues in a few fractions. This technique generally uses a small irradiation
field size for treatment planning and dose delivery. However, small fields can cause
problems in dosimetry, such as lateral electron disequilibrium (LED) [1]. The effect
is the leading cause of inaccuracies in dose calculation algorithms since measure-
ment data is required in algorithm configuration. Therefore, understanding the char-
acteristics of each dose calculation algorithm is one of essential things for
conducting SBRT.
6.1 Basics of Dose Calculation Algorithm
The fundamental equation in radiotherapy dose calculation is the linear Boltzmann

transport equation (LBTE) [2–4]. The LBTE describes the macroscopic behaviors
of photons and electrons in mediums (patients or phantoms). The LBTE can be
solved analytically only for simple cases. The direct solution of the LBTE can be
obtained using the Monte Carlo method (MC) [5, 6] or the grid-based Boltzmann
solver (GBBS) [2–4]. Both for MC and GBBS, intensive numerical calculations and
S. Sugimoto (*) · J. Takatsu

Department of Radiation Oncology, Juntendo University, Tokyo, Japan
e-mail: ssugimot@juntendo.ac.jp
T. Inoue
Department of Radiation Oncology, Juntendo University, Tokyo, Japan
Department of Radiology, Juntendo University Urayasu Hospital, Chiba, Japan

Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_6
84 S. Sugimoto et al.
much time are necessary for obtaining accurate results. Therefore, dose calculation
algorithms that approximately reproduce the MC or GBBS results with reasonable
calculation time have been introduced.
6.1.1 Model-Based Algorithm
Currently, the dose calculation algorithms used in commercial treatment planning

systems (TPS) are mainly model-based. In the model-based algorithm, instead of
directly solving the LBTE, the generation, transportation, and reaction of photons
and electrons in a medium are described with models, which simplify the complex
behaviors of photons and electrons in a medium and capture the essence of them.
The model-based algorithms give approximate solutions of the LBTE and contain
systematic errors from the exact solution. These errors should be carefully consid-
ered when applying model-based algorithms to inhomogeneous regions like lungs.
Radiation generation devices like a linear accelerator head are also modeled in the
model-based algorithms. The model-based algorithms include parameters deter-
mined from measurements and the MC simulation. Once the model parameters are
determined, the dose in a patient in all conditions can be calculated.
The model-based algorithms, including MC and GBBS, can be categorized by
inhomogeneity correction algorithm in the American Association of Physicists in
Medicine (AAPM) TG-65 report [7] and Knöös et al. [8]. For SBRT, the most prob-
lematic situation occurs for a small tumor in a lung, where LED causes complex
behavior of dose distribution. Figure 6.1 shows a percent depth dose (PDD) in a
1 × 5 cm2 field. A slab of lung material (ρ = 0.25 g cm−3) is inserted between 4 and
12 cm depths. A large dose reduction is observed in the lung region due to LED. The
pencil beam algorithm cannot reproduce the reduction, which does not treat changes
in lateral electron transport. Therefore, model-based algorithms applied in such
situations should appropriately consider the lateral electron transport. The recent
recommendations [10–12] allow only the algorithms which consider changes in the
lateral electron transport in a more or less approximate way (Category 4 in AAPM
TG-65 report or Type-B in Knöös et al.) in at least heterogeneous media. Table 6.1
summarizes the types of dose calculation algorithms adopted in this chapter.
Fig. 6.1 6 MV 100 cm SSD depth dose curves (top) and profiles at 10 cm depth (bottom) in a
water/lung/water phantom using Monte Carlo, superposition (collapsed cone convolution, CCC),
and pencil beam dose calculation. Note the good agreement between water/lung/water phantom for
narrow 1 × 5 cm2 fields as calculated by the Monte Carlo and superposition depth dose and dose
profile curves, and the overestimation of the pencil beam depth dose curve within the lung and the
underestimation of the lateral dose spread within the lung region. The water/lung/water phantom
had a slab of lung material (ρ = 0.25 g cm − 3) inserted between 4 and 12 cm. Adapted from Jeraj
et al. [9] with permission
6 Dose Calculation Algorithm 85
Table 6.1 Types of dose calculation algorithms. They are adopted and modified from Knöös et al.
[8] and Ojala [19]
Type Description Algorithm
A Models primarily based on equivalent path length scaling for Pencil beam
inhomogeneity corrections. Changes in lateral transport of
electrons are not modelled.
B Models that in an approximate way consider changes in lateral Convolution/
electron transport. superposition, AAAa
C Models that in an explicit way consider changes in lateral Monte Carlo method,
electron transport. GBBSb
a
Analytical anisotropic dose calculation algorithm. AAA can be classified as an intermediate
between Type-A and Type-B algorithms [11].
b
Grid-based Boltzmann solver
6.1.1.1 Convolution-Superposition Algorithm
One of the most common Type-B algorithms is the convolution-superposition (CS)

algorithm [13, 14]. In the CS algorithm, instead of transporting secondary electrons
produced by primary photons explicitly, a point kernel that represents dose distribu-
tion per unit TERMA (total energy release per unit mass) is used. The point kernel
is obtained from the MC simulation in water. When the CS algorithm is applied to
homogeneous water, the calculated dose is equivalent to those obtained from the
MC simulation without modification of the point kernel.
In a heterogeneous medium, the point kernel is modified to consider the lateral
electron transport by rescaling the dose kernel using the average density between
the TERMA deposition point and the dose deposition point. With the modification
of the point kernel, the change of the electron path length due to the change in the
density of the medium is approximately considered. In the CS algorithm, the travel-
ing direction of the secondary electrons affects the lateral electron transport. The
comparison between the CS algorithm and the MC indicates that the CS algorithm
works adequately in a 4 cm2 × 4 cm2 with a lung heterogeneity for lung densities
equal to or exceeding 0.3 g cm−3 and a dose calculation uncertainty increases when
lung density becomes smaller than 0.3 g cm−3 in small fields [15].
6.1.1.2 Analytical Anisotropic Dose Calculation Algorithm
The analytical anisotropic dose calculation algorithm (AAA) [16] was a pencil
beam (PB) algorithm with the modification to consider the lateral electron transport.
The simple pencil beam (PB) algorithm is a Type-A algorithm, which is primarily
based on equivalent path length scaling along the propagation direction for inhomo-
geneity corrections (Table 6.1). It does not consider the change of the lateral elec-
tron transport. In AAA, the pencil beam kernel is scaled by electron density, with
the scaling performed in the lateral direction to consider the change of the lateral
electron transport in an inhomogeneous medium. The forward-directed nature of the
secondary electron is approximately treated by introducing the buildup kernel.

Therefore, AAA can be classified as an intermediate between Type-A and Type-B
algorithms [11]. AAA is known to break down for small fields in regions involving
significant density variation [17].
6.1.2 MC and GBBS
The approaches to solving the LBTE by MC and GBBS are quite different. In MC,
the trajectory of a photon or electron in a medium is traced particle by particle. The
interactions of the particles and the medium are provoked statistically with proba-
bilities governed by the cross section between the particles and the medium. In
GBBS, the space is discretized into the grid, and the angular direction is also dis-
cretized. The photon and electron angular fluences are solved in the discretized grid
space. Their formulations are complicated and not further explained here. Details of
them can be found in references [2, 3, 5].
Both MC and GBBS treat electron transport directly. Therefore, they can take
account of the lateral electron transport in inhomogeneous media accurately com-
pared to the CS algorithm. MC and GBBS can be considered the advanced Type-B
algorithm. Ojala et al. categorized them as the most sophisticated dose calculation
algorithms (Type-C) [18, 19] (Table 6.1). However, MC and GBBS used in com-
mercial TPSs include the approximations to reduce calculation time to a reasonable
length; therefore, uncertainty originating from the approximations exists. They also
have the uncertainty from physical quantity like cross sections. Uncertainties in
GBBS are primarily of a systematic nature (e.g., cross sections, approximations
made during implementation, and resolution of discretization) [4]. MC includes
statistical uncertainty from its stochastic nature in addition to those of a systematic
nature [6]. Most TPSs implementing MC allow users to run the calculation with a
prerequisite statistical uncertainty.
6.1.3 Medium of Dose Deposition and Radiation Transport
Dose calculation algorithms calculate absorbed dose in a patient. The dose is

reported in dose-to-medium in medium (Dm,m), dose-to-water in medium (Dw,m), or
dose-to-water in water (Dw,w) in a TPS [20]. The dose-to-am in tm (Dam,tm) represents
the medium of dose deposition is am, and the medium of radiation transport is tm in
dose calculation. The difference among Dm,m, Dw,m, and Dw,w is approximately 1% in
soft tissue. For lung and bone, the differences can become more than several per-
cent. Figure 6.2 shows Dm,m, Dw,m, and Dw,w calculated using commercial TPSs,
Eclipse (Varian, USA) and Monaco (Elekta, Sweden), and Xio (Elekta, Sweden) in
a slab geometry consisting of water, bone, and lung. The AAPM TG-329 report [20]
offers information on which framework of dose calculation is adopted in a TPS.
a b
Fig. 6.2 The depth dose curves through slabs of different media with a 6 MV beam calculated
with (a) Eclipse Acuros XB (AXB, GBBS) dose to water (Dw,m) and dose to medium (Dm,m) and
AAA (Dw,w), (b) Monaco MC dose to medium (Dm,m) and dose to water (Dw,m) and Xio (CS, Dw,w).
Adapted from Kry et al. [21]
6.2 Comparison of Dose Calculation Algorithms for SBRT
Comparisons of dose calculation algorithms have been demonstrated in many phan-

tom and clinical studies. Chopra et al. investigated the dosimetric accuracy of five
dose calculation algorithms, Pencil Beam Convolution (PBC), Collapsed Cone
Convolution (CCC), Anisotropic Analytical Algorithm (AAA), Acuros XB (AXB),
Monte Carlo method (MC), for small open fields, which were incident on a water-
equivalent homogeneous phantom. PBC, CCC, and AXB implement the PB algo-
rithm, CS algorithm, and GBBS, respectively. The results showed there was
excellent agreement between all types of algorithms and measured PDDs/dose pro-
files. The dose difference between calculation and measurement was within 1.5%
for all algorithms [22]. For clinical liver SBRT, except for the case where a tumor
was close to the diaphragm, the target dose difference between the two algorithms,
AAA and AXB, was reported only in the range of 1% [23].
Although the dose differences between all types of calculation algorithms in
homogeneous media were negligible, larger differences between the calculation
algorithms were observed in inhomogeneity regions, including bone, lung, and soft
tissue. Tissue inhomogeneity between the high-density tumor and the surrounding
low-density tissue, where electronic disequilibrium becomes larger with decreasing
field sizes, complicates dose calculation [24].
6.2.1 Issues in Clinical Cases with Low-Density Material
Many studies have investigated the dosimetric differences between Type-A or

Type-B and Type-C algorithms for lung SBRT plans. Ojala et al. evaluated the accu-
racy of three dose calculation algorithms, PBC, AAA, and AXB, against a full MC
simulation for small lung tumors [18]. They demonstrated AXB showed a good
agreement with MC, while mean dose to smaller-sized PTVs had discrepancies up
to 20% and 60% for AAA and PBC, respectively. Figure 6.3 shows the representa-
tive isodose distributions and dose-volume histograms for lung SBRT plans with
three algorithms (PBC, AAA, and AXB) [25]. It has been reported that the PBC
algorithm can often lead to overestimating a target peripheral dose as high as 50%
[26]. This is because the PBC algorithm does not properly account for lateral elec-
tron scattering. AXB is considered a Type-C algorithm because the algorithm would
theoretically converge to the same solution as the MC algorithm. The dose calcula-
tion accuracy has been reported to be comparable to that in the full MC simulation
[27–29]. Tsuruta et al. reported that AXB values agreed with MC values within
3.5% for all dose indices in a population of 147 lung cancer patients treated by
Fig. 6.3 The isodose distributions in the axial slice at the isocenter and dose-volume histogram of
lung SBRT plans for the same patient calculated from the three algorithms. The red line was PTV,
the green line is the isodose line of prescription dose 5000 cGy (100%), and the light blue line is
an isodose line of 2500 cGy (50%). Adapted from Zhang et al. [25]. (OncoTargets and Therapy
2019:12 6385-6391 Originally published by and used with permission from Dove Medical
Press Ltd.)
SBRT [29]. Bush et al. found that dose calculation by AXB agreed with MC within
2.0% in regular lung material and within 2.9% in low-density lung material. The
difference between AAA and MC was up to 10.2% and 17.5%, respectively [30].
Han et al. reported that the CCC and AAA algorithms overestimated dose by
approximately 4.6% and 11.6% in the lung region compared to the MC and AXB
algorithms [28]. In general, kernel-based algorithms (Type-B) overestimate the
dose within the interface between the air/lung and the tissue due to their incapability
to model the electron-photon coupled transport across the interface to account for
scattered photons and the loss of electronic equilibrium. AAA is known to underes-
timate the dose in the lung surrounding the tumor but overestimates secondary
buildup in the lung-tumor interface, leading to a higher dose in the GTV region [31].
The CCC algorithm also had a large difference in the buildup region because this
algorithm does not accurately model the buildup region when entering from a low-
density to a high-density region [32].
6.2.2 Issues in Clinical Cases with High-Density Material
Accurate dose calculations in spine SBRT are also more difficult than those for
homogeneity tissues because of the increased atomic number in bone. Zhen et al.
investigated the dosimetric differences between IMRT and VMAT treatment plans
calculated with AXB, CCC, and AAA for spine SBRT [33]. The study found CCC
gives a statistically significant overestimation of the target dose, and AAA underes-
timates the target dose with no statistical significance compared to AXB [33]. The
overestimation in dose calculations by the CCC algorithm can be explained by
improper scaling of the water-derived dose deposition kernels due to the greater
scattering power from the higher atomic number of bone. Compared with Type-B
algorithms, MC algorithms report dose-to-medium (Dm,m), resulting in different
doses due to differences between the electron-stopping powers in bone and water
[34]. The dose-to-water (Dw,m) conversion in the lung case produces a negligible
difference [35, 36]. However, The difference between Dm,m and Dw,m is most dra-
matically seen in bone, where the electron-stopping power difference from water is
up to 10% [37]. Hardcastle et al. compared dosimetric results of spine SBRT plans
calculated using the AAA algorithm with those recalculated with the AXB algo-
rithm, which reported both Dm,m and Dw,m [34]. They showed reporting Dm,m and
Dw,m results in substantial differences in GTV dose, which depended on the density
of the bone in a target. Lytic lesions exhibited a minimal difference between AAA
and either reporting mode for AXB; however, increased CT number in blastic
lesions resulted in GTV D50% differences of up to 3.5% with Dm,m and 6% with
Dw,m. Differences between AXB Dm,m and AXB Dw,m were more significant; GTV
D50% was 2–9% higher when calculating with AXB Dw,m compared with AXB Dm,m
(Fig. 6.4). Generally, the Dm,m calculation in bone has shown better agreement with
AAA and CCC than Dw,m [28]. Careful consideration is necessary for selecting the
dose reporting mode for spine SBRT.
Fig. 6.4 (a) Dose distributions for a lytic lesion (top) and blastic lesion for AAA, AXB Dm,m, and
AXB Dw,m algorithms. The segmentations displayed are the GTV (red), PTV (vertebral body, cyan
and green), and spinal cord PRV. The white vertical line on the CT image shows the location of the
dose profile in (b). (b) Dose profiles along the white line in (a) for the lytic lesion (top) and blastic
lesion (bottom). Adapted from Hardcastle et al. [34]
6.2.3 Impact of Dose Prescription
Most previous clinical trials have used the dose-to-water algorithm to assess the
dose to tumors and normal tissues. For example, Nagata et al. reported a 45-month
outcome of 48 Gy in 4 fractions using the pencil beam algorithm for stage I non-
small cell lung cancer (NSCLC) (JCOG0403) [38]. Kimura et al. evaluated the effi-
ciency of SBRT using the superposition algorithm for centrally located stage IA
NSCLC (JROSG10-1) [39]. Recently, Videtic et al. reported the results of a clinical
trial using either a superposition or Monte Carlo dose algorithm (RTOG 0915/
NCCTG N0927) [40].
Dosimetric differences between dose calculation algorithms were also affected
by prescribing in the isocenter point or the PTV volume. Sarkar et al. found that
dosimetric differences between the Monte Carlo and model-based algorithms were
smaller for the point prescription than for the volume prescription [41]. Therefore,
the prescription method is as important as the calculation algorithm when referring
to previous studies for dose prescriptions and dose constraints.
Latifi et al. reported the local control for the same prescription dose of 50 Gy in
5 fractions with the PB and CCC algorithms [42]. A significant difference in recur-
rence rates between PB and CCC was investigated. The CCC algorithm signifi-
cantly reduced the recurrence rate more than the PB algorithm. This result could be
attributed to dose calculation inaccuracy of the PB algorithm, which did not provide
sufficient dose to a target in a low-density region. The type of dose calculation algo-
rithm used in dose calculation and reporting can greatly impact outcomes like local
control. However, technological developments such as improved accuracy of IGRT,
VMAT technique, and FFF beam have also contributed to treatment outcomes using
newer generation algorithms. It is important to note that the difference in local con-
trol cannot be solely due to the difference in dose calculation algorithms.
6.2.4 Impact of Dose Grid Size
Another important factor affecting the calculated dose for SBRT is dose calculation
grid size. In general, the smaller grid size reduces the averaging effect and results in
a better sampling of the structure voxels to the dose calculation grid [43]. The dose
calculation accuracy will decrease if large grid sizes are used in regions with steep
dose gradients, such as the penumbra, the buildup region, and the tumor periphery.
Kroon et al. compared 1 mm with 2.5 mm grid sizes for AAA and AXB for small
lung tumors. They found no statistically significant differences between the two grid
sizes for all AAA parameters. However, they found significant differences for PTV
D2% (near-maximum dose) in AXB [17]. They explained this difference by the sig-
nificantly improved accuracy of AXB under the conditions of electronic disequilib-
rium compared to AAA. Huang et al. investigated the impact of calculation grid size
on the dose differences of PTV with a density in the lung range (PTV_lung) between
the AXB and AAA algorithms [44]. They demonstrated that when a 1 mm grid size
was used, the dose difference in PTV_lung between the two algorithms was greater
than a 2.5 mm grid size (Fig. 6.5). The dose grid size should be selected carefully in
clinical practice. It has been recommended to use a uniform grid size of 2 mm or
smaller for SBRT planning [10].
Fig. 6.5 The

representative dose-volume
histogram of PTV_lung
(PTV with a density in the
lung range) calculated by
different algorithms and
calculation grid sizes for a
lung SBRT plan. Adapted
from Huang et al. [44]
6.3 Recommendations
There are several recommendations for dose calculation algorithms which should
be used in SBRT. The Type-A model-based algorithm should not be used in
SBRT. The AAPM TG-101 [10] and The ICRU report 91 [11] recommend using the
CS algorithm and above under the conditions of LED, such as the lung tissue inter-
face or tumor margin in a low-density medium. The ICRU report 91 explicitly rec-
ommends point kernel CS models as clinically acceptable for calculations in tissues
involving lung densities of around 0.3 g cm−3 for field sizes of 4 cm2 × 4 cm2 and
larger; the AAA is not recommended using in such circumstances. The Type-C
algorithms, such as MC techniques and GBBS, are recommended if available, espe-
cially for small fields with tissue heterogeneity.
For consistent interpretation of the clinical outcome of treatment, the media of
dose deposition and radiation transport in calculating and reporting dose should be
consistent. As a general recommendation, the Global Harmonization Group (GHG)
[21] recommends calculating and reporting doses in a Dm,m framework where pos-
sible. The GHG mentions that reporting dose in Dw,w is acceptable when a TPS does
not allow the user to select the medium of dose calculation. The GHG does not
recommend conversion from Dm,m to Dw,m. The AAPM TG-329 report [20] offers the
correction factors to obtain Dm,m in soft tissue from calculated doses for many com-
mercial TPSs.
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(JROSG10-1). Int J Clin Oncol. 2017;22:849–56.
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peripheral non-small cell lung cancer. Int J Radiat Oncol. 2019;103:1077–84.
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bution differences from five algorithms implemented in three commercial treatment planning
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42. Latifi K, Oliver J, Baker R, Dilling TJ, Stevens CW, Kim J, et al. Study of 201 non-small cell
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dence on dose calculation algorithm. Int J Radiat Oncol Biol Phys. 2014;88:1108–13.
43. Kan MWK, Leung LHT, Yu PKN. Dosimetric impact of using the acuros XB algorithm for
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Chapter 7
Treatment Planning
Mitsuhiro Nakamura
7.1 Respiratory Motion
The American Association of Physicists in Medicine (AAPM) has reported that the
degree to which tumors in the chest and abdomen move during respiration varies
widely [1]. Seppenwoolde et al. found that the movement of the tumor with respira-
tion was maximum in the cranial-caudal (CC) direction in the case of a tumor of the
lower lobe of the lung and was mostly elliptical when the tumor was located anterior
to the thorax [2]. Barnes et al. found that the mean extent of motion of tumors in the
lower lobes of the lungs was significantly greater than that of tumors in the middle
or upper lobes of the lung or mediastinal tumors [3]. Using volumetric cine com-
puted tomography (CT), Mori et al. showed that pancreatic tumors moved more
than 10 mm in the inferior direction during respiration and that geometric changes
were greater near the tail rather than the body or head of the pancreas [4]. In addi-
tion, it is well known that respiratory patterns change both in magnitude and period
and expiratory baseline drift of the respiratory signal occurs during treatment [5, 6].
Thus, treatment plans that do not consider respiratory motion may be associated
with a higher chance of missing the tumor. In contrast, the large target volume
obtained by overestimation of respiratory motion increases the irradiation dose to
the surrounding normal tissues, which might result in side effects. Several research-
ers have described the relationship between irradiation volume and the degree of
toxicity to normal tissues [7–9]. Therefore, respiratory motion is an important factor
to consider when generating stereotactic body radiotherapy (SBRT) for thoracic and
abdominal tumors.
M. Nakamura (*)
Department of Advanced Medical Physics, Graduate School of Medicine, Kyoto University,
Kyoto, Japan
e-mail: m_nkmr@kuhp.kyoto-u.ac.jp

Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_7
98 M. Nakamura
7.2 Patient Fixation
SBRT is generally characterized by extremely high fractional doses and high dose
gradients near the target boundary. Nagata et al. [10] found that most SBRT proce-
dures lasted less than 30 min. Hoogeman et al. noted that despite being immobi-
lized, the patient would leave the initial setup position after 15 min or more of
treatment [11]. This movement can lead to the underdosing of tumors and overdos-
ing of normal tissues. Therefore, a firm fixation of the patient is recommended to
minimize intrafraction movement. The technical details of patient fixation are
described in Chap. 6.
7.3 Computed Tomography and Determination of Internal

Target Volume
One of the major challenges in performing target delineation of moving tumors is

the movement of the target due to respiration or intrafraction motion, which can
introduce considerable geometric uncertainty in radiotherapy. This section describes
the relationship between CT images and the determination of internal target volume
(ITV) or internal gross tumor volume (iGTV).
7.3.1 Computed Tomography Slice Thickness
Current treatment planning is based primarily on CT. In many clinical situations, a

CT slice thickness of 1–3 mm is recommended to improve longitudinal resolution
and enhance tumor detectability in the CC direction [12, 13]. A higher vertical reso-
lution reduces the partial volume effect and allows for accurate rendering in the CC
direction.
7.3.2 Respiratory Motion Management
As discussed in Sect. 8.1, tumors in the chest and abdomen move and deform with
respiration. Various methods have been used to deal with tumor motion during
SBRT, including suppression of respiratory motion by abdominal compression,
breath-holding, respiratory-gating, and real-time tumor tracking. Appropriate CT
imaging is required for each technique. A specific example of CT imaging is
described below.
7 Treatment Planning 99
7.3.2.1 Inhibition of Respiratory Motion by Abdominal Compression
It is necessary to visualize the full range of tumor motion on CT even if respiratory

motion is suppressed. However, it has been recognized that organ motion during
conventional CT under free-breathing can cause several motion artifacts, such as
wrong arrangement of axial slices and individual organs being captured as different
parts [14–16]. Such motion artifacts can lead to inaccurate representation of the
shape, volume, and location of normal organs and target volumes and can cause
significant rendering errors in treatment planning. There are three common methods
of CT to avoid these drawbacks: inhalation/exhalation hold CT, slow CT, and four-
dimensional (4D) CT.
7.3.2.1.1 Inhale/Exhale Breath-Hold Computed Tomography
One way to determine ITV or iGTV under free-breathing is to acquire a breath-hold

CT image at both expiratory and inspiratory phases, and subsequently perform
image fusion. However, under breath-hold conditions with voice instructions,
patients tend to breathe consciously [17], which may increase the range of tumor
motion compared with forced shallow breathing or free-breathing conditions. The
use of a visual feedback system is effective to avoid amplification [18].
7.3.2.1.2 Slow Computed Tomography
In slow CT, the CT gantry rotates very slowly during the acquisition of each slice,
and the rotation time is typically 4–6 s. This results in the delineation of the volume
of the tumor in a single rotation, but it may not be able to identify fine structures
surrounding the solid region of the tumor [19]. Lagerwaard et al. found that a single
slow CT could capture only 80% of the average volume obtained using three slow
CT scans [20]. In addition, Nakamura et al. reported that slow CT with a rotation
time of 4 s could not fully capture lung tumor motion when the breathing period was
less than 4 s [21]. Either repeated slow CT or a single slow CT combined with fluo-
roscopy is required to overcome this drawback. If the ITV or iGTV is found to be
insufficient, it is manually corrected by combining it with X-ray fluoroscopic data.
7.3.2.1.3 Four-Dimensional Computed Tomography
Currently, 4D-CT includes both oversampled CT data acquisition and retrospective

sorting of respiratory signals recorded during CT. Respiratory signals are based on
the respiratory phase or displacement. Two main approaches to 4D-CT have been
developed: helical [22–24] and cine [25–27].
100 M. Nakamura
In the helical approach, overlapping projection data are acquired using a very
low helical pitch. The pitch is set low enough to allow the acquisition of projection
data for the entire respiratory cycle for each slice position. Before image reconstruc-
tion, the respiratory state of interest is selected. Projection data corresponding to the
selected respiratory state are rearranged to reconstruct the image and finally create
a 3D-CT data set for that respiratory state.
In contrast, in the cine approach, images of each couch position are acquired
repeatedly in axial scan mode. Cine duration is set to be longer than the duration of
the observed maximum respiratory cycle so that image data can be acquired through-
out the respiratory cycle. Multiple images are reconstructed at each couch position
and sorted based on respiratory signals. Finally, a 4D-CT data set is generated by
assembling the CT images representing the target (in terms of respiratory phase or
abdominal displacement) at each position.
A common approach is to define an ITV or iGTV that encompasses the extent of
tumor motion in all 4D-CT images. Some systems with a maximum intensity pro-
jection (MIP) tool that creates an image in which each voxel is set to the maximum
CT number for that voxel in the 4D-CT image set have been used in cases of lung
tumors [27, 28]. MIP imaging can yield ITV or iGTV if the tumor is surrounded by
low-density lung tissue but may underestimate ITV or iGTV if the tumor is attached
to the mediastinum, chest wall, or diaphragm [28]. Furthermore, the degree of
underestimation of the volume by the MIP tool has been found to increase with the
degree of respiratory variability of the patient [29]. Correcting the delineated MIP
images by visually confirming the extent of the tumor motion in each 4D-CT image
has been found to minimize the underestimation of ITV or iGTV.
7.3.2.2 Breath-Holding
The advantage of the breath-hold method is that it uses physiological fixation to

minimize movement and strain on nearby normal tissues. However, this approach
requires the cooperation of the patient and the effort of the staff to train all patients
in a consistent manner. Breath-holding can be categorized into active breath-
holding, voluntary deep breath-holding, and breath-holding with or without breath
monitoring. Although intrafraction variability of up to 2.5 mm has been observed
(Table 7.1) [30–38], some reports caution about deep inspiration breath-hold. When
breath-hold CT is used for treatment planning, the intrafraction variability should be
included in the ITV or iGTV after multiple breath-hold CT images are acquired and
reproducibility is assessed.
7.3.2.3 Respiratory-Gating and Real-Time Tumor Tracking
Breath-hold CT may also be used for respiratory-gating irradiation and real-time

tumor tracking irradiation, but it should be noted that 4D-CT is preferable to breath-
hold CT at the same respiratory position because actions of respiratory muscles may
Table 7.1 Intrafraction variations in breath-hold techniques

Number of Repeatability
Study Site Technique patients Measurement (1 SD, CC)
Hanley et al. (1999) Lung DIBH 9 Diaphragm 0.9 mm
[30]
Remouchamps et al. Breast mDIBH 14 Lung surface 1.1 mm
(2003) [31]
Dawson et al. (2001) Liver ABC 8 Diaphragm 2.5 mm
[32]
Eccles et al. (2011) Liver ABC 21 Diaphragm 1.5 mm
[33]
Kashani et al. (2006) Lung ABC 10 GTV 1.4 mm
[34]
Glide-Hurst et al. Lung ABC 9 GTV Mean
(2010) [35] <2.0 mm
Nakamura et al. Pancreas Visual 10 GTV 1.0 mm
(2011) [36] feedback
Peng et al. (2011) Lung Visual 13 GTV 1.3 mm
[37] feedback
Lens et al. (2016) Pancreas DIBH 12 Fiducials and 1.7 mm
[38] diaphragm
Abbreviations: ABC Active breathing control, CC Cranial-caudal, DIBH Deep inspiration breath-
hold, GTV Gross tumor volume, mDIBH Moderately deep inspiration breath-hold, SD Standard
deviation
be different between breath-hold and free-breathing, and the tumor delay that occurs
during free-breathing is eliminated during breath-hold. It is also known that the
location of the implanted fiducial markers does not necessarily represent the loca-
tion of the tumor because the tumor and the marker move at different speeds during
respiration [39]. ITV or iGTV needs to account for such intrafraction variability and
potential changes in internal-external correlation factors [40, 41], both within the
gating window and over the entire respiratory cycle.
7.4 Targeting
The existing literature clearly shows that the main systemic source of error in radio-
therapy is target delineation. Such errors can only be minimized by using site-
specific delineation protocols and consensus delineation atlases. Target delineation
inconsistencies are considered an important source of uncertainty in treatment plan-
ning [42], and the definitions of GTV, clinical target volume (CTV), ITV or iGTV,
and planning target volume (PTV) for SBRT are based on data from International
Commission on Radiation Units (ICRU) reports 50 [43] and 62 [44].
102 M. Nakamura
7.4.1 Gross Tumor Volume and Clinical Target Volume
GTV (the primary tumor) can be determined using any of several imaging modali-
ties and should include lymph nodes that are grossly involved. CTV includes an
anatomically defined region (possibly including hilar or mediastinal lymph nodes or
margins around the tumor that are visible to the naked eye) that is thought to have
micrometastases. However, when SBRT is used, GTV and CTV are often consid-
ered identical [45–47].
7.4.2 ITV or iGTV
To address the issue of tumor motion, the use of ITV or iGTV, defined as an exten-
sion of CTV, was proposed to explicitly reflect target motion. Several approaches
have been followed to address issues of intra- and interfraction motions to deter-
mine ITV. Details of ITV or iGTV determination are discussed in Sect. 8.3.
7.4.3 PTV
PTV is used to address inaccuracies caused by the day-to-day setup of fractionated

treatment, mechanical uncertainties in the equipment, and uncertainties in dosime-
try. When internal surrogates are used, the extent of marker movement and rate of
fixation depend on the implantation procedure [39, 48, 49]. Since these factors vary
from institution to institution and even from device to device in the same institution,
these uncertainties also should be considered while determining the PTV.
7.5 Beam Arrangement
The purpose of SBRT is to ablate the tumor within the PTV, and such tissue destruc-
tion is not considered a cause of complications. Dose heterogeneity within the PTV
is usually considered acceptable and need not be considered a priority during plan-
ning. Therefore, it is common for SBRT plans to include a maximum point dose of
up to ~150% of the prescribed dose (Fig. 7.1, 7.2, 7.3).
In recent years, treatment planning has been accomplished using static fixed
beam, dynamic conformal arc, intensity-modulated radiation therapy (IMRT), or
volumetric-modulated arc therapy (VMAT) plans.
For static fixed beam and dynamic conformal arc techniques, it is necessary to
irradiate from multiple directions to focus doses as concentrically as possible on the
target. Adjustment of the multi-leaf collimator (MLC) margin is important from the
point of view of dose distribution [48, 50] (Fig. 7.1). When the MLC margin is close
Fig. 7.1 Beam’s eye views for (left) isocenter prescription and (right) peripheral dose prescrip-
tion. For isocenter prescription, the beam’s eye view multi-leaf collimator (MLC) aperture (yel-
low) is often larger than the planning target volume (PTV, red). In contrast, for peripheral dose
prescription, the beam’s eye view MLC aperture typically should be fitting to or smaller than the
PTV edge
Fig. 7.2 Comparison of dose distributions. The planning target volume (PTV) is indicated by a
pink circle. A dose of greater than 48 Gy is administered. (Left) Isocenter prescription. The pre-
scribed dose is 48 Gy at isocenter. PTV is not covered by prescribed dose. (Right) Peripheral dose
prescription. The prescription dose of 48 Gy is administered to the isodose line encompassing
100% of the PTV. R Right, L Left
to the beam penumbra (Fig. 7.1 [left]), a uniform PTV dose of up to 110% of the
prescribed dose can be obtained (Figs. 7.2 and 7.3); however, the dose drop outside
the PTV is slow. If the MLC margin matches or is much smaller than the beam
penumbra (Fig. 7.1 [right]), the dose drop outside the PTV is fast; however, the
maximum dose can be more than 125% of the prescribed dose and the PTV dose can
be non-uniform (Figs. 7.2 and 7.3).
VMAT has been gaining popularity because of its shorter delivery time and bet-
ter conformity [51]. In general, during IMRT or VMAT for moving tumors, a major
concern is interplay effects on MLC motion and the moving tumor that might lead
to underdosing of the tumor [52]. Shintani et al. [53] assessed the impact of
104 M. Nakamura
Fig. 7.3 Comparison of dose-volume histograms. Peripheral dose prescription (PD) vs. isocenter
prescription (iso). Note that lung doses with peripheral dose prescription are almost identical to
those with isocenter prescription. PTV Planning target volume, ITV Internal target volume
fractional dose and the number of arcs on interplay effects when VMAT was used
for lung tumors with large respiratory motions. They concluded that interplay
effects were negligible in VMAT-based SBRT for lung tumors with large respiratory
motions. However, the breathing motion during treatment can be different from that
during CT simulation [54]. Caution is needed when interpreting results of previous
studies in the context of clinical practice.
7.6 Beam Energy
For small beams, such as those often used in SBRT, the beam penumbra is narrower
due to the lateral transport of electrons in the medium, and beam energy is low. This
effect is more pronounced in a low-density medium such as lung tissue. The use of
low-energy photon beams, such as the 6-MV photon beam available in modern
treatment devices, provides a reasonable compromise between beam penetration
and penumbra properties required for the application of SBRT to the lungs.
7.7 Dose Calculation
The CT images used for dose calculation should reflect the respiratory state at the
time of beam irradiation. As shown in Table 7.2, for each patient, the most appropri-
ate CT data set should be used for dose calculation.
Table 7.2 Ideal computed tomography images used for dose calculation
Respiratory status during
Beam delivery technique beam delivery CT images
Inhibiting respiratory movement Forced shallow breathing AIP or slow CT images with
with abdominal compression abdominal compression
Breath-holding Breath-holding Breath-holding
Respiratory-gating Free-breathing (without Phase-specific 4D-CT images
abdominal compression)
Real-time tumor tracking Free-breathing (without Phase-specific 4D-CT images
abdominal compression)
Abbreviations: 4D-CT Four-dimensional computed tomography, AIP Averaged intensity projec-
tion calculated after phase-binning of 4D-CT images, CT Computed tomography
The dose calculation algorithm (including heterogeneity correction) and calcula-

tion grid size used in the treatment planning system affect the accuracy of the calcu-
lated dose distribution. If the accuracy of the dose calculation algorithm is low, there
will be a large difference between the planned dose and the actual irradiation dose.
Therefore, it is recommended to adopt a highly accurate dose calculation algorithm
and a fine grid size. Details of dose calculation are described in Chap. 7.
7.8 Normal Tissue Dose Tolerance
Normal tissue dose limits for SBRT are very different from those for conventional
radiotherapy because of the extreme dose and fractionation scheme. Therefore, nor-
mal tissue dose limits for SBRT should not be directly extrapolated from conven-
tional radiotherapy data. Particular attention should be paid to fraction size, total
dose, the elapsed time between fractionated irradiations, and overall treatment time.
These are important radiobiological factors that should be maintained within clini-
cally established parameters (often described in the existing literature regarding
SBRT). This issue becomes particularly important when planning new hypofrac-
tionated schedules and trials for which a reliable mechanism for estimating radio-
biological effects has not yet been established. Therefore, in the context of clinical
trials, fraction size, as well as the number of treatments and overall treatment time,
should be maintained in all patients throughout the trial to obtain reliable data on
treatment outcomes. Empirical critical organ tolerances for SBRT provided in the
evolving peer-reviewed literature must be considered [55].
7.9 Treatment Plan Reporting
The treatment plan for SBRT often includes the use of many beams, unconventional
dose fractionation, and varying irradiation frequency. It is important to accurately
communicate the details of the treatment plan and its execution to the treatment
106 M. Nakamura
team. The quality of the planned SBRT dose distribution can be assessed using
parameters that characterize target coverage, dose uniformity, dose delivered out-
side the defined target, and volume of normal tissue exposed to lower doses. A
simple way to describe these parameters is by using a table showing the dose-
volume histogram combinations of different organs and dose distribution to differ-
ent subvolumes of those organs. The following metrics are relevant: “respiratory
motion range,” “dose calculation algorithm,” “prescription dose,” “prescription
ICRU reference point or dose/volume,” “number of treatment fractions,” “total
treatment delivery period,” “target coverage,” “heterogeneity index,” “conformity
index,” and “the dose to organs at risk.”
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Part III
Clinical Applications
Chapter 8
Lung: Peripheral
Masaki Kokubo
8.1 Introduction
For many years, conventional fractionated radiation therapy has been used as a cura-
tive treatment for peripheral lung cancer in patients who cannot or refuse surgery.
Historically, however, the local control and survival rates of these treatments have
been unsatisfactory. Most deaths have been due to primary disease, and there has
been a need for more potent and effective treatments. Recent advances in three-
dimensional treatment planning that can produce steep dose distributions, respira-
tory motion assessment and management, and image-guided radiation therapy have
led to several retrospective studies increasing radiation doses per fractionation and
withdrawing prophylactic irradiation of lymph node areas. These results were
promising.
8.2 Japanese Experience
Dr. Uematsu of National Defense Medical College in Japan, who is the pioneer of
the Stereotactic Body Radiation Therapy (SBRT) for lung cancer, realized for the
first time the accelerator combined with CT system (named with FOCAL unit) in
the treatment room where the couch of the accelerator links that of the CT. By using
this system, 50 patients with pathologically proven T1 or T2 N0 lung cancer, who
were either medically inoperable or refused surgery, were treated between October
1994 and June 1999. In most patients, the dose was 50–60 Gy in five to ten fractions
for 1 to 2 weeks only to the primary lesion. Beam arrangements consisted of six to
M. Kokubo (*)
Department of Radiation Oncology, Kobe City Medical Center General Hospital, Kobe, Japan
e-mail: mkokubo@kcho.jp
Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_8
114 M. Kokubo
15 noncoplanar arcs. With a median follow-up period of 36 months, the 3-year over-
all survival rate and the 3-year local control rate was 66% and 94%, respectively [1].
Dr. Nagata of Kyoto University Graduate School in Medicine increased a single
dose up to 12 Gy at the isocenter and reduced fraction to four times. Nagata and his
colleague treated 45 patients between September 1998 and February 2004. Thirty-
two patients had T1 lung cancer, and the other 13 had T2 lung cancer. Nagata et al.
reported 16% tumors completely disappeared after treatment. During a median
follow-up of 30 months, no pulmonary complications greater than Grade 3 of
National Cancer Institute-Common Toxicity Criteria were noted. The 3-year local
control rate was 98%. The 3-year overall survival rate for T1 lung tumor was 83%
and that for T2 tumor was 72% [2].
The large series of SBRT for early-stage non-small lung cancer was reported by
Dr. Onishi of Yamanashi University who went to the national questionnaire. One
hundred and sixty-four patients with T1 lung cancer and 93 patients with T2 were
treated with SBRT using a variety of techniques, all noncoplanar arcs or multiple
static beams and mechanisms to reduce respiratory movement. Total dose of
18–75 Gy in one to 22 fractions were delivered. The median calculated biologic
effective dose (BED) was 111 Gy (range, 57–180 Gy) based on alpha/beta = 10. The
median age was 76 years old. During a median follow-up of 38 months, pulmonary
complications greater than Grade 2 of National Cancer Institute-Common Toxicity
Criteria were noted in only 5.4% of patients. In SBRT, local progression occurred in
36 patients (14.0%), and the local recurrence rate was 8.4% for a BED of 100 Gy or
more compared with 42.9% for less than 100 Gy (p < 0.001). The 5-year overall
survival rate of medically operable patients was 70.8% among those treated with a
BED of 100 Gy or more compared with 30.2% among those treated with less than
100 Gy (p < 0.05), and that of inoperable cases was 39% with a BED of 100 Gy or
more [3].
Nagata et al. reported the survey for the status of SBRT in Japan using the nation-
wide questionnaire. At the end of November 2005, 94 institutions responded to the
questionnaire. A total of 1111 patients with histologically confirmed lung cancer
were treated, including 637 had T1N0M0 and 272 had T2N0M0 lung cancer. The
most frequent schedule used for primary lung cancer was 48 Gy in four fractions,
followed by 50 Gy in five fractions. There were 14 (0.6% of all cases) reported
Grade 5 complications: 11 cases of radiation pneumonitis, two cases of hemoptysis,
and one case of radiation esophagitis [4] (Table 8.1).
In 2003, Radiation Therapy Study Group has been newly installed in Japan
Clinical Oncology Group; JCOG. Principal investigator was Professor Hiraoka of
the Department of Radiation Oncology and Image-Applied Medicine, Kyoto
University Graduate School of Medicine. For the first clinical examination of this
study group, the phase II study regarding SBRT for Stage IA non-small cell lung
cancer, JCOG0403, was initiated.
The purpose of JCOG0403 was to evaluate the safety and efficacy of SBRT,
consists of 48 Gy at isocenter in four fractions over 4–8 days, in both patients with
operable and inoperable Stage IA non-small cell lung cancer. Answers to the fol-
lowing two clinical questions were sought by this trial: First, can SBRT be an
8
Table 8.1 Prospective SBRT studies for lung cancer

Lung: Peripheral
Study No. of Operable or

name patients Phase T inoperable Dose Local control OS AE
JCOG0403 164 II T1 Both 48 Gy/4 fx@IC Operable Operable G3 7.8%
85.4%@3Y 68.3%@3y ≥G4 0%
Inoperable Inoperable
87.3%@3Y 63.7%@3Y
JCOG0702 28 I T2 Both Escalation (up to 60 Gy/4 fx@ 39%@3Y ≥G3 0%
PTV_D95)
JCOG1408 750 II T1 Both 42 Gy/4 fx@PTV_D95 vs 55 Gy/4 NA NA NA
(ongoing) fx@PTV_D95
RTOG0236 55 II T1– Inoperable 54 Gy/3fx@PTV_Margin 97.6%@3Y 55.8%@3Y G3 27%
2 G4 3.6%
G5 0%
RTOG0618 33 II T1– Operable 54 Gy/3fx@PTV_Margin 96%@2Y 56%@4Y G3 15%
2 ≥G4 0%
RTOG0915 94 III T1– Inoperable 34 Gy/1 fx vs 48 Gy/4 fx 89.4%@5Y in 29.6%@5Y in ≥G3 2.6% in
2 34 Gy 34 Gy 34 Gy
93.2%@5Y in 41.1%@5Y in ≥G3 11.1% in
48 Gy 48 Gy 48 Gy
115
116 M. Kokubo
alternative standard treatment modality for inoperable patients? Second, is SBRT

promising as an alternative to lobectomy for operable patients received lobectomy
for standard care? This study is different from Western study. Not only inoperable
cases but operable cases were included in this study. The primary endpoint is the
3-year overall survival rate. The patients with histologically or cytologically proven
stage IA non-small cell lung cancer, PS 0–2, PaO2 ≥60 torr, FEV1.0 ≥700 mL were
included, between July 2004 and November 2008, 169 patients from 15 institutions
participated in the clinical trials were enrolled in this JCOG0403. One hundred
inoperable and 64 operable in total 164 patients were eligible.
First, for the inoperable cases assessed by thoracic surgeons, it was assumed that
the 3-year survival rate of treatment up to now could be 35%, and that expected the
3-year survival rate of the study was 50%. The sample size of inoperable population
was determined as 100 to test the threshold value of 35% in terms of overall survival
rate of 3 years with the expected value of 50%, one-sided alpha of 0.05, and power
of 90%. If the lower limit of 90% confidence interval of the 3-year overall survival
rate exceeds the threshold value of 35%, SBRT is considered to be effective.
One hundred and four patients were included after patient restratification.
Seventy-seven were male and 27 were female. The median age was 78 years old,
and the median tumor size was 21 mm. The median follow-up period for inoperable
patients was 47 months. Regarding the main endpoint, the three-year overall sur-
vival rate was 59.9% (95% credible interval (CI): 49.6%–68.8%) of the 100 eligible
patients in 104 inoperable patients. The 3-year local control rate, which does not
include death as an event, was 87.3%. Fifty-five patients died, 17 (31%) of which
died of lung cancer and 38 (69%) of other causes. There were no lethal adverse
events. Grade 4 toxicity was observed in the following two cases: one dyspnea and
one hypoxia. Grade 3 toxicity was observed in the following nine cases: dyspnea,
nine; hypoxia, eight; pneumonia, seven; chest pain, two; and cough, one (It was
counted in duplicate) [5].
From these results, for the medically inoperable patients with T1 lung cancer,
SBRT should be a new standard treatment method replacing conventional radiation
therapy. Also, the 3-year local control rate was almost similar as the results from
Europe and the United States.
On the other hand, for operable cases, the 3-year overall survival rate of patients
with T1 non-small lung cancer by the Japanese Lung Cancer Registry was 81.3%.
Since SBRT is considered to be a less toxic procedure than lobectomy, SBRT is
promising enough to be an alternative treatment to surgery for operable patients
when the upper limit of the 95% CI of the 3-year overall survival rate obtained from
this study exceeds 80%. The sample size of operable population was determined as
62 by precision basis so that the 95% CI for the estimated overall survival rate of
3 years would be +/− 10% around the expected value of 80%.
Sixty-five patients were registered in this study. Forty-five were male and 20
were female. The median age was 79 and median tumor size was 21 mm. The
median follow-up period for operable population was 45 months. Of the eligible 64
operable patients, the overall survival rate of 3 years was 76.0% (95% CI:
63.3%–84.8%). The 3-year local control rate, which does not include death as an
8 Lung: Peripheral 117
event, was 85.4%. During the follow-up, 37 patients died, 18 (49%) of which died
of disease and 19(51%) of other causes. In operable population, Grade 4 and 5 tox-
icities were not observed. Grade 3 toxicity was observed in the following four cases:
chest pain, one; dyspnea, two; hypoxia, one; and pneumonitis, two (It was counted
in duplicate.) [5].
This is the first report in the world regarding SBRT efficacy and safety for medi-
cally operable patients with T1 lung tumor. This treatment is promising as an alter-
native to surgery for operable stage I non-small cell lung cancer.
JCOG Radiation Therapy Study Group have conducted the second clinical trial,
JCOG0702. Although SBRT shows good clinical results, the efficacy and safety of
SBRT for T2 lung tumors seem to be less certain than that for T1 lung tumors. The
local control rate of 3 years for T2 tumor was not satisfactory. Onimaru et al. and
Koto et al. reported that local control rate for T2 tumors was poorer than that for T1
tumors [6]. Onishi et al. reported that local disease recurrence was 9.7% for T1, and
20.0% for T2, respectively. They also reported that there was no remarkable differ-
ence in overall survival between T1 tumors and T2 tumors in the group with biologi-
cally effective dose equal to or larger than 100 Gy [3]. These results suggest that
dose escalation is one of the methods in order to improve clinical outcome of SBRT
for T2 cancer.
JCOG0702 is the phase I study in order to investigate the maximum tolerated
dose and to determine the recommended dose of SBRT for peripheral T2 non-small
cell carcinoma. Dose-limiting toxicity was Grade 3 radiation pneumonitis within
180 days after the start of SBRT but Grade 2 radiation pneumonitis was used as sur-
rogate dose-limiting toxicity because the incidence of Grade 3 radiation pneumoni-
tis was expected very low. Recommended dose was defined as equal to the maximum
tolerated dose. Dose was prescribed at D95 of PTV. Starting dose was 40 Gy in four
fractions, and dose was escalated by 5-Gy step with calculation using the superposi-
tion algorithm or equivalent method. This starting dose was decided based on esti-
mation that 40 Gy in four fractions at D95 of the PTV corresponds to 48 Gy in four
fractions calculated by the Clarkson algorithm at the isocenter in JCOG0403. The
isocenter dose of 40 Gy in four fractions at D95 ranged from 45.3 to 51.9 Gy in four
fractions. The maximum dose level was determined as 65 Gy in four fractions at
D95 of PTV before starting JCOG0702. Because the range of the volume of PTV is
broad in T2 tumors, the enrolled patients in this study have been stratified by PTV
volumes (PTV <100 cc or PTV ≥100 cc) to assess toxicities accurately.
In JCOG0702, continual reassessment method (CRM) was used to determine the
dose level that patients should be assigned to and the maximum tolerated dose
although traditional 3 + 3 design is popular in phase I study especially for cytotoxic
chemotherapy. CRM is a Bayesian approach and has some important advantages
compared to traditional 3 + 3 design. First, since CRM uses all the data of registered
patients in order to determine the next dose level, CRM can estimate the maximum
tolerated dose more precisely than traditional 3 + 3 design. In JCOG0702, Onimaru
et al. tried to determine the recommended dose based on the data with statistical
evaluation. They estimated the lower limit of 95% CI of the predicted maximum
tolerated dose. Second, rapid dose escalation is possible. The dose-limiting toxicity
118 M. Kokubo
of radiotherapy sometimes needs to be observed long time because some of the

dose-limiting toxicities like radiation pneumonitis are observed 3–6 months after
the completion of radiotherapy. The need for long observation may result in the long
period of phase I study in radiation oncology. In spite of required long observation,
CRM can shorten the study period compared to traditional design because smaller
number of patients are assigned to some dose levels and the total number of patients
can be smaller. In JCOG0702, the prior distribution of the dose-response curve and
the maximum tolerated dose was calculated based on the expected frequency of
Grade 2 radiation pneumonitis. The maximum tolerated dose was the dose level that
the expectation of posterior distribution for Grade 2 radiation pneumonitis was
around 25% in the pre-planned decision rule. The dose level and the numbers of
patients assigned to was calculated and updated once a month using CRM.
Eligibility criteria in JCOG0702 included pathologically or cytologically proven
NSCLC, peripheral T2N0M0 over 3 cm in diameter, PS 0–2, PaO2 ≥60 torr, FEV1.0
≥700 mL, either “age ≥20 years and unfit for lobectomy” or “age ≥70 years and
refusing surgery.” First, the results of the group with PTV <100 cc were reported
[7]. Fifteen patients were accrued from October 2008 to September 2012 in PTV
<100 cc group. Five patients were treated at 40 Gy, one at 45 Gy, three at 50 Gy, one
at 55 Gy, and five at 60 Gy. Tumor size ranged from 31 to 39 mm with a median of
32 mm. Only one patient experienced Grade 2 radiation pneumonitis at 60 Gy in
four fractions. The other 14 patients had Grade 1 or 0 radiation pneumonitis. Mean
lung dose ranged from 3.0 to 7.0 Gy for all patients. More patients should have been
assigned to the level of 60 Gy according to CRM, but enrolling more than five
patients to that level was not practical because of the difficulty of fulfilling the dose
constraints. Considering the generalizability of this study result, the maximum
assigned dose level was reduced from 60 Gy to 55 Gy. Median overall survival was
2.6 years. The 3-year overall survival was 39% (95% CI 11.4–67.1%). The recom-
mended dose was determined as 55 Gy in four fractions because the lower limit of
CI of the predicted recommended dose exceeded the adjacent dose level of 50 Gy.
The mean lung dose and the isocenter dose with 55 Gy in four fractions at D95 were
4.6 and 66.8 Gy, respectively.
Second, the results of the group with PTV ≥100 cc were reported [8]. Thirteen
patients were accrued. More patients should have been enrolled but authors decided
not to prolong the study period. No patients experienced Grade 3 radiation pneumo-
nitis. Two patients experienced Grade 2 radiation pneumonitis at 50 Gy in four frac-
tions. The predicted maximum tolerated dose was 50.2 Gy. The posterior probability
of Grade 2 radiation pneumonitis frequency over 40% was 5.3% for the dose level
of 50 Gy. The recommended dose was determined to be 50 Gy.
From the results of JCOG0403 and JCOG0702, a randomized phase III trial,
JCOG1408, commenced in Japan in February 2016. Currently, 42 Gy in four frac-
tions of stereotactic body radiotherapy prescribed at the D95% of the planning tar-
get volume, which is considered equal to the commonly used 48 Gy in four fractions
at the isocenter using an old dose calculation algorithm, is the standard treatment in
Japan for medically inoperable Stage IA non-small cell lung cancer and small lung
lesions clinically diagnosed as primary lung cancer. This study aims to examine the
superiority of 55 Gy in four fractions over 42 Gy in four fractions. A total of 750

patients are expected to be accrued in 7 years. The primary endpoint is overall sur-
vival and the secondary endpoints are progression-free survival, local progression-
free survival, patterns of failure, local control period, adverse events, and serious
adverse events. This trial is ongoing [9].
8.3 Western Countries Studies
A retrospective study at the German Technical University in Munich also treated

Stage I peripheral lung cancer with radiotherapy surrounding the tumor margins
with a 60% dose of 30–37.5 Gy in 10–12.5 Gy 3-year local control and survival
rates were 73% and 51%, respectively, late adverse events of Grade 3 or higher were
reported in about 6% of cases [10].
Indiana University conducted a classic phase I dose escalation study to assess
toxicity. It was performed in inoperable lung tumors ≤7 cm, 3–5 cm, and 5–3 cm
and was designed to cover 95% of PTV with 80% dose. Based on the results, the
recommended dose was determined to be 60 Gy in three fractions for tumors less
than 3 cm and 66 Gy in three fractions for tumors 3–7 cm [11].
These results seemed to be promising.
Indiana Group performed a phase II clinical trial in the same population as a
phase I. Seventy patients were enrolled. The purpose of this phase II study was vali-
dating toxicities and determining local control and survival rate using 60 Gy in three
fractions for T1 tumors and 66 Gy for T2 (35 patients each). The predicted local
control rate was set at 80%, which is higher than that ranging from 30% to 45% with
conventional radiation therapy. Median follow-up was 17.5 months. This study
demonstrated 2-year actuarial local control rate of 95%. Median overall survival
was 32.6 months and 2-year overall survival rate was 54.7%. But severe complica-
tion was observed in tumors located within 2 cm of the proximal bronchial tree.
Grade 3 or higher complication rate was up to 30% [12].
Based on the regimen and results of the Indiana University, RTOG conducted a
phase II trial of RTOG0236 for tumors located in peripheral lung, which was the
first North American multi-center, cooperative group study to evaluate SBRT in
medically inoperable patients with early-stage lung cancer. Dose was changed
54 Gy in three fractions with a new heterogeneous calculation method. Forty-four
patients with T1 tumor and 11 with T2 were evaluated with median follow-up of
34.4 months. Only one patient had a local failure. This trial confirmed an excellent
estimated tumor control rate and overall survival rate of 98% and 56%, 93%, and
40%, respectively, in 3 and 5 years. Also, no treatment death was reported and
Grade 3 or higher complication rate was only 16% in 3 years [13]. These outcomes
compare favorably to historical conventional radiation therapy studies.
Following the results of SBRT for unresectable peripheral lung cancer, a single-
arm phase II trial, RTOG0618, was initiated in operable patients with early-stage
non-small lung cancer. Thirty-three patients were enrolled and 26 patients were
120 M. Kokubo
evaluated. Twenty-three patients had T1 tumors and three had T2 tumors treated
with 54 Gy in three fractions. Primary endpoint was primary tumor control and
secondary were overall survival rate, adverse events, and the incidence of surgical
salvage. Only four patients had a primary tumor recurrence. The estimated 5-year
primary tumor control rate was 93%. The 5-year estimates of disease-free and over-
all survival were 26% and 40%, respectively. Median overall survival was 4.0 years.
Fifteen patients had protocol-specified treatment-related Grade 3 adverse events,
and two had Grade 4, but no five adverse events. These results suggest that SBRT is
effective for operable peripheral lung cancer and that salvage surgery is less fre-
quently required [14].
RTOG0915 was the only published randomized trial that compared two fraction-
ation schedules for biopsy-proven, node-negative peripheral lung cancer, 34 Gy in a
single fraction with 48 Gy in four fractions. A primary endpoint is greater than or
equal to Grade 3 toxicity. Secondary endpoints were rates of primary tumor control,
overall survival, and disease-free survival at 1 year. Ninety-four patients were
enrolled. Median follow-up was 30 months. Thirty-nine treated with a single frac-
tion and 45 with four fractions were well balanced of 84 analyzable patients. There
was no significant tumor control, but less toxic in a single fraction. In the United
States, a regimen of 54 Gy in three fractions is widely used. There is no clinical trial
between this regimen and 34 Gy in a single fraction, The only report compared
30 Gy in a single fraction to 60 Gy in three fractions was reported in ASTRO 2016
annual meeting, and there was no difference of tumor control and toxicity in
2 years [15].
In the Netherlands, the VU University Medical Center reported on 676 patients
treated with 54–60 Gy in three to eight fractions. Median follow-up was 33 months.
The 2-year local control rate was 95%.
SBRT seemed to be standard therapy for inoperable patients with peripheral
lung cancer; however, there are no comparative studies. SPACE (Stereotactic
Precision And Conventional radiotherapy Evaluation) is the first randomized phase
II trial comparing SBRT and conventional fractionated radiotherapy [16]. The
median follow-up was 37months with a three-year PFS 42% and no difference in
OS in both groups. Toxicity was low with no Grade 5 events. Pneumonitis of any
Grade was observed in 19% in SBRT and 34% in 3DCRT with p = 0.26, and
esophagitis in 8% and 30%, respectively, with p = 0.006. Here was no difference in
PFS and OS between SBRT and conventionally treated patients despite an imbal-
ance of prognostic factors. We observed a tendency of an improved disease control
rate in the SBRT group and they experienced less toxicity. SBRT is convenient for
patients and should be considered standard treatment for patients with inoperable
stage I NSCLC.
8.4 Phase III Study
Most SBRT studies for peripheral lung cancer have focused on the medically inop-
erable patients, but JCOG0403 and RTOG 0618 also included patients who are
operable. The results of these trials were interesting, Therefore, several phase III
trials comparing surgery and SBRT, the STARS, the ROSEL, and so on were con-
ducted, but all were terminated due to poor case accrual of eligible patients. There
is also an integrated analysis of the STARS/ROSEL trial [17]. In all, 58 patients
were analyzed: 31 for SBRT and 27 for lobectomy. The 3-year overall survival rates
were 95% for SBRT and 79% for surgery, with a p value of 0.037, a significant dif-
ference. The results, although an analysis of a small number of cases, suggest that
SBRT may be a minimally invasive treatment option for peripheral lung cancer in
the future. However, it was a small number study and the confidence interval for the
hazard ratio for overall survival was across one, so it has been criticized by arbitrary
interpretation. Additional prospective randomized trials are needed to evaluate the
role of SBRT for medically operable population.
In response to the earlier criticism, a new clinical trial using propensity matching
was planned [18]. This was called “revised STRAS,” a single-arm prospective trial
done at the University of Texas MD Anderson Cancer Center and enrolled patients
were newly diagnosed and histologically confirmed non-small cell lung cancer,
tumor diameter of 3 cm or less. This trial did not include patients from the previous
study. Fifty-four patients with peripheral tumor were enrolled in all 80 patients.
These patients were treated with 54 Gy in three fractions. The primary endpoint was
the 3-year overall survival. A surgical cohort from the MD Anderson Department of
Thoracic and Cardiovascular Surgery’s prospectively registered was used for the
propensity-matching analysis, Propensity matching consisted of determining a pro-
pensity score using a multivariable logistic regression model including several
covariates (age, tumor size, histology, performance status, and the interaction of age
and sex). The median follow-up time was 5·1 years. Overall survival of SBRT group
was 91% at 3 years and 87% at 5 years with no Grade 4–5 toxicity. No severe
adverse events were recorded. SBRT was well tolerated. Overall survival in the
propensity-matched surgical cohort was 91% at 3 years and 84% at 5 years. There
was no significant difference in overall survival between the two patient cohorts
from a multivariable analysis. SBRT is non-inferior to surgery but multidisciplinary
approach is recommended.
In the operable peripheral lung cancer, additional prospective randomized trial is
needed to determine the role of SBRT. However, SABRTooth, a British multicenter
study that examined the feasibility of a phase III randomized controlled trial com-
paring SBRT to standard surgery, concluded that it would be difficult to conduct the
study because of the treatment preferences of the patients [19]. Therefore, surgery
is still the standard treatment for operable patients. However, the results of several
phase III trials comparing SBRT and surgery are waited.
122 M. Kokubo
8.5 Conclusion
At present, SBRT is only the standard treatment for peripheral lung cancer that can-
not be operated on. However, the results of these clinical trials to date indicate that
SBRT should be offered as an alternative treatment for patients who refuse surgery.
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Chapter 9
Lung: Central
Takafumi Komiyama
9.1 Centrally and Ultra-Centrally Located Lung Tumors
A category of “centrally located lung tumors (CLTs)” has recently been described.
However, there have been no established criteria for defining it. Timmerman et al.
[1] defined it as “a tumor within 2 cm of the proximal bronchial tree (PBT).” They
performed a phase II clinical trial of stereotactic body radiation therapy (SBRT) for
stage I non-small cell lung cancer (NSCLC) (Stage IA: 60 Gy/3 Fr; Stage IB:
66 Gy/3 Fr), and observed a high frequency of severe toxicities in patients with
CLT. Thus, they recommended not to use the same regimen for CLTs. Then, “within
2 cm radius the trachea and bronchial tree” has been considered a “no-fly zone” for
high-dose radiation therapy and tumors within this area were excluded from RTOG
0236, which was a phase II clinical study of SBRT for peripherally located lung
tumors (PLT) performed by the RTOG [2]. Paying careful attention regarding radia-
tion dose fractionation and distribution and considering alternative treatment options
is needed when performing SBRT for CLT.
Subsequently, the criteria used for defining CLTs were extended not only to the
trachea and bronchi but also to the pulmonary arteries, esophagus, and other medi-
astinal organs considered as high-risk organs. Chang et al. used the criterion of the
tumor being within 2 cm of any mediastinal critical structure (bronchial tree, esoph-
agus, heart, brachial plexus, major vessel, spinal cord, phrenic nerve, recurrent
laryngeal nerve) [3]. In RTOG 0813, which was the RTOG’s phase I/II clinical
study in patients with CLT, the criteria indicated that the tumor is within 2 cm of the
PBT, while planning target volume (PTV) touching the mediastinal pleura [4].
Additionally, among CLTs, tumors in particularly high-risk areas are defined as
ultra-centrally located lung tumors (UCLTs). The definitions of UCLT have varied
T. Komiyama (*)
University of Yamanashi, Kofu, Japan
e-mail: takafumi@yamanashi.ac.jp
Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_9
126 T. Komiyama
widely: according to Chaudhuri et al., the gross tumor volume (GTV) directly abuts
the PBT or trachea [5]; according to Lodeweges et al., the PTV abuts or overlaps the
main bronchi, trachea and/or esophagus [6]; and according to Farrugia et al., the
GTV abuts either the PBT, trachea, mediastinum, aorta, or spinal cord [7]. Thus, the
definition of the category for CLTs and UCLTs varies greatly according to the report
up to present. These variances have major effects on the assessment of the safety of
their treatments. Therefore, when evaluating and comparing the results of SBRT for
CLTs and UCLTs, it is crucial to pay attention to how these tumors are defined in
the criteria.
9.2 Fatal Toxicity
On the ground that fatal toxicities, which are rare in SBRT for PLTs, have been
reported to occur not a little in that for CLTs and UCLTs, SBRT for CLTs and
UCLTs are considered separately from that for PLTs. As shown Table 9.1, the
reported fatal toxicities include hemoptysis [8–12], bronchial stenosis [13, 14],
esophageal ulcers [15], pneumonia [11], heart failure [16], and high-risk organs
were the trachea, bronchi, esophagus, and pulmonary arteries. Corradetti et al. per-
formed SBRT with 50 Gy/5 Fr for CLT adjacent to the right main bronchus in a
61-year-old woman and reported fatal hemorrhage due to airway necrosis 8 months
after treatment [8]. Rowe et al. also performed SBRT with 50 Gy/4 Fr for the treat-
ment of a centrally located metastatic lung cancer near the left main bronchus in a
75-year-old male and reported fatal hemoptysis due to airway necrosis 10.5 months
after treatment [9]. In contrast, Song et al. performed SBRT with 48 Gy/4 Fr for the
treatment of a bronchial tumor in the main bronchus and observed fatal hemorrhage
and aspiration pneumonia due to complete bronchial stricture; pneumonectomy was
performed to control the hemorrhage and pneumonia, but the patient was not saved
[13]. Stauder et al. performed SBRT with 48 Gy/4 Fr for the treatment of a tumor
obstructing the left main bronchus that developed in a patient who had undergone
right pneumonectomy and reported fatal bronchial obstruction due to tumor necro-
sis 7.5 months after treatment [14]. Moreover, Onimaru et al. performed SBRT with
48 Gy/8 Fr for the treatment of a tumor located posterior to the right main bronchus,
but 4 months later, the patient developed esophageal ulcers and died as a result of
bleeding from it after a month. In this patient, the maximum esophageal dose was
50.5 Gy/4 Fr, and the high dose given 1 cc of the esophagus was 42.5 Gy [15].
Horne et al. also performed SBRT with 48 Gy/8 Fr for the treatment of para-aortic
lymph node metastasis in a patient with a history of severe coronary arterial disease,
and reported fatal heart failure 2 months after treatment [16]. In a systematic review
reported in 2019 which included 10 articles, a total of 250 patients who received
SBRT for UCLTs the following high-risk indicators for treatment-related mortality
with SBRT for UCLTs were proposed: (i) tumor directly invades the PBT; (ii) ele-
vated maximum dose (≥180 Gy3) to the PBT; (iii) peri-SBRT bevacizumab use; and
(iv) antiplatelet or anticoagulant use [17]. To the best of my knowledge, even in the
9
Table 9.1 Fatal toxicities following SBRT for CLTs and UCLTs
Lung: Central
Grade 5 Time of onsetafter Dose Dose Dmaxa of Dmax of OAR

Author (year) Age Gender toxicity Organ at risk SBRT (months) prescription fractionation OARb (BED3c)
Onimaru N/ Male Esophageal Esophagus 5 Isocenter 48 Gy/8 Fr 50.5 Gy/8 Fr 156.6 Gy
(2003) [15] Ad ulcer
Song (2009) N/A N/A Bronchial Main 13 PTVe margin 48 Gy/4 Fr N/A N/A
[13] stricture bronchus
Unger (2010) 65 Male Bronchus Main 7 PTVD95%f 40 Gy/5 Fr 49 Gy/5 Fr 209.1 Gy
[10] fistula bronchus
Rowe (2012) 75 Male Hemoptysis Main 10.5 PTVD95% 50 Gy/4 Fr 54.2 Gy/4 Fr 299 Gy
[9] bronchus
Aoki (2018) 64 Male Hemoptysis Main 9 PTVD95% 56 Gy/7 Fr 63.33 Gy/7 255.3 Gy
[11] bronchus Fr
Horne (2018) N/A N/A Heart failure Heart 2 PTV margin 48 Gy/4 Fr N/A N/A
[16]
Abbreviation:
a
Dmax Maximum dose
b
OAR Organ at risk
c
BED3 Biologically equivalent dose calculated using an α/β = 3 Gy
d
N/A Not available
e
PTV Planning target volume OAR organ at risk
f
PTVD95% Covering 95% of the PTV
127
128 T. Komiyama
mediastinal organs, there have been no reports of fatal toxicities concerning SBRT
in major vessels except pulmonary arteries, spinal cord, laryngeal recurrent nerve,
and phrenic nerve.
9.3 Treatment Outcomes
Reported clinical outcomes of SBRT for CLT and UCLT are summarized in Tables
9.2 and 9.3. As shown, the subjects, radiation dose fractionation regimens, and treat-
ment outcomes vary widely [2, 4–18]. Chang et al. performed SBRT with 50 Gy/4
Fr, or, when the dose volume constraint could not be met, with 70 Gy/10 Fr in 100
patients with CLTs (tumors within 2 cm of bronchial tree, major vessels, esophagus,
heart, trachea, pericardium, brachial plexus, or vertebral body; at least 1 cm from
the spinal canal; and without direct involvement of the bronchial tree or mediastinal
structures. The 3-year local control rate (LCR) was 96.5%, the overall survival rate
(OSR) was 70.5%, and there was one grade 3 pneumonia and no grade 4 or 5 adverse
events [2]. Nishimura et al. performed SBRT with 40–60 Gy/5 Fr in 133 patients
with CLTs (within 2 cm of the PBT or mediastinum), including 15 patients with
T4-stage disease and mediastinal invasion, and found a 3-year LCR of 78.0% and
OSR of 54.1%, with five patients (3.7%) showing grade ≥3 adverse events, includ-
ing two patients showing grade 5 hemoptysis [12]. Chaudhuri et al. performed
SBRT with 50 Gy/4–5 Fr in six patients with UCLTs (the GTV directly abutted the
PBT or trachea), and found a 2-year LCR of 100% and OSR of 80.0%, with no
patients showing grade ≥2 adverse events [5]. In a systematic review reported in
2013, including 20 articles and a total of 563 patients who received SBRT for CLTs,
patients treated with dose fractionation schedules of BED10 at ≥100 Gy showed
approximately the same LCR and OSR to those with PLT. On the other hand, not a
small number of grade 5 adverse events exist in most of the studies included in the
review [18].
Recently, multi-institutional prospective studies have also been performed. The
NRG oncology/RTOG 0813 trial was a phase I/II clinical study of SBRT for inoper-
able, T1–2N0M0, centrally located NSCLC within or touching the zone 2 cm
around the PBT or immediately adjacent to the mediastinal or pericardial pleura.
The first primary objective was the determination of the maximum tolerated dose
(MTD), and second primary end point was estimation of the probability of 2-year
primary tumor control at the MTD. Prescription isodose (typically 60% to 90% of
the dose at the center of target) were selected, such that 99% of PTV received a
minimum 90% of the prescription dose, and avoidance of hot spot in organs at risk
(OAR). The SBRT fraction schedule was five fractions with 5 dose revels ranged
from 10 to 12 Gy/Fr in 0.5Gy/Fr increment. Dose-limiting toxicity (DLT) was
defined as any grade ≥3 adverse event that occurred within 1 year from the start of
SBRT, and MTD was defined as the dose at which the probability of DLT is closest
to 20% without exceeding it. The MTD was 12.0 Gy/Fr, and the probability of DLT
in that arm was 7.25%. The 2-year LCR for patients in the 11.5- and 12.0-Gy groups
9
Table 9.2 Clinical outcomes reported in studies on SBRT for CLTs

3-year 3-year
Author Definition of centrally Dose Dose local overall
(year) located Subjects N prescription fractionation (N) control survival Grade 3 <Toxicity
Chang Within 2 cm of the PBTa, NSCLCc primary 100 PTVdmarginal 50 Gy/4 Fr (82) 96.5% 70.5% Grade 3: 1e
Lung: Central
(2014) major vessels, esophagus, stage I or isolated 85–95% 70 Gy/10 Fr (18)

[2] heart, trachea, pericardium, recurrent (<6 cm) isodose line
brachial plexus, vertebral
body at least 1 cm from the
spinal canal, without direct
involvement of the BTb or
mediastinal structures, and
not associated with
atelectasis
Nishimura Within 2 cm of the PBT, or Primary NSCLC 133 60–80% 40 Gy/5 Fr (51) 78.0% 54.1% Grade 3: 3g
(2014) [12] within 2 cm of the or pathology isodose line 50 Gy/5 Fr (80) Grade 5: 2
mediastinal; at least one unknown lung covering the 60 Gy/5 Fr (2)
OARf was irradiated with tumor or PTV
greater than 25 Gy metastasis
Kimura 2 cm in all directions from Primary NSCLC 9 Isocenter 60 Gy/8 Fr N/Ai 76.2% Noneg
(2017) [20] PBT or immediately Stage IA
adjacent to the PRVh the
mediastinal or pericardial
pleura
(continued)
129
Table 9.2 (continued)
130
3-year 3-year
Author Definition of centrally Dose Dose local overall
(year) located Subjects N prescription fractionation (N) control survival Grade 3 <Toxicity
Bezjak 2 cm around the PBT or Primary NSCLC 102 99% of PTV 50.0 Gy/5 Fr (8) 50.0 Gy 50.0 Gy 50.0 Gy noneg
(2019) [4] immediately adjacent to T1–2(<5 cm) received a 52.5 Gy/5 Fr (7) 75.0% 75.0% 52.5 Gy Grade 5: 1
the mediastinal or minimum 55.0 Gy/5 Fr 52.5 Gy 52.5 Gy 55.0 Gy Grade 3: 3
pericardial pleura 90% of the (14) 100.0% 42.9% Grade 5: 1
prescription 57.5 Gy/5 Fr 55.0 Gy 55.0 Gy 57.5 Gy Grade 3: 5
dose (38) 85.7% 64.3% Grade 5: 3
60.0 Gy/5 Fr 57.5 Gy 57.5 Gy 60.0 Gy Grade 3: 5
(33) 86.7% 51.6% Grade 4: 1
60.0 Gy 60.0 Gy Grade 5: 1
84.7% 54.0%
Lindberg Less than or equal to 1 cm Primary lung 65 group A 67% isodose 56 Gy/8 Fr 83.0% 50.0% Group A
(2021) [20] from the PBT cancer or lung (≤1 cm from encompassing Grade 3: 7g
metastasis the main the PTV Grade 4: 2
(<5 cm) bronchi and Grade 5: 8
trachea):39 Group B
Group B Grade 3: 10
(others): 26 Grade 4: 4
Grade 5: 2
Abbreviation:
a
PBT Proximal bronchial tree
b
BT Bronchial tree.
c
NSCLC Non-small cell lung cancer
d
PTV Planning target volume
e
Toxicities were assessed by Common Terminology Criteria for Adverse Events (CTCAE) ver. 3.0
f
OAR Organ at risk
g
h
PRV Planning organ at risk volume
i
N/A Not available
T. Komiyama
9
Table 9.3 Clinical outcomes reported in studies on SBRT for UCLTs

2-year
Definition of ultra- Dose Dose fractionation 2-year local overall Grade 3<
Lung: Central
Author (year) centrally located Subjects N prescription (N) control survival toxicity
Chaudhuri (2015) GTVa directory abutted the NSCLCc 6 PTVD95%d 50 Gy/ 4 Fr (4) 100% 80.0% Nonee
[5] PBTb or trachea tumors 50 Gy/5 Fr (2)
with GTV abutting the
esophagus or that were
within the mediastinal
were excluded
Farrugia (2021) GTV abutting the PBT, NSCLC 43 PTVD95% 50.0 Gy/5 Fr (21) N/Af N/Af Grade 3: 4g
[7] trachea, mediastinum, 52.5 Gy/5 Fr (4)
aorta, or spinal cord 55.0 Gy/5 Fr (16)
57.5 Gy/5 Fr (1)
60.0 Gy/5 Fr (1)
Lodeweges (2021) PTVh abutting or Primary lung 72 PTVD95% 60 Gy/12 Fr 85.0% 52.0% Grade 3: 10g
[6] overlapping the main cancer or lymph Grade 4: 0
bronchi and/or trachea node metastasis Grade 5: 12
and/or esophagus of a lung tumor
Abbreviation:
a
GTV Gross tumor volume
b
PBT Proximal bronchial tree
c
NSCLC Non-small cell lung cancer
d
PTVD95% covering 95% of the PTV
e
f
N/A Not available
g
h
PTV Planning target volume
131
132 T. Komiyama
were 89.4% and 87.9%, respectively, and the 2-year OSR were 67.9% and 72.7%,
respectively. In overall dose revels, the number of patients with grade ≥3 adverse
events were 20 (20%), and there were 6 patients with grade 5 adverse events, the
latter consisting of bronchopulmonary hemorrhage (3), esophageal ulcer (1), sinus
bradycardia (1), and an unknown adverse event (1). The authors concluded that the
outcomes of this study were comparable with those of patients with peripheral
early-stage tumors [4]. The HILUS-Trial, a prospective multicenter phase II study
of risk-adapted SBRT for UCLTs (within 1 cm zone around the PBT) has been per-
formed in Sweden, Denmark, and Norway. The primary and secondary end points
were local control and toxicity, respectively. The patients were stratified to group A
(tumors ≤1 cm from the main bronchi and trachea) or group B (all other tumors). A
total of 65 patients (group A/group B, n = 39/26) were evaluated. The median tumor
diameter in all patients was 22 mm (range 9–54 mm). The dose (56Gy / 8Fr) was
prescribed to approximately the 67% isodose line as closely as possible encompass-
ing the PTV. The 2-year LCR was 83% in all patients, and no significant difference
was found between groups A and B. The OSR after 1, 2, and 3 years were 81%,
58%, and 50%, respectively. Regarding toxicity, 34% of the patients experienced
grade ≥3 adverse events, and 10 patients (9 from group A and 1 from group B)
developed grade 5 adverse events, consisting of hemoptysis (8), pneumonia (1), and
tracheoesophageal fistula (1). Univariate analysis revealed that the distance between
the tumor and main bronchus and D0.2cc, D0.5cc, and D1.0cc for the lumen of
main bronchus plus trachea had close correlations with grade 5 adverse events and
fatal bleeding. Moreover, seven of the eight patients who developed grade 5 hemop-
tysis had a maximal tracheal and/or bronchial doses (EQD2) of ≥100 Gy, except for
one patient with a dose of ≤70 Gy. The authors therefore recommend not to perform
SBRT with 56 Gy/8 Fr for tumors within 1 cm of the trachea and/or a main bronchus
(group A), and to treat safely for UCLTs. The maximum dose (EQD2) of the trachea
and main bronchi should be kept below 70–80 Gy [19].
In Japan, Kimura et al. performed a phase I clinical study of SBRT for centrally
located stage IA lung cancers. In that study, the dose constraints were based on the
planning organ at-risk volume (PRV), which was the volume of each OAR plus a
margin of 3 mm (skin plus 5 mm margin to OAR). Due to poor accumulation, ulti-
mately only 10 patients were enrolled in the study. Nevertheless, no patient had
grade ≥3 adverse events, and 60 Gy/8 Fr at the isocenter was set as the recom-
mended dose [20]. In addition, LungTech, a European Organization for Research
and Treatment of Cancer (EORTC) phase II study of SBRT for CLTs is in prog-
ress [21].
9.4 Treatment Planning
Considering severe, potentially life-threatening radiation toxicities to centrally

located serial OARs caused by SBRT for CLTs and UCLTs, it is essential to apply
alternative dose fractionation schedules and dose distribution for CLTs and UCLTs
9 Lung: Central 133
to PLTs. According to the guidelines of the American Society of Clinical Oncology

(ASCO) and the American Society for Radiation Oncology (ASTRO), to prevent
severe toxicity due to high-dose irradiation to mediastinal organs, it is strongly
recommended to avoid the use of 3-fraction regimens that are used with PLT, and
to consider 4- or 5-fraction regimens instead [22, 23]. The consensus guidelines
from the European Society for Radiotherapy and Oncology (ESTRO) and Advisory
Committee for Radiation Oncology Practice (ACROP) suggest that the conserva-
tive risk adopted fractionation for CLTs is needed; however, they do not make spe-
cific recommendations about optimal fractionation schemes [24]. In published
reports, dose prescription indicated a 60–90% isodose line covering at least 95% of
the PTV with the prescribed dose and/or covering 99% of the PTV with at least
90% of prescribed dose. Dose fractionations of 50–60 Gy/4–5 Fr were widespread.
In addition, the maximum dose used in PTV was generally kept at 110–130% of the
prescribed dose [2, 4, 12, 19, 21]. In clinical practice of SBRT for CLTs and ULCTs,
the most important factor to determine its indications and dose fractionation sched-
ules is dose constraints for mediastinal organs. Close attention should be paid to the
doses administered to organs for which grade 5 toxicities have been reported; that
is, the bronchial tree, esophagus, and pulmonary arteries. The dose constraints
which have been reported are summarized in Table 9.4. Among them, the dose con-
straints recommendations from the University of Texas’s Southwestern Medical
Center [25] are widely used. Moreover, various dose constraints for central airway
(trachea, PBT) have been recommended with clinical findings, such as the maxi-
mum dose at BED3 for the PBT not exceeding 180 Gy [17], and the maximum dose
for the trachea and bronchi at EQD2 being less than 70–80 Gy [19]. In contrast,
there has been few clinical information regarding toxicities of the esophagus. In
cases with grade 5 esophageal ulcers, the maximum dose of esophagus at BED3 was
154 Gy [15, 18], therefore, the maximum dose of esophagus at BED3 not exceeding
150 Gy is considered as a criterion. The SUNSET trial, which is a phase I clinical
study to determine the maximum tolerated dose of SBRT for UCLTs (tumors whose
PTV touches or overlaps the central bronchial tree, esophagus, pulmonary vein, or
pulmonary artery) is in progress [26]. It is expected that this study can provide fur-
ther guidance on dose constraints to central thoracic organs. The data from it have
been awaited.
In SBRT for CLTs and UCLTs, dose constraints are often defined in certain small
volumes of OARs; therefore, great care must be taken with the delineation of these
organs 16). Intensity-modulated radiation therapy is now widely used in SBRT for
CLTs and UCLTs to overcome the dose constraints of OARs, which is achieved
with comparative ease. However, to provide planned treatment in SBRT for CLTs
and UCLTs, high-precision image guidance techniques integrated respiratory
motion management that is equal or more precise than SBRT for PLTs are required
[27]. The cases that cannot meet the dose constraints of OARs and whose risk of
SBRT deemed too high, should be informed about alternative treatment options
including moderate hypo-fractionated regimens which would increase number of
fractions to ensure safety. Karasawa et al. performed moderate hypo-fractionated
radiation therapy at 75 Gy/25 Fr at the isocenter in 43 patients with CLTs (within
134
Table 9.4 Comparison of dose constraints among reported studies on SBRT for CLTs and UCLTs
JROSG10-1 [20]
UTSWMCa [25] RTOG0813 [4] HILUS [19] LungTech [21] SUNSET [26] (8 Fr)
(5 Fr) (5 Fr) (8 Fr) (8 Fr) (5–6 Fr) PRVc
OARb OAR OAR OAR OAR (OAR+3 mm)
Mediastinal organ Metric Constraint Metric Constraint Metric Constraint Metric Constraint Metric Constraint Metric Constraint
Trachea/main bronchus Max 40.0 Gy Max 63.0 Gy Max 48.8 Gy Max 44.5Gy Max 62.0 Gy <10 cc 54.5 Gy
<4 cc 16.5 Gy <4 cc 18.0 Gy 10 cc 50.0 Gy
Esophagus Max 35.0 Gy Max 63.0 Gy Max 41.6 Gy Max 40.0 Gy Max 40.0 Gy <5 cc 40.0 Gy
<5 cc 19.5 Gy <5 cc 27.5 Gy 5 cc 35.0 Gy
Pulmonary artery Max 53.0 Gy Max 63.0 Gy None None Max 62.0 Gy <1 cc 54.5 Gy
<10 cc 47.0 Gy <10 cc 47.0 Gy 10 cc 50.0 Gy <10 cc 47.5 Gy
Aorta <10 cc 58.0 Gy
Other major vessels <1 cc 48.0 Gy
Spinal cord Max 30.0 Gyd Max 30.0 Gy Max 33.6 Gy <0.5 cc 32.0 Gy Max 30.0.Gy Max 33.5 Gy
<0.35 cc 23.0 Gy <0.25 cc 22.5 Gy
<1.2 cc 14.5 Gy <0.5 cc 13.5 Gy
Heart/pericardium Max 38.0 Gy Max 63.0 Gy Max 41.6 Gy None Max 62.0 Gy <15 cc 40.0 Gy
<15 cc 32.0 Gy <15 cc 32.0 Gy 10 cc 50.0 Gy
Abbreviation:
a
UTSWMC University of Texas’s Southwestern Medical Center
b
OAR Organ at risk
c
PRV Planning organ at risk volume
d
Spinal cord and medulla
T. Komiyama
9 Lung: Central 135
2 cm of the bronchial tree and/or mediastinal organs); the 5-year LCR was 80.4%,
the OSR was 46.7%, and they found the treatment to be favorable and safe, without
serious adverse events affecting the serial organs [28].
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Chapter 10
Lung: Toxicities
Yukinori Matsuo, Noriko Kishi, Kazuhito Ueki, and Masahiro Yoneyama
10.1 Introduction
The lung has a longer history of stereotactic body radiotherapy (SBRT) than other
organs. Multicenter prospective clinical trials were planned in the early 2000s, and
their initial results were reported in the early 2010s. Long-term clinical outcomes,
including toxicities, have been reported in recent years. In the updated analyses of
phase 2 trials of SBRT for inoperable patients with non-small cell lung cancer
(NSCLC), grade 3–4 toxicities were observed in around 20% of patients [1, 2].
Most of the toxicities were related to the pulmonary or the chest wall. In the long-
term follow-up of the operable cohort of JCOG 0403, the incidence of grade 3 tox-
icities was 9%, most of which were respiratory and chest wall related, as in the
studies above [3]. Toxicities after SBRT for the lung can occur at various sites in the
thorax, including the respiratory system and the chest wall. This chapter describes
toxicities in SBRT for the lung by the site of occurrence.
Y. Matsuo (*)
Department of Radiation Oncology and Image-Applied Therapy, Graduate School of
Medicine, Kyoto University, Kyoto, Japan
Department of Radiation Oncology, Kindai University Faculty of Medicine,
Osaka-sayama, Japan
e-mail: ymatsuo@med.kindai.ac.jp
N. Kishi · K. Ueki · M. Yoneyama
Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_10
138 Y. Matsuo et al.
10.2 Toxicities by Sites
10.2.1 Lung
The most common toxicity occurring after SBRT for the thoracic tumor is radiation-
induced lung toxicity (RILT), including radiation pneumonitis (RP) and pulmonary
fibrosis. Various pathways, numerous cell types, cytokines, and regulatory mole-
cules are considered to be involved in the development of RILT. However, most of
its mechanisms are still unknown [4]. Corticosteroids reduce inflammatory cell
infiltration and cytokine expression. The activation of the angiotensin-converting
enzyme (ACE)/type 1 angiotensin receptor pathway by irradiation is demonstrated
in preclinical models, which might contribute to the decreasing risk of RP by ACE
inhibitor use [5].
10.2.1.1 Clinical Manifestations
Typical symptoms are dry cough, dyspnea, and respiratory insufficiency. Regarding
imaging features, acute changes on CT are observed as patchy consolidation, slight
homogeneous increase in opacity, and discrete consolidation in the area with 24 Gy
or more irradiated [6]. Typical late changes on CT are consolidation, volume loss,
bronchiectasis, mass-like fibrosis, scar-like fibrosis, and no evidence of increased
density [7], which were often difficult to distinguish from local recurrence. High-
risk factors which indicate local recurrence are as follows: sequential enlargement
on repeat CT, opacity enlargement after 12 months post-SBRT, bulging margin, the
disappearance of air-bronchograms, linear margin disappearance, ipsilateral pleural
effusion, and lymph node enlargement [8].
The risk factors for developing RP after thoracic irradiation are dose-volume
indices (DVIs), age ≥50 years, smoking history, prior history of irradiation, autoim-
mune disease, COPD, interstitial lung disease (ILD), and the use of systemic ther-
apy [9]. The existence of ILD is a well-known risk factor for RILT. According to a
systematic review of toxicity in medically inoperable patients with early-stage
NSCLC and coexisting ILD [10], the proportion of treatment-related ILD-specific
toxicity, which was defined as radiation pneumonitis grade 3 or worse or acute exac-
erbation of ILD, and treatment-related mortality was 25.5% and 15.6%, respec-
tively, after SBRT. Recent development of immune checkpoint inhibitors (ICIs) and
targeted therapies raises a concern about RILT when combining these medicines
with SBRT. Concurrent use of EGFR-inhibitors with SBRT may slightly increase
RILT according to Kroeze et al. [11], however, only limited data is available on this
topic. The overall rate of radiation pneumonitis grade 3 or worse was reported 8.1%
after combined thoracic SBRT and ICIs [12], which seems similar to that after
SBRT monotherapy.
10 Lung: Toxicities 139
Table 10.1 Dose constraints for five fractions proposed by UK SABR Consortium [52]
Organs Constraints for 5 fractions
Optimal Mandatory
Lung V20Gy 10% V20Gy 15%
Dmean 8 Gy
Heart D0.1cc 29 Gy D0.1cc 38 Gy
Brachial plexus D0.1cc 30.5 Gy D0.1cc 32 Gy
Proximal bronchus D0.1cc 35 Gy D0.1cc 38 Gy
Esophagus D0.1cc 35 Gy
Great vessels D0.1cc 35 Gy
Chest wall D0.1cc 43 Gy
Skin D0.1cc 39.5 Gy
D10cc 36.5 Gy
10.2.1.2 Dose Constraints
Lung DVI depends on the definition of normal lung, though contouring of the lung
varies among reports. The most common definition of lung contouring is the RTOG
atlas which defines the lung volume as a combined structure of the right and left
lung volumes while being contoured separately for evaluation [10, 13]. There is no
established consensus on which CT to use: breath-hold, free-breathing, or average
intensity projection.
HyTEC reported that most studies noted safe treatment with a rate of symptom-
atic RILT of <10% to 15% after lung SBRT with mean dose (Dmean) of the combined
lungs ≤8 Gy in 3 to 5 fractions and the total lung V20 Gy <10% to 15% [14]. Based
on the reports, the UK SABR Consortium recently updated the consensus on the
dose constraints for the lung (Table 10.1). In patients with ILD findings, strict dose
constraints would be preferred. The systematic review by Chen et al. [10] suggested
V20 Gy ≤6.5% and Dmean ≤4.5 Gy for patients with ILD.
10.2.2 Heart
Radiation-induced heart disease (RIHD) is one of the late toxicities which occurs
years or decades after irradiation. The clotting cascade, acute inflammation, chronic
inflammation, and fibroblast accumulation caused by irradiation are considered to
be associated with the development of RIHD [15].
The classical features of RIHD are as follows: acute pericarditis, pericardial effu-
sion, constrictive pericarditis, coronary artery disease, stenosis and regurgitation of
valves, arrhythmia, cardiomyopathy, and heart failure. The timing of the clinical
presentation varies depending on the involved part of the heart.
RIHD has been reported associated with treatment for lymphoma or breast can-
cer, while the literature on RIHD after lung SBRT is limited. The reported risk fac-
tors for RIHD are age at the treatment <50 years, prescribed dose >30 Gy, fractional
dose >2 Gy, hypertension, dyslipidemia, diabetes, smoking, structural heart disease,
and concurrent use of chemotherapeutic agents that cause cardiotoxicity [16].
Patients with lung cancer are often old and have comorbidities, among which car-
diac comorbidities account for 25–30% [15]. JACC Scientific Expert Panel pro-
posed the screening and diagnostic algorithm, which suggests that it is essential to
perform pre-treatment evaluation and careful follow-up after thoracic irradiation
based on chest X ray, echocardiography, annual history, and physical examina-
tion [16].
Dose constraints for the heart have not been well established. DVIs for the heart,
including mean dose, V5, V30, V35, V40, and V55, are suggested to be associated with
cardiac events in conventionally fractionated RT [15]. As for the dose constraints of
peripheral lung SBRT, the maximal dose (Dmax) <34 Gy and D15cc <28 Gy were used
Table 10.2 Dose constraints for JCOG 1408 [18]

Planning organ at risk volume Constraints for four fractions
Lung V40Gy 100 cm3
Dmean 18 Gy
V15Gy 25%
V20Gy 20%
Spinal cord Dmax 25 Gy
Esophagus/ pulmonary artery V40Gy 1 cm3
V35Gy 10 cm3
Heart V30Gy 15 cm3
Stomach/intestine V36Gy 10 cm3
V30Gy 100 cm3
Trachea/main bronchus V40Gy 10 cm3
Brachial plexus V25Gy 3 cm3
Other organs V48Gy 1 cm3
V40Gy 10 cm3
for the heart in the four-fraction schedule in RTOG 0915 [17]. JCOG 1408 uses
V30Gy ≤15 cm3 in four fractions for the heart (Table 10.2) [18]. For ultra-central
tumors, the SUNSET trial suggested dose constraints of Dmax <64 Gy and D10cc
<60 Gy in 8–10 fractions [19].
The heart consists of multiple substructures, which might have different radio-
sensitivities and lead to various cardiac events in patients with lung cancer who
received radiotherapy [15]. For example, doses lower than 5 Gy in the inferior seg-
ments of the heart may be associated with worse survival in patients treated for lung
lesions with SBRT [20]. Dose to the heart base >8.5 Gy was related to the decreased
survival rate [21]. The irradiated doses of superior vena cava or left atrium were
associated with changes in electrocardiogram [22, 23]. Further research is needed to
establish dose constraints for the heart substructures.
10.2.3 Brachial Plexus
The brachial plexus is one of the major organs at risk in SBRT for superior sulcus
or lung apex tumors, which account for 3–5% of lung cancer. Radiation-induced
brachial plexopathy (RIBP) is a late-onset, progressive, irreversible toxicity occur-
ring from 1 to 4 years after SBRT. The pathogenesis remains unknown but is
assumed to include nerve compression by indirect extensive radiation-induced
fibrosis, direct injury to nerves through axonal damage and demyelination and
injury to blood vessels [24].
The symptoms are neurogenic pain, numbness, and motor and sensory weakness.
Non-opioid analgesics, benzodiazepines, tricyclic antidepressants, and anti-
epileptics are used for pain control. The effectiveness of corticosteroids, hyperbaric
oxygen, pentoxifylline-tocopherol, and clodronate may relieve RIBP although there
is no established evidence yet.
The known risk factors for radiation-induced peripheral neuropathy other than
DVIs are as follows: concomitant or previous neurotoxic chemotherapy such as
cisplatin, vinca alkaloids, and taxanes, combined peripheral neuropathy or arteritis,
and pre-existing collagen vascular disease [24].
Dose to the brachial plexus should be related to the RIBP development. Forquer
et al. investigated 37 apical lesions which were treated with SBRT (the median dose
of 57 Gy in 3–4 fractions) [25]. The median of the maximum brachial plexus doses
of patients developing brachial plexopathy was 30 Gy (18–82 Gy). Two-year risk of

RIBP for Dmax >26 Gy was 46% vs 8% for Dmax ≤26 Gy (P = 0.04).
JCOG 1408 sets V25Gy ≤3 cm3 as a constraint for the brachial plexus in 4 fractions
(Table 10.2). The UK 2022 Consensus recommends D0.1cc <15 Gy for 1 fraction,
24 Gy for 3 fractions, 32 Gy for 5 fractions, and 39 Gy for 8 fractions as the manda-
tory constraints for the brachial plexus (Table 10.1).
10.2.4 Central Airways
SBRT for central lung tumors can cause late major airway toxicities. The risk of
toxicity must be balanced against the potential for local control of the tumor.
The most common side effects included hemoptysis, fistula formation, stenosis, and
occlusion [26, 27]. Doses to the main bronchi and the distance of the tumor to them
are suggested as risk factors for lethal toxicities in the central airways.
Definition of the proximal bronchial tree (PBT) in RTOG 0813 guidelines for con-
touring includes: the distal 2 cm of the trachea, the carina, right and left mainstem
bronchi, right and left upper bronchi, the intermedius bronchus, the right middle
lobe bronchus, the lingular bronchus, and the right and left lower lobe bronchi.
Lodeweges et al. retrospectively evaluated 72 patients treated with 60 Gy in 12
fractions for their ultra-central lung tumors with the PTV abutting the main bron-
chus in 79% and the trachea in 22% of patients [28]. The incidence of grade 3 or
higher toxicities was 21%, including 14% of grade 5 toxicities, all related to bron-
chopulmonary hemorrhage. Dmean of the main bronchus was associated with grade 3
or worse toxicities. Dmean of 91 Gy in the biologically effective dose with α/β of 3 Gy
(BED3), which corresponds to 54.6 Gy in the equivalent dose in 2-Gy fractions
(EQD2), was suggested as a threshold for the severe toxicities with the incidence of
56% vs. 11%. In the HILUS trial, a prospective multicenter phase 2 trial for tumors
located less than or equal to 1 cm from the PBT, 65 patients received SBRT with
56 Gy in 8 fractions [29]. Twenty-two patients (32%) experienced grade 3 to 5 tox-
icity, including 10 patients (15%) with treatment-related death. Dose to the com-
bined structure of the main bronchi and trachea and tumor distance to the main
bronchi were reported to be important risk factors for lethal bronchopulmonary
hemorrhage. The authors concluded that 56 Gy in 8 fractions should not be used for
tumors located 1 cm from the main bronchi and trachea. Even in the other patients
(i.e., tumors within 1 cm around the PBT but >1 cm from the main bronchi and
trachea), Dmax to the main bronchi/ trachea should be less than 70 to 80 Gy in EQD2
with α/β of 3 Gy.
Karlsson et al. evaluate the dose-response relationship between radiation-induced
atelectasis and bronchial dose in 74 patients treated with 20–50 Gy in 2–5 fractions
for central tumors [30]. They reported an incidence of 24.3% radiation-induced
atelectasis at a median time of 8 months. The median value of D0.1cc (in EQD2 with
α/β of 3 Gy) of the bronchial tree in patients who developed atelectasis was 210 Gy
vs. 105 Gy in those who did not. Duijm et al. analyzed the dose to the bronchial
structures in 134 patients with central tumors and calculated the normal tissue com-
plication probability of the side effects as seen on a CT scan [31]. When 0.5 cc of a
segmental bronchus was irradiated to 50 Gy in 5 fractions, it was about 50% likely
to be occluded radiographically. For the mid-bronchi and mainstem bronchi, the
50% risk level to develop grade 1 radiographically evident side effects (stenosis,
occlusion, or atelectasis) was Dmax of 55 Gy in 5 fractions and 65 Gy, respectively.
The UK 2022 Consensus recommends the dose constraints for PBT D0.1cc <38 Gy
for five fractions (Table 10.1).
10.2.5 Esophagus
The esophagus is another dose-limiting organ in the case of SBRT for centrally
located tumors. The high-grade toxicity events are relatively rare [32, 33]. However,
physicians should take care of unnecessary iatrogenic manipulation of the esopha-
gus or the use of systemic agents to reduce the risk of esophageal toxicities.
Reported side effects range from mild esophagitis to stricture, ulcer, perforation,
and tracheoesophageal fistula [34, 35]. Special attention is needed when SBRT is
delivered with concurrent use of systemic agents. Cox et al. reported 6.8% ≥G3
acute or late (late; 5%) esophageal toxicities in 182 patients treated with 24 Gy
single fraction paraspinal radiosurgery [36]. All grade 4 toxicities were associated
with radiation recall reactions after doxorubicin or gemcitabine chemotherapy, or
iatrogenic manipulation of the irradiated esophagus. Harder et al. reported 2 patients
(of a total 52 patients, 3.8%) with an esophageal fistula, both receiving adjuvant
antiangiogenic agents within 2 months after SBRT of 50 Gy with 5 Gy per frac-
tion [37].
Several retrospective studies evaluated the relationship between dose to the esopha-
gus and the risk of toxicity. Duijm et al. derived normal tissue complication proba-
bility (NTCP) models from 188 patients with central lung tumors treated with SBRT
(60 Gy in 8 fractions or 60 Gy in 12 fractions) and evaluated the following esopha-

gus dose constraints: D1cc <40 Gy in 8 fractions and <48 Gy in 12 fractions [38]. In
their series, high-grade esophageal toxicity occurred in 2.1% of the patients, includ-
ing 2 possible treatment-related deaths. Based on their NTCP models, the risk of
late high-grade (grade 3 or worse) toxicity is low (<1.5%), and the risk of acute
toxicity (grade 2 or less) is acceptable (<30%) when applying the dose constraints.
Wu et al. identified dosimetric parameters that may predict grade 2 or worse acute
esophageal toxicity in 125 SBRT patients [39]. They concluded that Dmax and D5cc to
the esophagus should be kept less than 44 Gy in EQD2 with α/β of 10 Gy and D5cc
≤22 Gy in EQD2 (α/β = 10 Gy), respectively, for keeping the acute toxicity rate
<20%. Nuyttens et al. created a dose-toxicity model for 56 patients treated in a
dose-escalation study (45–60 Gy in 3–7 fractions) for lung lesions [32]. There were
5 (9%) grade 2 esophageal complications. Their model predicted a 50% risk of late
grade 2 toxicity for Dmax of 43.4 Gy (101.4 Gy in EQD2 with α/β of 3 Gy) and D1cc
of 32.9 Gy (63.0 Gy in EQD2) Gy (in terms of 5-fraction equivalent dosing).
According to the recently published consensus by the UK SABR Consortium,
dose constraints to avoid grade 3 or worse toxicities of the esophagus are 15.4 Gy/1fr.,
25. 2Gy/3fr., 35 Gy/5fr., and 40 Gy/8fr. (Table 10.1). These constraints would keep
the risk of severe toxicity low.
10.2.6 Great Vessels
Great vessels in the case of thoracic SBRT include the aorta, vena cava, and pulmo-
nary artery. Radiation damage to these structures can result in hemoptysis, exsan-
guination secondary to rupture, aortic aneurysms or dissection, and pulmonary
hemorrhage.
Nishimura et al. reported dose distributions involving toxicity of major vessels
from a cohort of 381 patients who received 40–60 Gy in 5 fractions for centrally
located lung tumors [40]. They experienced two grade 5 hemoptyses, which
occurred more than a year after SBRT at the pulmonary artery and bronchus, near
the pulmonary hilum. The two patients received high doses at the pulmonary artery
(59.2 Gy and 61.3 Gy, respectively).
Xue et al. published a logistic dose-response model for aorta and major vessels
based on 625 cases [41]. The RTOG 0813 dose-tolerance limit of Dmax of 52.5 Gy in
5 fractions was found to have a 1.2% risk of grade 3–5 toxicity, and the Timmerman
limit of Dmax of 45 Gy in 3 fractions [42] had 2.3% risk.
10.2.7 Chest Wall and Ribs
Chest wall (CW) toxicities occur in 10–40% of patients who received SBRT for a
peripheral tumor. The toxicities are not fatal but can sometimes be troublesome to
the patient. CW consists of nerve and musculoskeletal tissue, and the composite α/β
ratio of CW is unknown, and the mechanisms of CW pain and the effect of the
SBRT fractionation scheme on CW toxicity are also unclear [43].
The incidence of severe CW pain requiring narcotic analgesics is about 2% [44].

The time to onset is considered to be 6 months or more after SBRT [45]. Some
reports indicated that CW pain precedes rib fracture (4.7–8.9 vs. 13.5–19.2 months)
[44, 46–48]. CW pain is not always due to rib fracture but can be due to intercostal
muscle or nerves damage by SBRT in the case without rib fracture. Dunlap et al.
reported pain resolved in about 50% of patients with any grade of CW pain and
about 40% of them with grade 3 CW pain. They also reported that all patients with
a rib fracture and CW pain continued to experience grade 2 or 3 CW pain [48].
Several clinical/treatment factors have been shown to be associated with CW
pain: tumor location in close proximity to the CW, large tumor/treatment volume,
obesity, female, younger age, continued smoking, high total dose, and hypofraction-
ation. The risk of CW toxicity would be low in patients with a distance between CW
and tumor of more than 1–2 cm [44, 49, 50]. Bongers et al. reported on a series of
500 patients and 530 tumors treated with risk-adapted fractionations based on tumor
location [51]. They reported that tumors in broad contact with the CW or tumors of
large size (T2) were irradiated with 60 Gy in 5 fractionations instead of 60 Gy in 3
fractionations and serious CW adverse events were rare.
The CW is defined as the 2–3 cm rind of the ipsilateral hemithorax outside the
lungs, including the ribs, intercostal muscles, and nerves. It is contoured at least
5 cm superiorly and inferiorly to the PTV [44, 52]. The ASTRO Guideline on SBRT
for early-stage NSCLC does not recommend trimming PTV or allowing undercov-
erage of the target to reduce CW toxicity [53].
The UK SABR Consortium recommends D0.1cc to the CW be kept lower than
30 Gy/1 fr., 36.9 Gy/3 fr., or 43 Gy/5 fr. to avoid grade 3 fracture or pain (Table 10.1).
For rib fractures, Pettersson et al. reported that the risk of rib fracture is stratified by
the amount of radiation received by 2 cm3 [54]. The small high radiation doses
delivered to which the ribs are well associated with fractures, with a risk close to 0
for D2cc <7.0 Gy × 3, and a 5% and 50% risk indicated for D2cc = 9.1 Gy × 3, and
16.6 Gy × 3, respectively.
10.2.8 Skin
Hypofractionated RT can cause acute severe skin adverse events. While few reports
are available on dermatitis after SBRT, skin necrosis and contracture can be
troublesome.
Welsh et al. reported that all grades of adverse events are about 39%, and grade 3 or
more are about 3% [55]. Moisturizing is encouraged prior to treatment, and cortico-
steroids, dimethyl isopropylazulene, zinc oxide ointment, and antibiotics are com-
monly used for grade 2 and above. Skin necrosis may require debridement [56]. The
following factors are known risk factors for skin adverse events [55, 56]: obesity,
diabetes, malnutrition, large tumor (GTV of 8 mL or more), posterior tumors close
to the skin surface, and a small number of coplanar beams (three or less).
The skin is defined as the 5-mm inner rind of body contour [57]. The CW volumes
receiving 20/30/35/40 Gy correlated with the risk of skin reactions [55]. In this
report, CW volumes receiving 30 Gy have the highest correlation (<50 mL, 22% vs.
≥51 mL, 44%; OR = 2.8, p = 0.02). Dose constraints from the UK SABR Consortium
consensus are given in Table 10.1.
10.3 Considerations on Re-irradiation
As long-term survival is achieved in lung cancer, more cases have to be considered for
re-irradiation for intrathoracic recurrence. In this situation, SBRT has the advantage
of high local control, while it has the disadvantage of the risk of serious adverse events.
The dose is an essential factor in determining re-irradiation. According to a
meta-analysis on the effectiveness and safety of re-irradiation with SBRT [58], the
incidence of toxicities of ≥ grade 3 was significantly different in patients with
cumulative doses of >145 Gy in EQD2 and < 145 Gy (15% vs. 3%). On the other
hand, the dose for re-SBRT was also associated with survival. The local control and
toxicity associated with using high doses of SBRT present a dilemma. Tumor loca-
tion is the other factor for repeat SBRT, and peripherally located recurrence is a
candidate for definitive re-irradiation with SBRT. Hearn et al. applied repeat SBRT
to 10 patients after excluding 22 patients who had large tumors, tumors abutting to
the mediastinum and chest wall, tumors within the zone of proximal bronchus, a
history of overlapping conventional RT before initial SBRT, severe medical
Table 10.3 Dose constraints for Organs α/β [Gy] Constraints (EQD2)
re-irradiation of the thorax
Spinal cord 2 Dmax 60 Gy
proposed by Rulach et al. [60]
Esophagus 3 Dmax 75–100 Gy
Brachial plexus 2 Dmax 80–95 Gy
Great vessels 3 Dmax 110–115 Gy
Proximal bronchus 3 Dmax 80–105 Gy
Skin/chest wall 2.5 ALARA
Heart 2.5 ALARA
Lung 3 Individualized
Abbreviations: ALARA As low as reasonably achievable,
EQD2 Equivalent dose in 2-Gy fractions
comorbidity, or persistent chest wall pain from initial SBRT [59]. The treatment
resulted in no grade 35 toxicity.
Rulach et al. summarized expert opinions on radical re-irradiation for NSCLC
[60]. Key recommendations included appropriate patient selection, diagnostic
workup for patients, and irradiation technique consisting of optimal image guidance
and highly conformal techniques. SBRT is a preferred technique when the re-
irradiation target is small with minimal overlap with previous irradiation. They pro-
posed the consensus cumulative dose constraints for the organs at risk in the thorax
(Table 10.3).
10.4 Summary
Various organs are at risk of toxicities in SBRT for the lung. Knowledge on the
toxicities is being accumulated and dose constraints for the organs at risk are getting
established. By taking these into account, most toxicities can be avoided. However,
extreme caution should be needed when SBRT is used in combination with new
agents or in re-irradiation.
Acknowledgments This work was partly supported by AMED under Grant Number 21ck0106581.
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Chapter 11
Liver
Yoshiko Doi
11.1 Etiology and Epidemiology
Primary liver cancer, including hepatocellular carcinoma (HCC) and intrahepatic

cholangiocarcinoma, was the sixth most commonly diagnosed cancer and third
leading cause of cancer-related death worldwide in 2020 [1]. The difference in mor-
bidity and mortality by gender was two–three times greater in men than in women.
The regional age-standardized incidence rates of liver cancer in 2020 were highest
in Eastern Asia, especially Mongolia, where the incidence rate is much higher than
in other countries. Main HCC risk factors include chronic hepatitis B virus (HBV)
or hepatitis C virus (HCV) infection, aflatoxin-contaminated foods, heavy alcohol
intake, excess body weight, type-2 diabetes, and smoking. Main risk factors vary by
region, with chronic HBV infection and aflatoxin exposure being the main causes in
regions at high risk of developing HCC (China, Korea, sub-Saharan Africa), and
HCV infection in other countries (Japan, Italy, Egypt). Mongolia, which has the
highest incidence of HCC, has the highest HBV; co-infections such as HCV and
alcohol consumption are thought to be the cause. Interestingly, the incidence and
mortality rates of liver cancer have been declining since the late 1970s in many
high-risk countries in East and Southeast Asia, including China, Taiwan, Korea, and
the Philippines, and since the 1990s in Japan. This effect is due to a decrease in the
number of HBV and HCV infections and exposure to aflatoxin as well as promotion
of vaccination against HBV.
HCC-related prognoses remain poor owing to the presence of underlying chronic
liver disease, late diagnosis, and frequent recurrence or progression after treatment
[2, 3]. To obtain better treatment results, early detection of HCC is necessary. In
Japan, a complete nationwide surveillance program covered by the National Health
Insurance has been established, and active surveillance is being conducted for
Y. Doi (*)
Hiroshima High-precision Radiotherapy Cancer Center, Hiroshima-shi, Japan
Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_11
154 Y. Doi
high-risk patients with chronic liver disease due to various factors, such as viral
hepatitis and alcohol consumption. As a result, as many as 66% of all cases are treat-
able with intent to cure at initial diagnosis, either by resection or percutaneous abla-
tion [4], which contributes to improved survival of liver cancer in Japan.
In contrast, in other parts of Asia and in Western countries, the early diagnosis
rate of HCC does not exceed 30% [5], especially in Western countries, where 50%
of cases are at an advanced stage at diagnosis. In the United States, despite an over-
all decline in the incidence and mortality rates of the most common cancers between
2003 and 2012, liver cancer incidence has shown an opposite trend, more than tri-
pling since 1980 [6, 7]. Racial disparities in HCC incidence, demographics, tumor
characteristics, treatment response, and total mortality have also been investigated.
According to the National Health and Nutrition Examination Survey, Blacks are
more likely than any other racial/ethnic groups to have chronic HCV infection, an
important risk factor for HCC. In the southern states of the United States, where
Blacks are particularly overrepresented, risk factors for HCC other than viral hepa-
titis, such as obesity, smoking, and alcohol consumption, which increase the overall
incidence of liver cancer in the United States are prevalent [6, 7].
Although the incidence of hepatitis has declined worldwide in recent years due
to vaccines and antiviral drugs, this increase in incidence due to other causes, such
as nonalcoholic fatty liver disease, is expected to have a significant impact on global
liver cancer incidence and not only the United States [1].
11.2 External-Beam Radiation Therapy (EBRT)
Professional organizations in each country have clearly established HCC treatment

algorithms. In particular, the clinical practice guidelines developed by the Barcelona
Clinic Liver Cancer (BCLC) of the University Hospital of Barcelona (a multidisci-
plinary team of all professionals involved in liver cancer founded in 1986) are rec-
ognized as important guidelines for treating liver cancer. These guidelines classify
patients according to tumor size and number, liver function status, and Eastern
Cooperative Oncology Group (ECOG) performance status (PS), from early stage
(BCLC 0 or A) to late stage (BCLC D) so that the best treatment strategy can be
determined for each patient [8]. This method of classifying treatment strategies
based on HCC progression and liver function status is widely used in other guide-
lines. The European Association for the Study of the Liver (EASL), in collaboration
with the European Organization for Research and Treatment of Cancer (EORTC),
also used the BCLC staging criteria to develop guidelines based on the grading of
recommendation, assessment, development, and evaluation (GRADE) system [9].
According to EASL-EORTC guidelines, liver transplantation, resection, and percu-
taneous ablation therapy are recommended treatments for early-stage HCC. However,
the number of patients who are eligible for liver transplantation is limited and unre-
alistic because various conditions must be met to perform liver transplantation in
clinical settings. The Japanese guidelines for HCC treatment state that resection or
11 Liver 155
percutaneous ablation therapy should be the treatment of choice for ≤3 nodules,

each ≤3 cm, in HCC [10]. Although stereotactic body radiation therapy (SBRT) for
small HCC has very good outcomes, likely comparable to resection and ablation, no
solid evidence (insufficient evidence and weak recommendation) exists to support
EBRT in the management of HCC; hence, many published guidelines unfortunately
conclude that it is not recommended as an initial treatment for HCC [8–10].
Historically, EBRT for HCC has been performed with caution owing to the rela-
tively high radiosensitivity of liver tissue and the technical limitations of tumor
delineation and irradiation. However, advances in diagnostic imaging and equip-
ment for radiotherapy, coupled with a better understanding of the tolerable irradi-
ated dose for the normal liver, have led to an increase in clinical data on the use of
EBRT for primary liver cancer over the past two decades. Multiple retrospective
studies and phase I and II trials have demonstrated that EBRT, when used as the
definitive treatment option for carefully selected patients with early-stage HCC,
provides positive results similar to those reported for other liver-directed treatments,
such as resection and percutaneous ablation therapy. In 2018, although the recom-
mendation was low, the American Association for the Study of the Liver Diseases
(AASLD) guidelines clearly stated that SBRT can be used as an alternative to abla-
tion therapy in the local treatment of small HCC for cases in which surgery was not
indicated [11]. In light of the rapid advances in EBRT research for HCC and the
trend of accumulating evidence, in January/February 2022, the American Society
for Radiation Oncology (ASTRO) published new clinical guidelines on EBRT for
primary liver cancer [12]. Currently, high-quality evidence to guide the use of
EBRT, including SBRT, for HCC is limited. However, an ASTRO guideline task
force comprising a multidisciplinary group of radiation oncologists, medical oncol-
ogists, and surgical oncologists determined that careful validation of low-to moder-
ate quality evidence supports considering EBRT as a reasonable treatment option.
In the ASTRO clinical guidelines, EBRT is recommended as a potential first-line
single-therapy option in patients with macrovascular invasion-negative HCC who
are not candidates for curative treatment (surgery or percutaneous ablation therapy).
In these patients, EBRT alone is recommended as a potential alternative first-line
therapy along with catheter-based therapies. These specific cases are as follows: no
candidates for surgery due to medical comorbidities, poor liver reserve, and tumor
location or size; no candidate for percutaneous ablation therapy due to technically
suboptimal situations, including lack of ultrasound echogenicity/visibility, rela-
tively large tumor size (>3 cm), and tumor location in close proximity to the dia-
phragm, gallbladder, or large vessel. EBRT is also recommended as a consolidative
treatment option for patients with liver-confined HCC who have incomplete
response to percutaneous ablation therapy or catheter-based therapies, and as a sal-
vage treatment option in patients with locally recurrent HCC after surgery, percuta-
neous ablation therapy, or catheter-based therapies. It also states that the
recommended EBRT technique is super- or moderately hypofractionated EBRT, the
so-called SBRT, in 3, 5, or 15 fractions; however, selection should be based on
tumor location, underlying liver function, and available technology at each institu-
tion. The NCCN guidelines (Ver. 5.2021) also recommend locoregional therapy for
156 Y. Doi
patients who are ineligible for curative surgical treatment. In addition to percutane-
ous ablation therapy and TACE, radiation therapy (especially SBRT) is listed as an
option for such locoregional therapy [13].
Thus, the status of EBRT for HCC is confusing, with some guidelines explicitly
considering EBRT as a treatment for HCC, while others do not. Prospective studies
comparing EBRT with other treatment modalities are important to establishing con-
vincing evidence for the effectiveness of EBRT for HCC. However, considering the
current situation in which resection and percutaneous ablation therapy are widely
practiced as standard treatments in various hospitals, it is difficult to conduct a pro-
spective study. The only notable phase III trial is currently underway in China
(NCT03898921) [14]. Initiated in 2019, this study aimed to compare radiofrequency
ablation (RFA) and SBRT for previously untreated small HCC (solitary tumor
≤5.0 cm without vascular invasion), expecting to accrue 270 participants with a
primary endpoint of a three-year overall survival (OS) rate. If the study is success-
fully completed, the results may provide important evidence worth considering in
HCC clinical guidelines.
11.3 Dose Prescription
There are various reports on SBRT dose fractionation and dose-defining methods,
including the resulting dose heterogeneity of the target tumor, ranging from 23 to
75 Gy in 3–6 fractions [15]. In general, one would think that a higher dose would
also have a higher local effect, but excellent local control rates were also observed
in cases in which HCC was treated with relatively low-dose SBRT regimens. Ohri
et al. analyzed results of a systematic quantitative review of published experience
with hepatic SBRT and concluded on no evidence of improved local control after
SBRT for HCC when higher intensity dosing regimens were used [16]. A meta-
analysis evaluating the efficacy of SBRT for HCC revealed a median EQD2 (dose
equivalent to treatment with 2 Gy per fraction) estimate for the prescribed dose of
83 (range, 48–115) Gy in the 32 studies evaluated [17]. In a study aimed at estab-
lishing tumor control probabilities (TCP) for liver tumors, the EQD2 for a 6-month
local control rate of 90% in HCC was estimated to be 84 Gy [18]. Unfortunately, the
optimal dose-response relationship is still unclear in the available literature because
it must be balanced by several factors, including baseline liver function, tumor vol-
ume, and proximity to nearby luminal structures. A review of the older literature
shows that HCC has not historically been considered a particularly radiosensitive
tumor. However, it has become clear that unnecessarily increasing doses can be
detrimental and worsen prognosis because both HCC and liver tissue are highly
radiosensitive [19]. Thus, it is important to perform SBRT with appropriate dose
constraints that consider the dose to a normal liver. (Liver dose constraints are
described in detail in other section.)
From many papers, there is a potential clinical benefit in terms of improved local
control when using dose escalation (biologically effective dose assuming α/β = 10
11 Liver 157
(BED10); 6500–10,000 cGy), provided OAR constraints can be met. The ASTRO
clinical guidelines describe in detail the recommended EBRT doses and fraction-
ation for HCC depending on the patient’s baseline liver function, typically defined
by the Child–Turcotte–Pugh (CTP) class. For example, 4000–5000 cGy in 3–5 frac-
tions is recommended for patients with baseline CTP class A liver function. In
Japan, patients eligible for SBRT have basically baseline CP class A to B7 liver
function, and dose fractionation of SBRT is mainly 3500–4000 cGy in 4–5 frac-
tions, with dose prescription based on an isodose curve in which 95% of the PTV is
covered by the prescribed dose and 60–80% of the maximum dose is fit to the edge
of each PTV.
11.4 Number and Size
There are no strict rules regarding the number of patients indicated for SBRT. Many
reported prospective trials have performed SBRT for multiple lesions (less than 4
HCCs). According to the Japanese guidelines, 1–3 HCCs are targeted as an indica-
tion for SBRT. If there are more than 4 HCCs occurring simultaneously, TACE is
usually recommended. However, SBRT should not be ruled out for patients with
multifocal HCC, and although there is little evidence, carefully selected patients for
whom local therapy is being considered may be treated with EBRT alone or in addi-
tion to TACE.
There are also no strict rules regarding SBRT size. In a prospective study con-
ducted overseas, SBRT was also performed for large HCC with tumor sizes >10 cm.
In the Japanese guidelines, SBRT is considered for tumors approximately 3–5 cm.
An association between local control and tumor size has been demonstrated, and
some reports suggest that tumors larger than 3–5 cm may require more intense dose
titration because of the possibility of inferior local control [16, 20, 21]. In a retro-
spective study that combined sequential therapy of SBRT plus TACE for large mac-
rovascular invasion-negative HCC with a median size of 8.5 (range 5.1–21) cm,
BED10 >10,000 cGy, and EQD2 of ≥7400 cGy were significant prognostic factors
for survival outcomes. However, it should be noted that the larger the tumor size and
higher the dose, the higher is the dose to the normal liver. Proton therapy has excel-
lent dose concentration, making it easier to deliver high doses to lesions while pre-
serving liver function. Since additional attention must be paid to the tolerable dose
to the liver when combining high-dose SBRT and TACE for large HCC, proton
therapy, which can reduce adverse events to the liver, should be considered a treat-
ment option.
158 Y. Doi
11.5 Dose Constraints: Liver
Patients with HCC are prone to liver toxicity after radiotherapy due to underlying
liver disease and comorbidities [22], and preservation of liver function is very
important for successful radiotherapy for liver cancer. Radiation-induced liver dis-
ease (RILD) is pathologically characterized as a veno-occlusive disease (VOD), and
is categorized into “classic” and “non-classic” RILD [23, 24]. The variability in
reporting the of RILD stems from the heterogeneity in liver toxicity definitions,
EBRT regimens used, baseline liver function, and other prior treatments such as
surgery and ablation therapy. In contemporary studies, classic RILD (defined as
anicteric hepatomegaly and ascites, and elevation of alkaline phosphatase out of
proportion to other transaminases, typically occurring within 4 months, and often
exhibiting severe fatal complications) has been rarely reported because of recent
advances in imaging and radiation techniques, including SBRT. “Non-classic
RILD” (e.g., CTP class score increases of ≥2), typically occurring between 1 week
and 3 months after therapy, mostly reported rates of 5%–15%. It is well known that
greater volumes of uninvolved liver (liver minus gross tumor volume) exposed to
increasing irradiation doses increase the risk of RILD, most notably in patients with
cirrhosis. To reduce RILD risk, it is important to accurately evaluate and minimize
the irradiation dose to the uninvolved liver, specifically in the low-dose range. To
avoid hepatic toxicity, the dose-volume limit guidelines recommended by the
Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) for nor-
mal liver dose constraints of 3–6 fractions of SBRT have been offered. For example,
the mean uninvolved liver irradiated dose (MLD) should be <13–18 Gy, or ≤15 Gy
for an MLD of ≥700 mL of the normal liver [24]. The ASTRO clinical guidelines
describe in detail the dose constraints to the liver according to baseline liver func-
tion and type of fractionation regimen. For SBRT in five fractions, the recommended
dose constraints of MLD were as follows: mean dose <1500–1800 cGy and ≥700 cc
<2100 cGy in patients without cirrhosis, mean dose <1300–1500 cGy and ≥700 cc
<1500 cGy in patients with Child-Pugh class A, and mean dose <800–1000 cGy and
≥500 cc <1000 cGy in patients with Child-Pugh class B7. This guideline empha-
sizes that the selection of fractionation regimen and degree of dose escalation must
be carefully balanced against the dose to the uninvolved liver and risk of RILD [12].
Repeat SBRT is sometimes performed because frequent intrahepatic recurrences
are reported to occur frequently after treatment of hepatocellular carcinoma (68%
over 5 years) [25]. However, few reports have accurately evaluated the risk of devel-
oping RILD after repeated SBRT. Kimura et al. conducted a multi-institutional ret-
rospective study after repeated SBRT (≥2 courses [median, 2; range, 2–5 times]) for
189 lesions in 81 patients [26]. According to the results, the 5-year OS rates from
the first SBRT was 60.4%, and the 3-year OS rate from the second SBRT was
61.0%. There was also no significant difference in the incidence of G3 or higher
adverse events during the follow-up period between the two groups. Although these
results alone seem to indicate that repeated SBRT can be performed without any
11 Liver 159
problems, it is important to understand that there was a strong bias in the included
case group: the hilar region rarely underwent repeated SBRT to avoid CBD toxicity.
Liver function also deteriorates over time in patients with cirrhosis, and the cumula-
tive irradiation tolerance dose to the liver with repeated SBRT remains unknown.
Gkika et al. reported that a higher cumulative irradiation dose to the liver did not
cause liver necrosis or RILD; however, they suggested that post-SBRT fibrosis due
to repeated SBRT in different regions may lead to increased portal pressure [27].
Although repeated SBRT is not contra-indicated, careful case selection (e.g., well-
preserved patients who have good liver function, good performance status, and
small tumors that are not hilar) is important for successful repeated SBRT.
11.6 Dose Constraints: GI Tract
Gastrointestinal (GI) toxicity is another severe problem associated with SBRT for
HCC. Kang et al. reported that five (10.5%) of 47 patients experienced > grade 3 GI
toxicity, including grade 4 gastric ulcer perforation in two patients (4.3%) [28]. In
patients with liver cirrhosis, portal hypertension probably affects GI mucosal
defense and healing mechanisms, whereas liver cirrhosis increases GI toxicity [29].
For general SBRT (3–5 fractions) indications, it is recommended that the target
proximity to the luminal GI tract should be >2 cm from the tumor to avoid adverse
events in the GI tract [30]. Some studies have investigated the relationship between
the irradiation dose and GI toxicity in patients with HCC who received radiother-
apy. Kim et al. investigated the association between DVH and GI toxicity in 73
HCC patients treated with a median total dose of 36 Gy and a daily dose of 3 Gy
[31]. They reported that the 1-year actuarial rate of grade 3 GI toxicity in patients
with V35 Gy <5% of all the gastroduodenum was significantly lower than that in
patients with V35 ≥5% (4% vs. 48%, p <0.01). Yoon et al. also investigated 90
patients treated with conventional EBRT (median 37.5 Gy in 2–5 Gy per fraction)
for HCC in the adjacent GI tract [32]. In the multivariate analysis, V25 Gy in the
entire stomach and V35 Gy of the entire duodenum predicted grade ≥2 gastroduo-
denal toxicity; the gastric toxicity rate at 6 months was 2.9% for V25 ≤6.3% and
57.1% for V25 >6.3%, and the duodenal toxicity rate at 6 months was 9.4% for V35
≤5.4% and 45.9% for V35 >5.4%. These results suggest that GI toxicity is associ-
ated not only with the maximum dose, but also with the volume at which the medium
dose is irradiated. Studies have used hypofractionated radiotherapy (HFRT) to pro-
vide more effective radiation therapy for HCC in the adjacent GI tract. Tsurugai
et al. used HFRT with a dose gradient prescription (42 Gy in 14 fractions) for HCC
to the adjacent GI tract, keeping the dose to the PTV as high as possible while keep-
ing the dose to the overlapping area between the PTV and the intestinal structures
low [33]. As a result, they achieved good local control (11.3% local recurrence rate
at 2 years) and a low incidence of GI toxicity (only one patient (0.02%) of 66
160 Y. Doi
patients developed grade 3 gastroduodenal bleeding). In highly skilled facilities

with careful treatment planning, HFRT with a dose gradient prescription can be use-
ful for HCC in the adjacent GI tract. The ASTRO clinical guidelines describe dose
constraints on bowel structures in detail. For SBRT in five fractions, the recom-
mended bowel structure dose constraints are as follows: D0.03 cc <3200 cGy and
D10 cc <1800 cGy to the stomach, D0.03 cc <3200 cGy and D5 cc <1800 cGy to
the duodenum, D0.03 cc <3200 cGy and D5 cc <1950 cGy to the small bowel, and
D0.03 cc <3400 cGy and D20 cc <2500 cGy to the large bowel [12].
11.7 Clinical Results of Stereotactic Body Radiation

Therapy (SBRT)
The vast majority of studies, including retrospective studies and phase II trials,
reported 2- to 5-year local control rates of ≥90%, which compares favorably with
those reported for other ablative liver-directed therapies [34–43]. Takeda et al.
reported that a phase II study investigating the results of prior SBRT with TACE in
90 patients showed that the 3-year local control, liver-related cause specific survival
and overall survival rates were 96.3%, 72.5%, and 66.7%, respectively [41]. In
recent years, results of several prospective phase II studies have been published.
Kimura et al. conducted a phase II multicenter study of SBRT for previously
untreated first-episode small HCC. Thirty-six patients were enrolled in this study
between 2014 and 2018 [42]. The local control rate was 90% and the 3-year OS rate
was 78%. Also, Grade 3 or higher SBRT-related toxicities were observed in four
patients (11%); however, grade 5 toxicities were not observed. Jang et al. conducted
a multicenter phase II trial to evaluate the safety and efficacy of SBRT in patients
with unresectable HCC who showed incomplete response after TACE [43]. In total,
74 patients were enrolled between January 2012 and April 2015, and 65 eligible
patients were analyzed. In this study, the progression-free and overall survival rates
were 48% and 84% at 2 years, and 36% and 76% at 3 years, respectively. And the
actuarial rate of treatment-related severe toxicity at 1 year was 3%. Although many
patients in these studies were elderly or had comorbidities that precluded standard
treatment (surgery or ablation therapy), the good outcomes and high safety profile
of SBRT can be attributed to its favorable results, including high local control rates
and mild toxicity. Considering that, according to the EASL guidelines, the 5-year
OS rate is expected to be 40–70% when very early to early-stage HCC tumors are
treated with curative intent [9], the results of this study meet expectations of cura-
tive treatment for early-stage HCC. Prospective phase II studies of SBRT for patients
with relatively small HCC lesions are presented in Table 11.1.
11 Liver
Table 11.1 Phase II studies of SBRT for patients with relatively small HCC lesion
Median
duration of
Median Mainly Follow-up
Median age tumor prescription month Overall
Author Country n (range) Indication size (mm) dose (range) Local control survival
Takeda Japan 90 73 ≦4 cm 23 35–40 Gy 41.7 96.3% @3Y 66.7%@3Y
(2016) (48–85) all pts. received TACE (10–40) (6.8–96.2)
sessions
Kim Korea 32 59.5 ≦3 lesion cumulative 21 36–60 Gy/4 fr 27 90.6% @1Y 96.9% @1Y
(2019) (42–83) diameter ≦6 cm (10–45) D95 (12–55) 80.9% @2Y 81.3% @2Y
prior liver directed therapy,
mainly TACE
Kimura Japan 36 73.5 Newly diagnosed, solitary 23 40 Gy/5 fr 20.8 90% @2Y 84% @2Y
(2020) (57–85) (10–50) 80%isodose (4–57) 90% @3Y 78% @3Y
Jang Korea 65 61 Unresectable HCC, all pts. 24 45–60 Gy/3 fr 41 97% @2Y 84% @2Y
(2020) (44–84) received 1–5 TACE sessions (10–99) ≧D90 (4–69) 95% @3Y 76% @3Y
Durand-Labrunie France 43 72 Newly diagnosed, solitary 28 45 Gy/3 fr 48 98% @1.5Y 72% @1.5Y
(2020) (43–91) (10–60) 80%isodose (14–175) 69% @2Y
161
162 Y. Doi
11.8 Comparison of Outcomes by Treatment Modalities
Due to the lack of existing data directly comparing SBRT with other treatments,
there are papers that attempted propensity score matching (PSM) analysis. Regarding
comparisons between resection and SBRT, Su et al. compared the clinical outcomes
of patients who underwent resection and SBRT for one or two HCCs ≤5 cm. The
5-year OS rates of resection and SBRT were comparable after PSM (p = 0.405)
[44]. Regarding comparisons between TACE and SBRT, Sapir et al. compared out-
comes in patients with one to two tumors who underwent TACE to 114 tumors (in
84 patients) or SBRT to 173 tumors (in 125 patients) with PSM. The 2-year LC
proportion favored SBRT (91%) compared to TACE (23%) (P < 0.001) [45]. A
meta-analysis also showed better OS with SBRT compared to TACE alone [46].
Regarding comparisons between RFA and SBRT, four studies reported that SBRT
revealed equivalent or superior LC compared to that of RFA among five studies
[47–51]. There are four studies with partly conflicting results for OS, probably
because of a failure of matching important factors for HCC prognosis [48–51].
Among them, three studies with closely matching baseline liver function scores,
showed that the OS was similar between RFA and SBRT [48, 49, 51]. Eriguchi et al.
reported systematic review and meta-analyses focusing on BCLC-factors matching
[52]. They concluded that when BCLC factors were properly adjusted, the results of
the meta-analysis revealed equivalent OS and better LC for SBRT compared
with RFA.
11.9 Application of SBRT/EBRT to Advanced Lesions
For patients with macrovascular invasion-positive HCC, a well-known poor prog-

nostic factor, systemic chemotherapy is considered the standard of care, and other
multiple treatments, including surgery, catheter-based therapies, and EBRT are also
available in carefully selected patients. Several prospective trials have examined the
therapeutic efficacy of TACE plus EBRT in patients with macrovascular invasion-
positive HCC [53–56]. Yoon et al. conducted a randomized open-label clinical trial
to evaluate the efficacy and safety of TACE plus EBRT compared to sorafenib [53].
Between 2013 and 2016, 90 eligible patients were analyzed: 45 participants each in
the sorafenib and TACE plus EBRT groups. They concluded that first-line treatment
with TACE plus EBRT was well tolerated and provided improved progression-free
survival, objective response rate, time to progression, and overall survival compared
to sorafenib. Recently, several results from SBRT use in patients with macrovascu-
lar invasion-positive HCC are available [57, 58]. A meta-analysis reported a signifi-
cantly higher response rate in the SBRT group than the conventional fractionated
irradiation±TACE group [59]. It is anticipated that further research will be con-
ducted on the application of SBRT in patients with macrovascular invasion-
positive HCC.
11 Liver 163
11.10 CT Appearance of Tumor Response After SBRT
Modified RECIST (mRECIST), which incorporates not only the reduction in tumor
diameter but also the effect of tumor necrosis, is commonly used to determine treat-
ment efficacy after RFA and TACE for HCC [60]. However, after SBRT, many
tumors are known to slowly shrink and remain hypervascularized because it takes
time for cell death to occur. Therefore, it is difficult to accurately determine efficacy
using conventional evaluation criteria, such as mRECIST. One study showed a mea-
surable decrease in size of 35% at 3 months, 48% at 9 months, and 54% at 12 months
after SBRT [61]. Another report noted that all 67 HCCs treated with SBRT either
remained unchanged or decreased in size in the first 12 months post-treatment (34%
unchanged and 66% decreased), with none demonstrating an increase in size during
this time [62]. Several reports have described the contrast enhancement patterns of
SBRT-treated HCC. Kimura et al. reported the dynamic CT appearance of tumor
responses after SBRT for HCC, whereas residual early arterial enhancement was
observed >3 months after SBRT in 28.4% lesions (19/67 lesions) [63]. They con-
cluded that early assessments within 3 months could result in misleading response
evaluations. Sanuki et al. also reported SBRT in 42 cases of HCC with early-stage
staining and evaluated the treatment efficacy using mRECIST on dynamic CT [64].
The complete response rate increased over time to 24%, 67%, and 71% at 3, 6, and
12 months after treatment, respectively, with some cases remaining with early stain-
ing of contrast medium for more than 2 years. The correlation between radiographic
images and pathology in HCC after SBRT is very interesting; however, reports are
limited because SBRT is used as a last resort when RFA or surgery is contra-
indicated; moreover, there are few studies on lesions resected after SBRT. Mentiratta-
Lala et al. evaluated imaging of six patients who underwent liver transplantation
after SBRT and four patients with normalized tumor markers and found that resid-
ual blood flow does not indicate residual viable tumor, as some patients had residual
early staining of contrast medium on imaging, even when the tumor was controlled
pathologically or hematologically [65].
Furthermore, after SBRT, the liver parenchyma and not only the tumor included
in the SBRT treatment area undergoes characteristic changes over time. In early
post-SBRT, there is geographic arterial phase hyperenhancement (APHE) in off-
target parenchyma adjacent to the treated HCC, which persists for approximately
6 months [66]. APHE of the liver parenchyma within the treatment range of SBRT
is a change that appears due to reduced vascular perfusion by VOD and reduced
drainage effect by the hepatic vein, and not due to inflammation, as in radiation
hepatitis [67–69].
Although most studies have used CT imaging to evaluate radiation-induced
parenchymal changes, including APHE, some have used Gd-EOB-MRI and
diffusion-weighted imaging (DWI) in recent years [62, 66, 70, 71]. In cases after
SBRT for HCC, areas of hepatic parenchymal changes occur along a constant iso-
dose line (20 Gy–30 Gy in 3–5 fractions) in the hepatobiliary phase of the
Gd-EOB-MR image, allowing evaluation of the positioning accuracy of SBRT. In
164 Y. Doi
a pre-SBRT b 40Gy/4frs c after 4 months d after 7 months e after 12 months
Arterial phase
hepatobiliary phase
Fig. 11.1 Image changes over time after SBRT. (a) Early darkening in arterial phase/defect area
in hepatobiliary phase lesion just below the diaphragm. (b) We performed SBRT 40 Gy/4 frs. (c–e)
Hepatic parenchymal changes around HCC appeared after SBRT in hepatobiliary phase. There
was residual early arterial enhancement or unchanged size even after SBRT, however gradually
disappeared early arterial enhancement over a year
other words, the liver parenchyma changes around the HCC after SBRT, which is
shown in the hepatobiliary phase of the Gd-EOB-MR image and can be considered
a treated area after SBRT. These changes in Gd-EOB-MR images may help deter-
mine treatment efficacy for HCC with residual early arterial enhancement or
unchanged size even after SBRT (Fig. 11.1). DWI, which is independent of changes
in tumor blood flow, has also been reported useful in predicting treatment response
after SBRT. DWI is an MRI sequence that utilizes the diffusion of water molecules
in the tissue. Because HCC cells are smaller than normal liver cells, the signal inten-
sity of an HCC nodule is higher than that of the liver parenchyma. Therefore, DWI
is an indirect indicator of the presence or absence of HCC and is expected to be a
response indicator after SBRT for HCC.
Since characteristic temporal changes occur in the tumor and surrounding liver
parenchyma after SBRT, it is important to perform a comprehensive evaluation
using not only a single modality but also multiple modalities to determine treatment
efficacy. Without doubt, an increase in HCC size after SBRT or new nodular APHE
within HCC lesions after SBRT is highly suggestive of residual or recurrent viable
disease [72]. However, HCC after SBRT is not considered to still have a viable
lesion if APHE remains; however, the size of the tumor remains unchanged.
Japanese guidelines recommend that “local control” be defined as the absence of
spread of the treated lesion (no progression), regardless of the presence or absence
of APHE, when determining the efficacy of SBRT for HCC. Furthermore, when
evaluating the response rate, care should be taken at the time of decision. Several
reports suggest that it takes at least 6 months to achieve a maximum response; there-
fore, it is advisable to set a sufficient period of time based on an understanding of
the characteristics of change over time after treatment. Imaging evaluation for HCC
after SBRT should be approximately every 3–4 months for dynamic CT or MRI
imaging.
11 Liver 165
11.11 Summary—Eligibility of SBRT for HCC
Although there are no randomized prospective trials on the outcomes of SBRT for
HCC, excellent local control for HCC after SBRT has been often observed and is
being implemented not only in research but also in routine clinical practice. SBRT
should be considered for patients who are presently ineligible for resection or abla-
tion therapies. The eligibility criteria for SBRT are considered as follows:
1. CP class A or B.
2. <3 HCC nodules, up to 50 mm in diameter (within 2–3 cm is more suitable),
with or without vascular invasion.
3. Inoperability due to poor general condition.
4. Unsuitability for ablation therapy because of tumor location (e.g., just below the
diaphragm, liver surface, and near vasculature) or tumor invisibility on
ultrasonography.
5. Patient situation is as follows: obesity, bleeding tendency, or undergoing dialysis.
6. Patients who refused surgery or ablation therapy or had recurrence after surgery,
ablation therapy, and TACE.
Although the application of a treatment algorithm developed by various institu-
tions is the first choice in the treatment of HCC, in practice, there are many cases in
which salvage therapy is necessary due to residual tumor after local treatment, local
progression, or local intrahepatic recurrence. There is already sufficient data on the
efficacy of SBRT in this patient population requiring salvage therapy. It is important
to have multiple effective treatment options to improve the overall prognosis of
HCC. Further studies are needed to clarify when and how patients with localized
HCC can be best treated.
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Chapter 12
Kidney
Hiroshi Onishi
12.1 Reasons Why SBRT Is Receiving Attention for Renal

Cancer Therapy
According to recent reports showing good local response without severe toxicity,
SBRT has gotten to be presented as an optional treatment for medically inoperable
patients by very high age or comorbidities in NCCN guideline 2022 [1]. The rea-
sons why SBRT for renal cancer has been promising were thought to be as follows.
12.1.1 Renal Cancer Shows Lower α/β Compared

to Other Cancers
The biological effect of radiotherapy is expressed as “total dose × (1 + 1 dose/

[α/β])” when using linear-quadratic model. Because renal cancer shows lower α/β
values, (about 2.6 Gy [2]) compared to many other cancers (about 10 Gy), larger
radiation doses would theoretically result in better therapeutic effect and relatively
less occurrence of late adverse events. Therefore, in renal cancer, SBRT with a
larger radiation dose has greater value than for other cancers that show higher
α/β values.
H. Onishi (*)
Department of Radiology, School of Medicine, University of Yamanashi, Yamanashi, Japan
Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_12
172 H. Onishi
12.1.2 RCC Has Traditionally Been Considered

to be Radio-Resistant
Radiotherapy has hardly been considered as a curative therapy for RCC because this
cancer was considered to have lower sensitivity to radiation. In the medical treat-
ment guidelines for renal cancer, radiotherapy was mentioned only as a palliative
treatment for metastatic lesions. However, based on recent reports of therapeutic
results, SBRT can be applied as a curative therapy for RCC, and the concept of
radiotherapy for RCC has changed significantly.
12.1.3 After Removal of the Affected Kidney, Recurrence of

Cancer Frequently Occurs in the Remaining Kidney,
and the Patient Is Forced to Undergo Dialysis After the
Second Nephrectomy.
Renal cancer or degeneration of renal function is experienced by many patients with

one remaining kidney after nephrectomy of the affected kidney, so they are often
forced to undergo dialysis after a second nephrectomy. Hence, there are great expec-
tations for SBRT because this method can avoid dialysis after treatment.
12.1.4 An Increase of Abscopal Effect Can Be Expected After

a Single Irradiation with a High Dose, and the Effect
May Be Further Enhanced by Combined Use of
Immune Checkpoint Inhibitors.
Abscopal effect refers to an effect of radiation that induces regression of tumor

lesions in a non-irradiated area due to increased tumor antigen, and dendritic cell–T
cell interactions after irradiation [3]. Although the abscopal effect has been reported
in cases of RCC as well as in patients with malignant melanoma and malignant
lymphoma, little attention was paid to it because the effect was weak and did not
occur often. However, it was found that the abscopal effect can increase after a
single treatment with a large radiation dose as given by SBRT due to increase of
cancer antigen [4]. A further increase of abscopal effect can be expected by com-
bined immunostimulation using Nivolumab, a PD-1 antibody that is an immune
checkpoint inhibitor [5], and whose application to renal cancer was recently cov-
ered by insurance.
12 Kidney 173
12.2 Techniques of SBRT for RCC
SBRT for primary RCC requires accurate image guidance, and countermeasures
against moving of the irradiation site due to breathing. The kidney is an organ which
has a large movement interfractionally and intrafractionally. The internal motion of
the kidney can be affected by the position, volume, and peristaltic movement of the
surrounding gastrointestinal tract, as well as moving due to breathing. Therefore,
the movement of the kidney should be examined carefully before planning the treat-
ment. A variety of measures should be taken against movement due to breathing
including pressure, temporary breath-holding, synchronization, and tracking.
In the author’s institution, as shown in Fig. 12.1, setup errors and interfractional
breathing movement are corrected simultaneously each time by CT imaging in the
same room with breath-holding using the Abches [6], a ventilation unit which dis-
plays breathing volume. In case breath-holding was incomplete, a metal coil was
placed transarterially to use as a marker, and tracking radiation was applied using
the CyberKnife. For irradiation with breath-holding, the maximum error due to
respiratory movement was measured by 3 breath-hold CT scans, and PTV was
determined by adding a further 3–5 mm.
Although standard methods have not been established for planning SBRT ther-
apy, a consensus statement was issued by the International Radiosurgery Oncology
Consortium for Kidney (IROCK), an international study group for kidney cancer
SBRT irradiation [8]. Prescribed radiation doses vary depending on the institution,
such as 25 Gy/1 dose, 36–54 Gy/3 doses, 56 Gy/8 doses, or 50–70 Gy/10 doses.
The Treatment Planned in the Author’s Institution is as Follows (1–16):

1. Some method of controlling respiratory movement (abdominal pressure, breath
synchronization, temporary breath-holding, etc.
2. For the dorsal side and lateral side only, trunk fixation using a suction bag.
3. Algorithms are calculated by superposition, AAA-equivalent, or Monte
Carlo method.
4. Image-guided radiotherapy (IGRT) for each irradiation.
5. Contrast medium (dynamic imaging) for the planning CT if at all possible, and
imaging by slices of 2 mm or less. For patients who cannot use contrast medium
because of renal insufficiency, a simple MR image is obtained and fused with
the treatment plan CT to surround the GTV.
6. GTV (Gross Tumor Volume) = The renal tumor after arterial phase and contrast
CT (or MRI) is fused with simple CT images.
7. CTV (Clinical Target Volume) = GTV.
8. CTV = GTV + 3 mm for patients in whom contrast medium cannot be used, or
where tumor contour is unclear
9. ITV = CTV + variation in the positions obtained by three CT sessions with
breath-holding (measured individually for three axial directions)
10. PTV = CTV + 3 mm
11. MLC margin = PTV + 0 to 3 mm
174 H. Onishi
Fig. 12.1 SBRT method and an example of beams arrangement (non-coplanar 10 beams) with
dose distribution of SBRT for renal cancer in the author’s hospital. Setup errors and interfractional
breathing movement are corrected simultaneously each time by on-rail CT imaging in the same
room [7] with breath-holding using the Abches [6], a ventilation unit which displays breath-
ing volume
12. Non-coplanar static ports (5 or more) or dynamic arcs (5 arcs, 400° or more),
using IMRT or VMAT would be desirable.
13. In principle, the prescribed radiation dose is calculated as D95 (PTV) and set to
be equal to around 70% of maximum dose.
14. PTV can be suitably adjusted when it is difficult to meet radiation dose
constraints.
12 Kidney 175
15. Table 12.1 shows radiation dose constraints in Yamanashi University. For the
intestinal tract, however, as there is a great deal of uncertainty due to its move-
ment or volume changes, it is necessary not only to observe the dose constraint
but also to reduce the irradiation dose as much as possible.
16. Prescribed radiation doses are set maximally within the range of constraints
indicated in Table 12.1: 5–7 Gy/once/day, 3–5 times/week, 10 irradiations total,
up to 50–70 Gy total dose.
Dose constrains arranged according to representative fraction numbers made
from the above-referenced consensus statement [8], Siva’s clinical trial protocol [9],
and the author (Yamanashi)‘s method were shown in Table 12.2.
Table 12.1 Dose constraints for risk organs in the author’s institution
Organs at risk (no margins) Dose constrainta Subjected volume
Kidney Two kidneys BED3 < 60 Gy Mean (diseased kidney-PTV)
One kidney BED3 < 50 Gy
Lung V20 < 10% Lung-PTV
Spinal cord BED2 < 100 Gy Max
Gastrointestine BED3 < 144 Gy ≤1 cc
BED3 < 105 Gy ≤10 cc
Other organs BED3 < 240 Gy ≤1 cc
BED3 < 172 Gy ≤10 cc
a
BED3 Biological effective dose with α/β = 3Gy
Table 12.2 Dose constrains according to representative fraction numbers

Fraction number
Organs at risk 1 fraction 3 fractions 5 fractions 10 fractions
Spinal canal <1 cc to 8 Gy <0.03 cc to Max 30 Gy Max 35 Gy
<0.03 cc to 18 Gy
12 Gy Max 22.2 Gy
Duodenum and Max 26 Gy <1 cc to 24 Gy <5 cc to 20 Gy Max <1 cc to
intestine 5 cc < 22.5 Gy Max 30 Gy 30 Gy 52 Gy
<10 cc to
43 Gy
Stomach 1.5 cc < 15.4 Gy 5 cc < 22.5 Gy Max 30 Gy <1 cc to
5 cc < 22.5 Gy Max 30 Gy 52 Gy
<10 cc to
43 Gy
Colon 1.5 cc < 26 Gy 1.5 cc < 42 Gy Max 38 Gy <1 cc to
<20 cc to 25 Gy 52 Gy
<10 cc to
43 Gy
176 H. Onishi
12.3 Problems in Planning SBRT for Renal Cancer
There are some problems with using SBRT for renal cancers, including the follow-
ing (a–g):
(a) The dose to the target tissue cannot be determined in many cases because of
hemorrhage risk or other risks.
(b) Many histological tissue types have been reported for renal cancer. Optimal
irradiation doses may vary depending on the tissue, but the variations have not
yet been clarified and remain for future study.
(c) Even when radiation dose constraints are followed based on the treatment plan
CT, as the position or shape of the intestinal tract may change when radiation is
applied, care should be taken not to irradiate the intestinal tract with higher
radiation doses than those calculated. The volume of the intestinal tract may
change between doses during the dosing period. To allow for this, a large PRV
margin should be set when planning treatment, and changes in the intestinal
tract should be examined several times for about 30 min before irradiation, and
the daily difference should be determined.
(d) When the tumor is located anteriorly or laterally, the ascending colon and duo-
denum in the right kidney and the descending colon and stomach in the left
kidney may not easily meet dose constraints, and it may be difficult to use
SBRT depending on the site. In such cases, hyaluronic acid liquid is experimen-
tally inserted percutaneously to make a space [10] Preventive administrations of
gastric secretion inhibitors such as proton pump inhibitors or H2-receptor
antagonists may be preferable in cases the tumor is located near duodenum.
(e) In patients with low kidney function or with only one kidney, or in patients with
a large kidney tumor, deterioration of renal function after SBRT may be a
problem.
(f) When the tumor is located in the hilum of the kidney or an inferior medial posi-
tion, there is a theoretical possibility of radiation damage (such as hemorrhage,
stricture or perforation) to the renal pelvis and urinary tract. However, in the
author’s institution, marked adverse events have not been experienced in the
renal pelvis and urinary tract. Exact radiation dose constraints or very late com-
plications in the intestinal tract and urinary tract remain unknown and are sub-
jects for future research.
(g) Since the gold marker for marking is not covered by insurance, the marker has
been used off-label, or an angiography coil for marking can be used as a coun-
termeasure against hemorrhage in some cases. As tracking was impossible
without a marker, and IGRT was also difficult to perform, a wider PTV margin
was sometimes required. Insurance coverage to include the marker is desired.
12 Kidney 177
a b c
Fig. 12.2 A case of SBRT for RCC. (a) Before the start of SBRT. (b) Radiation dose distribution
(yellow line indicates 70 Gy/10 doses). (c) Four years after the end of SBRT
12.4 Examples of SBRT for RCC
Figure 12.2 shows the radiation dose distribution and image process in a patient
who underwent SBRT for RCC in the author’s institution. RCC typically progresses
very slowly, and continuously regresses after SBRT. It is important to understand
this specific characteristic to evaluate the effect of radiotherapy on this cancer. We
collected autopsy specimens from patients who showed continuous regression of
renal cancer over several years, and by histological observations, found that 90% of
tumor lesions became necrotic [11].
12.5 Results of SBRT for RCC
SBRT has been used in many patients with RCC as a Gamma Knife therapy for
cerebral metastatic lesions. Shuto et al. [12] reported that 82.6% local control was
obtained by the Gamma Knife therapy with a mean peripheral dose of 21.8 Gy for
a total of 314 metastatic cerebral lesions from RCC in 69 patients. Subsequently,
Svedman et al. [13] conducted a phase I/II trial of extracranial SBRT in patients
with primary and metastatic RCC and reported a 93% local control rate after irradia-
tions of 32 Gy/4 doses to 45 Gy/3 doses.
Table 12.3 shows local control rates and adverse events reported in major articles
on SBRT for primary RCC lesions [14–21]. Svedman et al. reported local control in
six cases (observation periods of 10–70 months), and mild renal dysfunction in only
1 case after SBRT with 30–40 Gy/3–4 doses in a total of 7 primary RCC lesions
[14]. In the author’s institution, a total of 10 patients with primary RCC (judged by
image diagnosis) have undergone SBRT, and no local exacerbation was reported in
178 H. Onishi
Table 12.3 Local control rates and adverse events reported in major articles on SBRT for primary
RCC lesions
Author Dose/
(reference Patients Median follow-up fractionation Local
number) number duration (months) number control Toxicity
Svedman [14] 7 39 30 Gy/3fr, 86% Grade 1–2: 58%
40 Gy/4fr
Beitler [15] 9 26.7 40 Gy/5fr, 100% Grade 1–2: 33%
42 Gy/6fr
Teh [16] 2 9 24-48 Gy/3–6 100% Not reported
fractions
Funayama [17] 10 48 50–70 Gy/10 100% Grade 4,5:20%
fractions (solitary kidney
cases)
Staehler [18] 40 28 25 Gy/1 fraction 98% Grade 1: 15%
Siva [19] 126 9–57.5 16-72Gy / 3-16fr 80– Grade
Review 100% 1–2:20–89%
Grade 4: 10%
Siva [20] 223 20–120 14–70 Gy/1-10fr 97.8% at eGFR: −5.5%
Pooled 2y
analysis
Correa [21] 372 6–89 15–70 Gy/1-10fr 97.2% Grade 3–4: 1.5%
Review eGFR: −7.7 mL/
min
all the patients during 11 to 89 months of follow-up [17]. In 2012, Siva et al. con-
ducted a systematic review for 10 articles and found that local control was 93.9% in
a total of 126 cases [19]. In 2018, international multicenter pool analysis was per-
formed for 223 cases by IROCK and showed that local control rate present disease
survival rate and event-free survival rate were 97.8%, 91.9%, and 65.4%, respec-
tively, when the number of fraction(s) is set to 1–10 and when a biological equiva-
lent dose (BED) is set to 33.6–124.8 Gy (α/β = 10 Gy). Although there appeared no
difference in local control rates between a single dose therapy group and a divided
dose therapy group, a higher survival rate and a lower metastasis rate were obtained
in the single dose therapy group [20]. A low α/β and the abscopal effect were con-
sidered to be involved in these favorable results, and further studies on prescribed
radiation dose with dose division are awaited2. In 2019, Correa et al. performed a
systematic review of meta-analyses for a total of 372 cases from 26 reports, and
methods of prescribing radiation doses, and therapeutic effect and occurrence of
adverse events were analyzed [21]. The results showed that a total of 26 Gy/1 dose
or a total of 40 Gy/5 doses were the most widely used methods, and local control
rate, occurrence of grade 3 or 4 adverse events, and change in eGFR were 97.2%,
1.5%, and a decrease of 7.7 mL/min, respectively.
Regarding the course of post-treatment over time, the rate of tumor shrinkage
after treatment is often characteristically slow, from results of SBRT for primary
lesions of the authors [17]. Very slow regression of tumor after SBRT is one of the
12 Kidney 179
features of RCC, and the tumor tended to be misunderstood as having radiation

resistance due to this feature. It is important to grasp this feature of RCC to evaluate
therapeutic effect after SBRT. Concerning adverse events, as mentioned earlier,
dose-dependent functional degeneration of the normal kidney and radiation enteritis
were sometimes a problem when the digestive tract came close to the tumor lesion.
The frequency of serious adverse events can be reduced by setting dose constraints
for normal organs. However, when the renal tumor is located anterolaterally of the
kidney, the colon, or duodenum may come close to the tumor lesion. There were
many cases where it was not possible to apply SBRT, or an insufficient radiation
dose had to be used. As a countermeasure to deal with such cases, attempts have
been made to inject a liquid spacer percutaneously between the kidney tumor and
the intestinal tract.
12.6 Comparison with Other Therapeutic Modalities
In a propensity score matching study, the therapeutic effect of SBRT was compared
to those of partial nephrectomy, cryotherapy, and RFA, and it was found that the
overall survival rate obtained by SBRT was significantly inferior to those obtained
by the other therapeutic methods [22]. Although only 174 cases of SBRT were
included among a total of 91,965 cases in this propensity score matching study, at
the present time, SBRT is assumed to have lower priority as a treatment option for
primary renal cancer. However, because favorable results have been obtained
in local control rates by SBRT, this option is considered valuable for patients in
whom other therapeutic methods are considered high risk, and for patients with only
one kidney or with comorbid renal disorders who want to avoid starting dialysis
after nephrectomy.
12.7 Summary and Future Outlook
SBRT can be applied to RCC by taking advantage of the low α/β ratio of RCC, and
it is considered to possess high clinical value as a curative radiation therapy which
is safe and effective and allows radiotherapy to be completed in a short period of
time. This method should be considered a promising treatment strategy particularly
in inoperable patients, or patients who are concerned about dialysis after nephrec-
tomy such as those with a single kidney. Therefore, more indications of SBRT for
RCC are expected. In addition, enhancement of the abscopal effect by combined use
with the PD-1 antibody preparation, which is already covered by insurance, is
extremely promising both for research and clinically.
However, long-term outcomes in a large number of patients remain to be investi-
gated and, when the tumor is irradiated with a high dose, accurate tolerance doses
for the other organs surrounding the affected kidney such as the intestinal tract,
180 H. Onishi
normal kidney, renal pelvis, urinary tract, or blood vessels have not been deter-
mined. More case data and thorough follow-up studies are required.
Among uropathies, SBRT for prostatic cancer has already been approved to be
covered by insurance. In the future, the effectiveness of SBRT is expected to be
established also for other cancers such as renal pelvis cancer, ureteral cancer, blad-
der cancer, lymph node metastasis and metastasis in the vertebrae, and further
expansion of indications for SBRT is desired.
References
1. NCCN Clinical Practice Guidelines in Oncology Kidney Cancer Version 4.2022 https://www.
nccn.org/home
2. Ning S, Trisler K, Wessels BW, et al. Radiobiologic studies of radioimmunotherapy and exter-
nal beam radiotherapy in vitro and in vivo in human renal cell carcinoma xenografts. Cancer.
1997;80(12 Suppl):2519–28.
3. Law AW, Mole RH. Direct and abscopal effects of x-radiation on the thymus of the weanling
rat. Int J Radiat Biol Relat Stud Phys Chem Med. 1961;3:233–48.
4. Wersäll PJ, Blomgren H, Pisa P, et al. Regression of non-irradiated metastases after extracra-
nial stereotactic radiotherapy in metastatic renal cell carcinoma. Acta Oncol. 2006;45:493–7.
5. Park SS, Dong H, Liu X, et al. PD-1 restrains radiotherapy-induced Abscopal effect. Cancer
Immunol Res. 2015;3:610–9.
6. Onishi H, Kawakami H, Marino K, et al. A simple respiratory indicator for irradiation dur-
ing voluntary breath holding: a one-touch device without electronic materials. Radiology.
2010;255:917–23.
7. Onishi H, Kuriyama K, Komiyama T, et al. A new irradiation system for lung cancer com-
bining linear accelerator, computed tomography, patient self-breath-holding, and patient-
directed beam-control without respiratory monitoring devices. Int J Radiat Oncol Biol Phys.
2003;56:14–20.
8. Siva S, Ellis RJ, Ponsky L, et al. Consensus statement from the international radiosurgery oncol-
ogy consortium for kidney for primary renal cell carcinoma. Future Oncol. 2016;12:637–45.
9. Siva S, Chesson B, Bressel M, et al. TROG 15.03 phase II clinical trial of focal abla-
tive Stereotactic radiosurgery for cancers of the kidney—FASTRACK II. BMC Cancer.
2018;18(1):1030.
10. Hasegawa T, Takaki H, Miyagi H, et al. Cardiovasc Intervent Radiol. 2013;36(4):1144–6.
11. Onishi H, Kawasaki T, Zakoji H, et al. Renal cell carcinoma treated with stereotactic radio-
therapy with histological change confirmed on autopsy: a case report. BMC Res Notes.
2014;26(7):270.
12. Shuto T, Inomori S, Fujino H, at al. Gamma knife surgery for metastatic brain tumors from
renal cell carcinoma. J Neurosurg. 2006;105:555–60.
13. Svedman C, Sandström P, Pisa P, et al. A prospective phase II trial of using extracranial stereo-
tactic radiotherapy in primary and metastatic renal cell carcinoma. Acta Oncol. 2006;45:870–5.
14. Svedman C, Karlsson K, Rutkowska E, et al. Stereotactic body radiotherapy of primary
and metastatic renal lesions for patients with only one functioning kidney. Acta Oncol.
2008;47:1578–83.
15. Beitler JJ, Makara D, Silverman P, et al. Definitive, high-dose-per-fraction, conformal, stereo-
tactic external radiation for renal cell carcinoma. Am J Clin Oncol. 2004;27(6):646–8.
16. Teh B, Bloch C, Galli-Guevara M. The treatment of primary and metastatic renal cell carci-
noma (RCC) with image-guided stereotactic body radiation therapy (SBRT). Biomed Imaging
Interv J. 2007;3(1):e6.
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17. Funayama S, Onishi H, Kuriyama K, et al. Renal cancer is not radioresistant: slowly but con-
tinuing shrinkage of the tumor after stereotactic body radiation therapy. Technol Cancer Res
Treat. 2019;18:1533033818822329.
18. Staehler M, Bader M, Schlenker B, et al. Single fraction radiosurgery for the treatment of renal
tumors. J Urol. 2015;193:771–5.
19. Siva S, Pham D, Gill S, et al. A systematic review of stereotactic radiotherapy ablation for
primary renal cell carcinoma. BJU Int. 2012;110(11 Pt B):E737–43.
20. Siva S, Louie AV, Warner A, et al. Pooled analysis of stereotactic ablative radiotherapy for pri-
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21. Correa RJM, Louie AV, Zaorskyet NG, et al. The emerging role of stereotactic ablative radio-
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22. Uhlig A, Uhlig J, Trojanet L, et al. Stereotactic body radiotherapy for stage I renal cell carci-
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Chapter 13
Spine
Kei Ito and Yujiro Nakajima
13.1 Overview of Spine Stereotactic Body

Radiotherapy (SBRT)
SBRT is a high-precision radiotherapy technique that delivers a high ablative bio-

logical dose in a few fractions while sparing the adjacent organs-at-risk and has
several advantages when used as a treatment for spinal metastases. A systematic
review of SBRT for de novo spinal metastases showed promising outcomes, with
1-year local control (LC), complete pain response, and neurological injury rates of
90%, 54%, and 0.2%, respectively [1]. In a systematic review of spine SBRT admin-
istered as reirradiation therapy, the rates of LC at 1 year, overall pain response, and
radiation myelopathy occurrence were 76% (66–90%), 65–81%, and 1.2%, respec-
tively [2]. Another meta-analysis showed that postoperative spine SBRT for meta-
static epidural spinal cord compression (MESCC) achieved an LC of 88.9% [3].
Moreover, SBRT has been showed to produce long-term LC and a high response
rate to radiation-resistant metastases [4].
13.2 Patient Selection
Although the potential indications for spine SBRT are wide, eligibility criteria for
this modality are unclear owing to the insufficient evidence from large-scale ran-
domized controlled trials. The most widely used global criteria are based on the
“neurologic, oncologic, mechanical, and systemic (NOMS)” decision framework
proposed by physicians at the Memorial Sloan Kettering Cancer Center [5]. This
K. Ito (*) · Y. Nakajima

Department of Radiation Oncology, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan
Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_13
184 K. Ito and Y. Nakajima
Fig. 13.1 Criteria for Indications Factors when

determining the indications SBRT for RT considering SBRT
for spinal SBRT as indication
suggested by the authors. 1 Absolute Oligometastases
Re-irradiation
MESCC, metastatic
epidural spinal cord MESCC
compression, SBRT,
stereotactic body
radiotherapy; RT,
Relative Pain Long-term
radiotherapy prognosis
Radioresistance
Imminent
0 None
fracture
framework helps to determine a specific treatment approach that covers both radio-
therapeutic and surgical procedures based on four factors. Nonetheless, the frame-
work has some limitations as follows: (i) oligometastasis or painful metastases are
not described as the subjects, (ii) radioresistant tumors are an absolute indication,
(iii) there is insufficient information regarding the proper use of SBRT and conven-
tional radiotherapy, and (iv) it is derived from expert opinions rather than being
evidence-based.
Our own criteria for SBRT eligibility are shown in Fig. 13.1 and consist of two
axes: “indications for radiotherapy” and “factors when considering SBRT.”
“Indications for radiotherapy” include oligometastases, painful lesions, MESCC,
and imminent fractures [6]; these are ranked high-to-low according to priority of
SBRT. “Factors when considering SBRT” (i.e., not conventional radiotherapy) are
also ranked according to priority and include radioresistant tumors, previously irra-
diated lesions, and long-term prognosis. The absolute indication is set to 1.0, while
no indication is set to 0. SBRT should be considered if the sum of two applicable
factors from each axis (three or more factors for some patients) is ≥1.0. However,
we are unable to determine the specific numbers to assign to the relative indication
factors that range from 0.1 to 0.9. Moreover, clinicians must also consider age, per-
formance status, cancer type, pathophysiology, and the patient’s wishes when judg-
ing the indication for SBRT in clinical practice.
The American Society for Radiation Oncology guidelines mention exclusion cri-
teria for spine SBRT [7], some of which include (i) worsening or progressive neu-
rologic deficit, (ii) the inability to lie flat on the table for SBRT, (iii) a life expectancy
of less than 3 months, and (iv) radiosensitive histology such as multiple myeloma.
This information may also be helpful in clinical practice.
13 Spine 185
13.3 Methodology
13.3.1 Planning Images
13.3.1.1 Treatment Planning Computed Tomography (CT)
Because spine SBRT requires 30 min or more per fraction to complete, patients
must be positioned in a manner that allows for long-term immobilization while
remaining comfortable. For cervical or upper thoracic (typically to T3) spinal
lesions, patients are immobilized using a thermoplastic head-and-shoulder mask as
well as a head-and-shoulder vacuum cushion. For midthoracic or lower spinal
lesions, a full-body vacuum cushion is used while the patient is in a stable supine
position. A retrospective study found that an immobilization device with 6 degrees
of freedom used to set up spine SBRT resulted in margins of error within 1.2 mm
and 0.9 degrees with 95% confidence [8].
The American Association of Physicists in Medicine Task Group 101 and the
Spine Response Assessment in Neuro-Oncology (SPINO) group recommend CT
slice thicknesses of 1–3 mm and ≤2 mm, respectively [9, 10]. CT scans with thin
slices improve the accuracy of contouring, CT-magnetic resonance imaging (MRI)
fusion, and dose calculation.
13.3.1.2 MRI
Performing non-contrast-enhanced MRI or CT with myelography is necessary to

delineate the spinal cord and cauda equina, and SBRT is contraindicated if these
tissues cannot be contoured using either method. MRI is preferred over CT with
myelography given that the former can be used to delineate the gross tumor volume
(GTV), especially for epidural tumors [11].
Reproducibility of spinal alignment during CT is strictly required when perform-
ing MRI. Hence, we recommend the use of immobilization devices during MRI. The
preferred procedures for detecting the spinal cord are T1-weighted and T2-weighted
axial non-contrast-enhanced sequences. The routine use of gadolinium contrast
agent is controversial because both the normal bone marrow and tumor are enhanced
within the spinal bone segment, which makes them difficult to distinguish from
each other [10]. The SPINO group recommends an MRI slice thickness of 1–2 mm
with no skip [10].
In terms of spinal instrumentation, certain measures should be taken to reduce
metal artifacts. These include the use of nonmagnetic (namely, titanium) implants
as well as using countermeasures during MRI such as (i) using a lower magnetic
field strength, (ii) increasing the bandwidth, (iii) using spin-echo instead of gradient
echo, (iv) shortening the echo spacing, and (v) using view-angle tilting [12].
T2-weighted images with or without short-tau inversion recovery can also contour
the spinal cord and cauda equina [11]. In patients with metal artifact from hardware,
a combination of MRI and CT myelogram is useful for spinal cord delineation [11].
13.3.2 Contouring
13.3.2.1 Target Volume Definition
The definitions of each target are summarized in Table 13.1 [13]. MRI is preferred
over CT with myelography because it can be used to delineate the GTV. The
International Spine Radiosurgery Consortium recommends clinical target volume
(CTV) expansion based on the GTV location, wherein the spine is divided into six
sectors: the vertebra, both pedicles, both transverse processes, and spinous process
(Fig. 13.2). The CTV of a subclinical tumor that has invaded the marrow space
includes the sectors encompassing and adjacent to the GTV [13]. Although a set-up
margin of 2–3 mm is added to the CTV to create the planning target volume (PTV),
the latter is subtracted in areas where it overlaps with the spinal cord [13].
The target settings when performing postoperative SBRT are summarized in
Table 13.1 [14]. Notably, the CTV includes the tumor bed as determined using pre-
operative images, whereas surgical instrumentation and incisions are not included
in the CTV unless involved. Moreover, the CTV covers up to 5 mm of the epidural
space cranio-caudally because tumors tend to spread along the dura [15].
13.3.2.2 Defining Organs-at-Risk
T1-weighted or T2-weighted MRI is used to delineate the spinal cord, with a

1–2 mm margin added to create the planning organ-at-risk volume (PRV) of the
cord [16]. The physiologic motion of the spinal cord is <0.5 mm in all directions,
which is relatively insignificant compared to potential gross patient motion [17].
For the cauda equina, the thecal sac is contoured using T2-weighted MRI with no
margins added. Although substituting the PRV of the cord with that of the thecal sac
is an option [18], this can risk causing both an excess and deficiency in the margin
in cases where the spinal cord is not exactly centered in the spinal canal.
Table 13.1 Summary of contouring guidelines for each spine SBRT target
Target
volume De novo SBRT [13] Postoperative SBRT [14]
GTV Contour GTV using all available Residual disease on postoperative images
images
CTV Bony CTV expansion to account for Bony CTV expansion to account for
subclinical spread. subclinical spread based on preoperative MRI.
Circumferential CTVs encircling Surgical instrumentation and incisions not
the cord should be avoided. included unless involved.
Up to 5 mm beyond paraspinal extension and
cranio-caudally for epidural disease
PTV Uniform margin ≤3 mm (never Uniform margin ≤2.5 mm (never overlaps
overlaps with cord) with cord)
CTV Clinical target volume, GTV Gross tumor volume, MRI Magnetic resonance imaging, PTV
Planning target volume, SBRT Stereotactic body radiotherapy
13 Spine 187
Fig. 13.2 International Spine Radiosurgery Consortium anatomic classification system for con-
sensus target volumes for spine radiosurgery [13]. The spine is divided into six sectors: the verte-
bra, both pedicles, both transverse processes, and spinous process
Nerve roots isolated from the spinal cord or cauda equina are generally not con-
sidered organs-at-risk given the low incidence of radiculopathy [19]. However,
some trials impose dose constraints on the brachial plexus and sacral nerves [20],
which control limb movements.
13.3.3 Optimal Dose Fractionation Schedule
Various dose fractionations are used across different facilities, and there is no broad
consensus on the optimal dose fractionation for spine SBRT [21]. The evidence-
based optimal dose fractionations according to the purpose of SBRT (oligometasta-
ses, painful lesions, or MESCC) are shown in Table 13.2.
A meta-analysis comparing the prescribed doses for spine SBRT revealed that a
greater cumulative dose led to a higher 2-year LC rate in patients receiving 1–5 frac-
tions [22]. We recommend a dose fraction schedule based on those used in the
SABR-COMET trial (16 Gy/1 fraction, 18 Gy/1 fraction, 20 Gy/1 fraction, 30 Gy/3
fraction, and 35 Gy/5 fraction) [23] and in the dose comparison trial conducted by
Zelefsky et al. (24 Gy/1 fraction and 27 Gy/3 fraction) [24]. If the treatment goal is
a 2-year LC rate >80%, the appropriate dose fractionations reportedly are 18 Gy/1
fraction, 20 Gy/1 fraction, 24 Gy/1 fraction, 30 Gy/3 fraction, and 35 Gy/5 fraction;
a regimen of 24 Gy in a single fraction produced the highest estimated 2-year LC
rate (96%) per Soltys et al. [22]. In contrast, other studies identified a high dose per
fraction as a risk factor for vertebral compression fractures (VCFs) [25, 26]. A
multi-institutional retrospective study showed that ≥24 Gy/fraction and 20–23 Gy/
Table 13.2 Optimal dose Indication Optimal dose fractionations

fractionations according to the
Oligometastases 18, 20, 24 Gy/1 Fr;
SBRT purpose
30 Gy/3 Fr; 35 Gy/5 Fr
Painful lesion 24 Gy/2 Fr
MESCC 24 Gy/2 Fr, 30 Gy/5 Fr
Fr Fraction, MESCC Metastatic epidural spinal
cord compression
fraction were significant predictors of VCF when compared to the ≤19 Gy/fraction
on multivariate analysis (hazard ratios = 5.25 and 4.91, respectively) [26].
Fractionated SBRT is effective in avoiding the risk of VCFs.
Two phase III trials comparing conventional radiotherapy with SBRT with
respect to pain relief have been performed [20, 27]. In the RTOG 0631 trial compar-
ing SBRT using 16 or 18 Gy in a single fraction with conventional radiotherapy
using 8 Gy [27], the pain response rates after 3 months were 41.3% vs. 60.5%
(p = 0.99), showing no superiority for SBRT. The low SBRT dose may have contrib-
uted to these results. Meanwhile, in the SC.24 trial that compared SBRT using
24 Gy in two fractions with conventional radiotherapy using 20 Gy in five fractions
[20], the complete pain response rates after 3 months were 35% vs. 14% (p < 0.001),
demonstrating the superiority of SBRT. These data indicate that a prescribed dose of
24 Gy in two fractions is the most optimal for pain palliation.
Two single-center, single-arm, phase II trials that evaluated the clinical outcomes
of surgery followed by SBRT (30 Gy in five fractions or 24 Gy in two fractions) in
patients with MESCC [28, 29] revealed 1-year LC rates of approximately 90% and
good maintenance of ambulatory function with minimal toxicity. However, in cases
where the tumor is adjacent to the spinal cord, it may be better to increase the SBRT
fraction size. The dose constraint to the spinal cord for a radiation-naive region is
reportedly 12.4 Gy in a single fraction [30], which results in the delivery of 27.78 Gy
(biological equivalent dose with α/β = 10 [BED10]) to the epidural tumor in contact
with the spinal cord. In a regimen involving five fractions, 38.10 Gy (BED10) can
be administered to the epidural tumors because the spinal cord dose constraint
would be 25.3 Gy [30]. In other words, by increasing fractionation, it is possible to
escalate the minimum dose delivered to a gross tumor, which would contribute
towards achieving LC [31–33].
However, the above recommended doses may vary depending on conditions such
as irradiation history or radioresistance.
13.3.4 Optimizing the Target Dose Distribution
The prescribed dose is generally delivered to 90–95% of the PTV [23, 27].
Additionally, an isodose prescription is used to sharply reduce the dose outside the
PTV, while administering a high dose within it. Several dosimetric analyses have
13 Spine 189
shown a positive correlation between LC and the marginal dose to the GTV but not
to the PTV [31–33]. Therefore, an isodose prescription, which produces a steep
dose gradient and a hotspot in the target, is suitable not only for dose reduction to
the organs-at-risk but also to produce excellent LC.
If the GTV is not located near the spinal cord, its dose can be strengthened by
increasing the dose heterogeneity in the target. For example, the protocol of the
SC.24 trial allowed for a dose heterogeneity of +50% to the PTV [20]. If the GTV
is in contact with the spinal cord, the minimum GTV dose should be as close as
possible to the spinal cord dose constraint (with the latter being prioritized). The
created dose distribution should be visually checked for a steep dose gradient around
the spinal cord, considering that the maximum photon dose fall-off gradient is
10–13% per mm [34].
13.3.5 Dose Constraints
13.3.5.1 Spinal Cord and Cauda Equina
Table 13.3 summarizes the representative dose constraints for the spinal cord when
administering spine SBRT [9, 30, 35–38]. There are three dose constraints of 12.4,
14, and 16 Gy in a single fraction at the maximum point dose (with a point defined
as 0.035 cc or less [9]). Several studies examining SBRT for de novo spinal metas-
tases using the strictest constraint (maximum point dose of 17 Gy in two fractions
for thecal sac or PRV of the cord [30]) did not observe radiation myelopathy [29, 40,
41]. Reports that calculated dose constraint of 14 Gy adopted the spinal cord itself
(without PRV margin) as the structure of interest [9, 35–37] (Table 13.3). Some
reports that used this setting did not confirm radiation myelopathy in the long-term
follow-up [27, 42]. By alleviating the dose constraint to the spinal cord, it is possible
to increase the minimum dose delivered to an epidural tumor located near the cord.
However, radiation oncologists should use the 16 Gy dose constraint with caution in
clinical practice due to the small sample size of this phase I trial [38].
Sahgal et al. investigated the tolerated dose to the thecal sac among patients
treated with spine SBRT after initial conventional radiotherapy [39]. They recom-
mended (1) the cumulative maximum dose to the thecal sac normalized to 2 Gy
fractions assuming an α/β of 2 (EQD22) was ≤70 Gy, (2) an SBRT maximum thecal
sac EQD22 was ≤70 Gy, (3) an SBRT component comprised less than 50% of the
cumulative normalized dose, and (4) a minimum time interval to reirradiation SBRT
of at least 5 months. The specific dose constraints to the cord and thecal sac accord-
ing to initial radiation dose are summarized in Table 13.3.
Table 13.3 Representative dose constraints for the spinal cord or cauda equina (maximum
point dose)
Dose reporting Radiation
structure history 1 Fr 2 Fr 3 Fr 5 Fr
Sahgal et al. [30] Thecal sac None 12.4 Gy 17 Gy 20.3 Gy 25.3 Gy
AAPM TG101 [9] Spinal cord None 14 Gy N/A 21.9 Gy 30 Gy
Kim et al. [35] Spinal cord None 14 Gy 18.3 Gy 22.5 Gy 28 Gy
and medulla
Katsoulakis-Gimms Spinal cord None 14 Gy 19.3 Gy 23.1 Gy 28.8 Gy
model [36, 37]
Ghia et al. [38] Spinal cord None 16 Gy N/A N/A N/A
Sahgal et al. [39] Thecal sac 20 Gy/5 Fr–37.5 9 Gy 12.2 Gy 14.5 Gy 18 Gy
Gy/15 Fr
40 Gy/20 Fr, 45 N/A 12.2 Gy 14.5 Gy 18 Gy
Gy/25 Fr
50 Gy/25 Fr N/A 11 Gy 12.5 Gy 15.5 Gy
AAPM American Association of Physicists in Medicine, Fr Fraction, N/A Not available, TG
Task group
13.3.5.2 Esophagus
A retrospective data analysis by Cox et al. found that 6.8% of their patients devel-
oped grade ≥3 esophagitis caused by single-fraction SBRT for de novo spinal (C5–
T10) metastases (14/204 lesions) [43]. Based on dose-volume analysis, the authors
recommended that ≤2.5 cc of the esophagus should receive 14 Gy, with the maxi-
mum dose to the esophagus not exceeding 22 Gy. The esophagus (including the
esophageal wall and luminal contents) was contoured as a solid structure on CT
simulation images (without MRI); no internal margin was added. Notably, all seven
patients who experienced grade 4 or higher esophagitis had previously received
chemotherapy.
13.3.6 MESCC
13.3.6.1 Treatment Strategy
SBRT for MESCC requires a treatment strategy that is markedly different from that
required for other subjects. A randomized controlled trial that enrolled patients with
symptomatic, single-level MESCC demonstrated the superiority of surgical decom-
pression followed by 10 fractions of conventional radiotherapy using 30 Gy as the
first-line therapy over conventional radiotherapy alone [44]. However, another study
found that local failure as assessed by radiographic findings occurred in up to 70%
of patients during the first year following the standard treatment [45], suggesting
that postoperative conventional radiotherapy using 30 Gy was insufficient for long-
term tumor control.
13 Spine 191
SBRT has been performed to improve LC in patients with MESCC. However,

surgical intervention is required before administering SBRT to deliver a sufficiently
high tumoricidal dose to lesions that are adjacent to the spinal cord. A retrospective
study showed that patients with MESCCs of Bilsky grades 2 and 3 could benefit
from surgical resection before SBRT [46]. Another systematic review of retrospec-
tive studies investigating postoperative SBRT reported excellent outcomes, with a
crude LC rate of 88.6% at the final follow-up visit and a posttreatment ambulatory
status of 100% [11]. Two phase II trials of postoperative SBRT for MESCC have
been performed to date, with consistent results [28, 29]. Redmond, et al. reported
radiographic and symptomatic LC at 1 year were 90% [28]. Ito et al. reported that
1-year local failure rate was 13% and an improvement in ambulatory function was
confirmed in 13 (72%) of the 18 patients who exhibited impaired walking at regis-
tration [29].
13.3.6.2 Separation Surgery
The recently developed concept of separation surgery has shifted the treatment par-
adigm for MESCC from aggressive cytoreductive surgery towards less invasive
operations. Separation surgery is performed to create at least 2–3 mm tumor-free
space around the spinal cord via curettage, thereby enabling the delivery of a suffi-
cient SBRT dose to the tumor [47].
Lamina and pedicle/joint removal for decompression as well as vertebral destruc-
tion by the tumor itself can cause spinal instability, which requires instruments such
as pedicle screws, rods, and hooks to remedy. Fixation is generally extended to two
levels above and two levels below the affected vertebrae [48]. Considering the
delineation of the spinal cord for postoperative SBRT, titanium implants should be
used. Moreover, Carbon fiber/polyetheretherketone instrumentation is ideally rec-
ommended to reduce scattering and artifacts caused by these implants [49].
13.3.7 Follow-Up
13.3.7.1 Evaluation of LC
The SPINO group recommends conventional MRI for monitoring tumor response
after SBRT [10], with T1-weighted and T2-weighted axial non-contrast-enhanced
sequences preferred. T2-weighted axial images are particularly useful for assessing
paraspinal disease involvement. The recommended MRI follow-up frequency is
every 2–3 months after SBRT for the first 12–18 months (to confirm the presence or
absence of VCF) and every 3–6 months thereafter.
LC is defined as the absence of progression within the treated area [10]. To detect
progressive disease, T1-weighted MRI is useful for determining any increase in
tumor size and volume, while T2-weighted MRI can be used to evaluate
homogenous hypointensity [10]. Pseudoprogression occurs in 14–18% of patients

within 6 months of spine SBRT [50, 51], in which case repeat imaging and biopsy
are recommended [10].
13.3.7.2 Evaluation of Pain Response
Although previous investigations of palliative radiotherapy for bone metastases

used varying pain evaluation criteria [52], recently, the criteria defined by the
International Consensus Pain Response Endpoints is used as standard [53]. These
criteria are based on the amount of narcotic analgesics administered and use a
numerical rating scale of 0–10. This scale is used by the patients themselves to score
the worst pain during the preceding 3 days. Pain response is defined as complete or
partial response, defined as (1) pain reduction of ≥2 points without an increase in
analgesic use or (2) reduction of the analgesic by ≥25% from baseline without an
increase in pain [53].
13.3.8 Adverse Effects
The frequency of adverse effects is higher with SBRT than with conventional radio-
therapy. However, serious adverse effects are rare if dose constraints are followed.
Adverse effects are described below in order of their occurrence.
13.3.8.1 Pain Flare
Pain flare generally indicates a temporary aggravation of pain that occurs within
24–48 h after irradiation. A study of steroid-naïve patients who underwent SBRT
found that the incidence of pain flare was 68% (28/41 patients) [54], whereas
another of patients who were administered dexamethasone 1 h prior to SBRT and
for 4 days post-SBRT found the incidence of pain flare to be 19% (9/47 patients)
[55]. In contrast, other studies found the incidences of pain flares to be relatively
low at 23% (44/195 patients) [56] or 14.4% (73/507 patients) [57] despite the lack
of steroid use.
13.3.8.2 Pharyngeal and Esophageal Toxicity
These toxicities are commonly encountered in patients who undergo SBRT for cer-
vical and thoracic spinal metastases, and typically occur 2 weeks after irradiation
and last for a week. Severe toxicities such as esophageal fistula and perforation have
also been reported [29, 58]. Although the dose constraint of the esophagus is
13 Spine 193
described above (Sect. 13.3.5), the tolerable doses to the pharynx have not been
confirmed via dosimetric analyses.
13.3.8.3 VCF
High-dose radiation damages the bone matrix and degrades the vascular supply to
the bone, leading to bone fractures [59]. The incidence rate of VCF within 5 years
post-SBRT was significantly higher than that post-conventional radiotherapy (22%
vs. 7%, p = 0.044) according to a matched pair analysis [60]. A systematic review
also revealed that SBRT for spinal metastases causes VCFs in 13.9% (404/2911) of
spinal segments within a median time of 1.6–3.3 months [61]. Multivariate analysis
revealed that the greatest risk factors for VCF are lytic disease, baseline VCF, higher
dose per fraction, spinal deformity, older age, and tumor involvement in more than
40% of the vertebral body [61].
A high dose per fraction has reliably been found to be a risk factor for VCF. In
one multi-institutional study, the cumulative 1-year incidences of VCF were 39%
with ≥24 Gy/fraction, 19% with 20–23 Gy/fraction, and 10% with ≤19 Gy/fraction
[26]. Another meta-analysis of spine SBRT found that single-fraction SBRT was
associated with a significantly higher VCF rate than multi-fraction SBRT (19.5%
vs. 9.6%, p = 0.039), whereas there was no relationship between the total BED of
SBRT and VCF rate [25].
The spinal instability neoplastic score is used to evaluate spinal instability in
patients with spinal metastases [62] and is relied on by spine surgeons to determine
the indications for surgical treatment. Some studies have shown that a high spinal
instability neoplastic score is also a risk factor for SBRT-related VCFs [63–65].
13.3.8.4 Radiation Myelopathy
A systematic review found that SBRT for de novo and previously irradiated spinal
metastases caused radiation myelopathy in 0.1% and 1.2% of patients, respectively
[1, 2]. The RTOG0631 and SC.24 phase III trials that investigated SBRT for de novo
spinal metastases found that radiation myelopathy was absent in patients who
underwent the procedure [19, 27]. As such, an appropriate dose constraint can keep
the radiation myelopathy rate extremely low.
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Chapter 14
Oligomets
Nobuki Imano
14.1 Definition of Oligometastatic Disease
Oligometastatic disease (OMD) is a concept that was proposed in 1995 by Hellman

and Weichselbaum, based on the pattern of breast cancer progression [1]. It is an
intermediate condition between locoregionally advanced and polymetastatic dis-
ease and is thought to be curatively treatable. Various clinical trials have been con-
ducted to develop curative local treatments, in addition to standard care or systemic
chemotherapy. The definition of OMD in these clinical trials has varied. Several
reviews and guidelines have been developed to systematize the concept of OMD
[2–5] (Table 14.1).
In the European Society for Radiotherapy and Oncology (ESTRO)—American
Society for Radiotherapy and Oncology (ASTRO) consensus document, no clear
size or number of metastatic lesions is specified as a characteristic of OMD, although
it is indicated that the number of metastatic lesions (three or less or five or less) and
the size (5 cm or less) have been used to define OMD in past trials [2].
Imaging evaluation is crucial for the diagnosis of OMD, and appropriate evalua-
tion by either PET-CT or head MRI is recommended. The ESTRO and European
Organisation for Research and Treatment of Cancer (EORTC) consensus recom-
mendation states that imaging should be performed using methods appropriate for
imaging sites of common metastases and for detecting small lesions for each histo-
logical type [3].
N. Imano (*)
Department of Radiation Oncology, Graduate School of Biomedical Health Sciences,
Hiroshima University, Hiroshima, Japan
e-mail: imano@hiroshima-u.ac.jp
Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_14
Table 14.1 Clinical trials for OMD with lung cancer
200
Author Number of Primary Local Dose

(year) N OMD type lesions Design endpoint treatment fractionation RT prescription Main result
Gomez, 49 De novo OMD ≤ 3 lesions Randomized PFS SRT, NA NA PFS: 11.9 months vs
et al. (Synchronous: phase II Hypofraction- 3.9 months
(2016) 94%, Local ated RT, CRT, (HR = 0.35, 90% CI:
Metachronous: treatment + CT surgery 0.18–0.66, p = 0.0054)
6%) vs CT OS: 41.2 months vs
17.0 months
(HR = 0.30, 90% CI:
0.12–0.75, p = 0.017)
Iyengar 29 De novo OMD ≤ 5 lesions Randomized PFS SBRT 21–27 Gy/1fx, PTV D95%, PFS: 9.7 months vs
et al. (Primary+5) phase II 26.5–33 Gy/3 60–90%_isodose 3.5 months
(2018) Local treatment fx, (HR = 0.30, 95% CI:
+ CT vs CT 30–37.5 Gy/5 0.11–0.82, p = 0.01)
fx,
45 Gy/15 fx
Bauml 45 De novo OMD ≤ 4 lesions Phase II PFS SRT, surgery, NA NA PFS: 19.1 months (95%
et al. (Synchronous: local treatment + CRT CI, 9.4–28.7 months)
(2019) 31%, Pembrolizumab OS: 41.6 months (95%
Metachronous: CI, 27.0–56.2 months)
6 9%)
Weiss 25 Repeat OMD, ≤ 3 lesions Phase II PFS SRT Total dose was Brain: PTV PFS: 6 months (95% CI,
et al. induced OMD local decided D95%, 2.5–11.6 months)
(2019) treatment + TKI according to 50–100%_isodose OS: 29 months (95% CI,
localization and Others: PTV 21.7–36.3 months)
size of lesion D95%,
60–100%_isodose
Iyengar 24 Repeat OMD, ≤ 6 lesions Phase II PFS SBRT 18–20 Gy/1fx, NA PFS: 14.7 months, OS:
et al. induced OMD Local treatment 27–33 Gy/3 fx, 20.4 months
(2014) +TKI 35–40 Gy/5 fx
N. Imano
14 Oligomets 201
14.1.1 Classification of OMD
The ESTRO and EORTC consensuses have been established for the classification of
OMD [2]. In these documents, classification was based on the following five ques-
tions and divided into nine categories of disease states (Fig. 14.1).
Question 1: Does the patient have a history of polymetastatic disease before current
diagnosis of oligometastatic disease?
Question 2: Does the patient have a history of oligometastatic disease before the
current diagnosis of oligometastatic disease?
Question 3: Has oligometastatic disease been first diagnosed more than 6 months
after the primary cancer diagnosis?
Question 4: Is the patient under active systemic therapy at the time of oligometa-
static disease diagnosis?
Question 5: Are any oligometastatic lesions progressive on current imaging?
OMD diagnosis based on imaging is first classified as genuine or induced OMD
depending on whether there is a prior history of polymetastatic disease (PMD)
(Question 1). Genuine OMD is further classified into de novo, with no history of
oligometastasis; and repeat, with a history of oligometastasis (Question 2). De novo
OMD is further classified as synchronous or metachronous OMD, depending on
whether more than 6 months have passed since the diagnosis of the primary tumor
(Question 3). Metachronous, repeat, and induced OMD were further classified into
oligorecurrence, oligopersistence, and oligoprogression, depending on whether the
patient was undergoing chemotherapy (Question 4) and whether the disease had
progressed (Question 5). The prognosis and optimal treatment strategies may differ
for each OMD category. Currently, clinical trials are not necessarily based on this
classification. However, it may be necessary to develop treatment strategies based
on these disease states. This consensus is gradually becoming widespread and will
serve as the basis for future treatment strategies. This chapter discusses each clinical
trial based on this classification. In the following sections, the clinical trials to date
will be summarized, as well as the ongoing clinical trials for each primary site and
for clinical trials not specifying the primary tumor, with respect to the evidence for
oligometastases.
14.1.2 Non-small Cell Lung Cancer
Patients with non-small cell lung cancer (NSCLC) and distant metastases were pre-
viously associated with poor prognoses; however, the progress of molecular tar-
geted drugs against driver gene mutations and immunotherapy has increasingly
improved the outcomes of these patients. Among distant metastatic cases, patients
with OMD have been found to have better survival outcomes than patients with
polymetastatic disease, and they account for 25–50% of all metastatic NSCLC cases
202 N. Imano
Fig. 14.1 Classification of oligometastatic disease
[1] In addition, the survival of patients with OMD can be prolonged by local treat-
ment [6–12]. As mentioned above, OMDs have been classified into nine categories
based on five questions. The EORTC lung cancer group published a consensus on
the definition of synchronous OMD and recommended its use to classify patients in
future clinical trials [4]. According to the consensus, synchronous OMD is defined
as a condition with up to five distant metastases in up to three organs, and radical
treatment is technically feasible for all tumor sites with acceptable toxicity. The
involvement of mediastinal lymph nodes was not considered. 18F-FDG PET/CT
and brain imaging (preferably MRI) are considered mandatory for the diagnosis of
OMD. In addition, we describe the modalities that should be used to diagnose each
metastatic site. Evidence from recently published clinical trials of OMD in NSCLC
is primarily based on synchronous OMD. This chapter summarizes the evidence of
OMD in NSCLC for each OMD category.
14.1.3 Clinical Trials for De Novo OMD (Synchronous OMD,

Metachronous OMD) with Non-Small Cell
Lung Cancer
Two randomized phase II trials showed that local treatment significantly prolonged
progression-free survival (PFS) in OMD patients with NSCLC. Gomez et al. con-
ducted a multicenter, randomized phase II trial comparing local treatment combined
with maintenance chemotherapy to maintenance chemotherapy alone for de novo
14 Oligomets 203
OMD patients with NSCLC [7]. In this trial, three metastatic sites after the initial
systemic therapy were defined as OMD. A total of 49 patients were enrolled in the
study; 25 received local treatment combined with maintenance chemotherapy, and
24 received maintenance chemotherapy alone. The trial was terminated soon after
an interim analysis revealed a significant improvement in PFS in the local treatment
arm. The median PFS were 11.9 months (90% CI: 5.7–20.9) in the local treatment
arm and 3.9 months (90% CI: 2.3–66) in the maintenance chemotherapy arm
(HR = 0.35, 90% CI: 0.18–0.66, p = 0.0054). In addition, long-term results of this
trial showed improvements in OS of 41.2 months in the local treatment arm vs.
17.0 months in the maintenance chemotherapy arm (HR = 0.30, 90% CI:0.12–0.75,
p = 0.017) [8]. In both groups, there were only two grade 3 toxicities, and no grade
4 adverse events or treatment-related deaths. In this study, both radiotherapy and
surgery were acceptable as local treatments, and the total dose and technique of RT
could be determined by institutional decisions as long as the intent was curative.
Hypofractionated radiotherapy or SBRT were the most common treatments (n = 12,
48%), followed by a combination of surgery and RT (n = 6, 24%). All but one
patient in this study received RT. In this study, 94% and 6% of patients had synchro-
nous and metachronous OMD, respectively. This trial demonstrated that local treat-
ment plus maintenance chemotherapy improved PFS compared to maintenance
chemotherapy alone in OMD patients with three or fewer distant metastases. This
study differs from the study by Iyengar et al. in that it included patients with brain
metastases and EGFR or ALK mutations.
Iyengar et al. conducted a single-center randomized phase II trial comparing
SBRT plus maintenance chemotherapy with maintenance chemotherapy alone in
patients with de novo OMD with NSCLC [9]. Patients harboring EGFR or ALK
mutations were excluded from the study. OMD was defined as metastasis to up to
five sites other than the primary site. The primary endpoint was PFS. There were 14
and 15 patients in the SBRT plus maintenance chemotherapy and maintenance che-
motherapy arms, respectively. The median PFS for SBRT plus maintenance chemo-
therapy arm was 9.7 months vs. 3.5 months for maintenance treatment (HR = 0.304,
95% CI: 0.113–0.815, p = 0.01). Interim analysis showed a significantly improved
PFS in the SBRT plus maintenance chemotherapy arm, and the trial was terminated
early. Toxicities were comparable in both groups, with four grade 3 toxicities in the
SBRT plus maintenance chemotherapy arm and two grade 3 toxicities in the main-
tenance therapy group. Local treatment in this trial did not include surgery; only
SBRT was administered. Accepted RT dose included 21–27 Gy single fraction,
26.5–33.0 Gy in three fractions, and 30.0–37.5 Gy in five fractions prescribed to the
60–90% covering isodose, covering 95% of the PTV, although 45 Gy in 15 fractions
was allowed if the OAR dose constraint was difficult to achieve. The most common
treatment was a single irradiation at 12 sites (39%). This study demonstrates the
value of local therapy in SBRT patients with up to five distant metastases. The pro-
portions of synchronous and metachronous OMD were not reported in this study.
Bauml et al. conducted a single-arm phase II trial to evaluate the efficacy of anti-
PDL1 immune checkpoint inhibitors in combination with local treatments [10].
Fifty-one patients with de novo OMD or NSCLC were included in this trial. OMD
204 N. Imano
was defined as up to three metastatic lesions after first-line chemotherapy. Patients

treated locally received pembrolizumab as maintenance therapy. After a median
follow-up of 25 months, the median PFS was 19.1 months (95% CI: 9.4–28.7 months,
p = 0.005) compared to 6.6 months in the historical control group, showing a statis-
tically significant improvement. The results of this study were better than those
reported by Gomez and Iyengar and may indicate that the addition of an immune
checkpoint inhibitor to local treatment is effective. However, it should be noted that
the patients were enrolled after local treatment in the trial, which excluded those
with disease progression after local treatment. Local treatments used in the trial
were reported as SRT in 67%, surgery in 67%, and CRT in 51% (including dupli-
cates); however, no details of treatment, such as RT dose or prescription, were
shown. Most patients in this study had metachronous OMD (69%), and patients
with synchronous OMD tended to have poorer PFS than those with metachronous
OMD (HR: 1.98, 95% CI: 0.87–4.52, p = 0.10). Also, PFS tended to be worse in
patients who were negative for PDL-1 compared to those who were positive for
PDL-1 (≥ 1%) (HR: 3.10, 95% CI: 0.88–10.93, p = 0.08).
14.1.4 Clinical Trials for Induced OMD and Repeat OMD

with Non-Small Cell Lung Cancer
Weiss et al. conducted a phase II trial to evaluate the efficacy of local treatment
combined with EGFR-TKIs for OMD patients with EGFR-mutated NSCLC who
showed disease progression after responding to EGFR-TKIs. OMD was defined as
three or fewer lesions. The inclusion and exclusion criteria did not consider a his-
tory of PMD, suggesting that patients with induced OMD and repeat OMD were
eligible. A total of 25 patients were enrolled. PFS was 6 months (95% CI:
2.5–11.6 months) and OS was 29 months (95% CI: 21.7–36.3), which showed a
significant improvement over historical controls. In this study, both surgery and
SRT were acceptable local treatments. The total dose and fractionation of SRT were
determined based on the location and size of the lesions. Erlotinib was used as an
EGFR-TKI in combination with radiation therapy, and the protocol required a 3-day
rest period before and after radiotherapy. No grade 3 or higher adverse events were
attributed to SBRT, whereas two cases (8%) of acne skin rash that seemed to be
attributed to erlotinib were observed.
Iyengar et al. conducted a phase II study to evaluate the efficacy of concurrent
SBRT combined with erlotinib in patients with EGFR-mutated NSCLC in whom
early systemic chemotherapy had failed. Twenty-four patients were enrolled in the
study. The PFS was 14.7 months and the OS was 20.4 months, which were better
than those of the historical controls. In this study, only SBRT was used as a local
treatment. 18–20 Gy single fraction was used in 20% of patients, and 27–33 Gy in
three fractions and 35–40 Gy in five fractions were used in 40% each. Erlotinib was
14 Oligomets 205
started 1 week before SBRT and continued concurrently with SBRT until progres-
sive disease was observed. Although the study showed good results, two patients
(8%) had grade 3 toxicities related to SBRT (pneumonitis and back pain).
14.1.5 Ongoing Trials for OMD with Non-small Cell

Lung Cancer
The SARON trial (NCT 02417662) is a multicenter, randomized, controlled phase

III trial for patients with synchronous OMD with driver mutation negative NSCLC,
designed to evaluate the efficacy of radical radiotherapy or SBRT used in conjunc-
tion with standard chemotherapy [13]. Its primary endpoint is OS. OMD has been
defined as 1–5 metastatic lesions in up to a maximum of three organs. A total of 340
patients will be enrolled in the study by August 2022. The NRG LU-002 (NCT
03137771) trial is a phase II/III trial in which patients with synchronous or meta-
chronous OMD and NSCLC are randomly assigned to receive systemic therapy plus
SBRT (plus surgery) or systemic therapy alone. The primary endpoint of this phase
III trial is OS. OMD is defined as the presence of up to three metastatic lesions. A
total of 400 participants are expected to be enrolled by August 2022. If the results of
the SARON or NRG LU-002 trials are positive, one of these trials will be the first
phase III trial to prove the benefit of local treatment in OMD patients with
NSCLC. The currently planned JCOG2108 trial is a multicenter, randomized, con-
trolled, phase III trial for patients with metachronous OMD and NCSLC. Its pri-
mary endpoint is OS. OMD is defined as the presence of up to three metastatic
lesions. To date, most clinical trials on OMD in NSCLC have focused on synchro-
nous OMD. This study focuses on metachronous OMD (postoperative oligorecur-
rence), which may have a better prognosis than synchronous OMD [10]. The results
of this study are expected to shed light on the significance of local treatment of
metachronous OMD.
14.2 Breast Cancer
Breast cancer (BC) is the most common cancer in women worldwide, and most BC
deaths result from distant recurrence or metastatic disease. The current standard
treatment for metastatic breast cancer patients is chemotherapy, biologic therapy,
and/or hormonal therapy. Among BC patients with metastatic disease, almost half
have only 1–2 metastases [14], and 90% have four or fewer metastases. There are
many retrospective studies that have shown the benefits of metastasis-directed ther-
apy for selected patients with limited metastatic disease [15–21]. A study examining
206 N. Imano
the prognosis of oligometastases of various primary tumors reported that patients

with BC have a better prognosis than those with other primary cancers and may
benefit more from MDT [22]. Therefore, BC is potentially suitable for metastasis-
directed therapy in many OMD patients [22–25].
14.2.1 Clinical Trials for OMD with Breast Cancer
Trovo et al. conducted a multicentric single-arm phase II trial that investigated the
benefit of radical radiotherapy to all metastatic sites for extracranial OMD patients
with BC. OMD was defined as up to five metastatic lesions without brain metastases
[26]. Fifty-four patients with de novo OMD were included in this trial. After a
median follow-up of 30.6 months, the one- and two-year PFS were 75% and 53%,
respectively. The two-year LC and OS rates were 97% and 95%, respectively.
Radical radiotherapy treatments used in this trial included SBRT and fractionated
IMRT. The dose fractionation used in this trial was 30–36 Gy in three fractions
(66%), 45 Gy in three fractions (15%), and 60 Gy in 25 fractions (19%). radiother-
apy was well tolerated, and no grade 3 or higher toxicities were observed.
Milano et al. reported the updated results of a phase II prospective trial including
48 OMD patients with extracranial BC who received SBRT at all metastatic sites.
OMD was defined as up to five metastatic lesions without brain metastases [27].
Most patients received 10 fractions of radiation (typically 50 Gy each). With a
median follow-up period of 4.4 years, the 5-year OS rates for patients with bone-
only metastasis were 83%, while for patients with visceral disease the 5-year OS
rates were 31% (p = 0.002). The 5-year local control rate also tended to be better in
patients with BO than in those without it (100% vs. 73%, p = 0.076). This study
suggests that the efficacy of local therapy may depend on the site of metastasis.
David et al. conducted a single-institution prospective trial on single-fraction
SBRT for patients with bone-only OMD with BC [28]. Patients with up to three
metastatic bone sites were included in this study. A single fraction of 20 Gy was
administered for 80% of the isodose, covering 95% of the PTV. With a median fol-
low-up period of 24 months, the 2-year LC, PFS, and OS rates were 100%, 67%,
and 100%, respectively. None of the patients experienced toxicity of grade 3
or higher.
14.2.2 Ongoing Trials for OMD with Breast Cancer
The NRG BR-002 (NCT 02364557) trial is a phase II/III trial in which patients with
de novo OMD and BC are randomly assigned to receive systemic therapy plus
SBRT/surgery or systemic therapy alone. The primary endpoint of this phase III
trial was OS. OMD was defined as the presence of up to four metastatic lesions.
Patients with brain metastases were excluded from the study. At the time of writing,
14 Oligomets 207
the final report has not yet been made, but it was reported at ASCO in 2022 that the
trial would not proceed to Phase III due to a lack of improvement in PFS in Phase
II. The STEREO-SEIN trial (NCT 02089100) is a multicenter, randomized, con-
trolled phase III trial for patients with de novo OMD and ER-positive luminal BC
designed to evaluate the efficacy of SBRT in combination with systemic therapy. Its
primary endpoint is PFS. OMD is defined as 1–5 metastatic lesions. A total of 280
patients will be enrolled in the study, which is expected to be completed by February
2023. The currently planned JCOG2110 trial is a multicenter, randomized, con-
trolled phase III trial for patients with de novo OMD and BC. Its primary endpoint
is OS. OMD is defined as the presence of up to three metastatic lesions. This trial
differs from the other trials in that it also included patients with brain metastases.
14.3 Prostate Cancer
Prostate cancer (PCa) is the second most common cancer in men, and the sixth lead-
ing cause of cancer-related deaths worldwide. Systemic therapy, mainly with andro-
gen deprivation therapy (ADT), is the major treatment modality for prostate cancer
with distant metastases. Patients with limited distant metastases and external beam
radiotherapy for primary lesions reportedly show reduced PSA failure [29, 30]. On
the other hand, SBRT for distant metastases has been investigated in patients whose
primary tumors are under control. Owing to the better prognosis of PCa, even with
distant metastases, compared to lung or breast cancer, the role of SBRT has been
examined as a means of prolonging ADT-free time rather than improving OS. Several
trials have examined the significance of SBRT for distant metastases in patients
with OMD and PCa.
14.3.1 Clinical Trials for OMD with Prostate Cancer
Ost et al. conducted a randomized phase II study in which OMD patients with recur-
rent PCa were randomly assigned to either PSA surveillance every 3 months or
metastasis-directed therapy for all lesions. OMD was defined as the presence of up
to three lesions. MDT included both metastasectomy and SBRT [31]. The recom-
mended radiotherapy dose was 30 Gy delivered in three fractions. Treatment was
prescribed at 80% of the maximal dose covering 90% of the PTV. The primary
endpoint was ADT-free survival. ADT was initiated for symptomatic progression,
progression to more than three metastases, or local progression of known metasta-
ses. With a median follow-up period of 3 years, the ADT-free survival was 21 months
in the MDT arm, compared to 13 months in the surveillance arm (HR = 0.60, 80%
CI: (0.40–0.90); p = 0.11). The quality of life was similar between the arms, possi-
bly because of a lack of statistical power to detect a significant difference. Although
six patients experienced grade 1 toxicity in the MDT arm, no grade 2 or higher
208 N. Imano
toxicities were observed. This was the first prospective trial to demonstrate the ben-
efits of MDT in patients with OMD and PCa.
Siva et al. conducted a single-arm prospective trial to investigate the feasibility and
tolerability of metastasis-directed SBRT in patients with OMD PCa [32]. OMD was
defined as up to three metastatic lesions. A total of 33 patients were enrolled in the
study. 20 Gy single fraction was prescribed at the periphery at 80% of the maximal
dose, covering 95% of the PTV. With a follow-up period of 2 years, SBRT was fea-
sible in 97% of cases. Only one patient (3%) had grade 3 adverse events (vertebral
fractures). The one- and two-year local progression-free survival rates were 97%
(95% CI: 91–100) and 93% (95% CI: 84–100), respectively, and the distant progres-
sion-free survival rates were 58% (95% CI: 43–77) and 39% (95% CI: 25–60), respec-
tively. In those not on androgen deprivation therapy (ADT; n = 22), the 2-year freedom
from ADT was 48%. The authors concluded that a single 20 Gy SBRT was feasible
and tolerable with avoidance of ADT in approximately half of the patients at 2 years.
Bowden et al. reported an interim analysis of a phase II single-institution trial to
evaluate the efficacy of SBRT for all metastatic sites in OMD patients who relapsed
after definitive local treatment for primary PCa [33]. OMD was defined as up to five
metastatic lesions. In total, 199 patients were enrolled in this study. The primary
endpoint was the proportion of men who did not require treatment escalation within
2 years of the initial SBRT. A dose of 50 Gy in 10 fractions was prescribed for the
PTV. After a median follow-up of 35.1 months, 51.7% of patients did not require
systemic therapy 2 years after SBRT (95% CI: 44.1–59.3). The median length of
treatment escalation-free survival over the entire follow-up period was 27.1 months
(95% CI: 21.8–29.4 months). There was no difference in the efficacy of SBRT for
treating 4–5 vs. 1–3 lesions. PSA levels declined in 75% of patients. No late grade 3
toxicities were observed. This interim result suggests that SBRT is beneficial for
delaying treatment escalation in OMD patients with up to five lesions. The ORIOLE
trial is a randomized phase II trial evaluating the efficacy of SBRT in patients with
OMD and hormone-sensitive PCa. Fifty-four men with oligometastatic PCa were
randomized in a 2:1 ratio to receive SBRT or observation. This trial defined OMD as
the presence of up to three lesions with a size requirement of less than 5 cm in length
and less than 250 cm3 in volume. The primary endpoint was disease progression at
6 months. Prescribed doses ranging from 19.5–48.0 Gy in 3–5 fractions. With a
median follow-up period of 18.8 months, progression at 6 months occurred in seven
of 36 patients (19%) in the SBRT arm and in 11 of 18 patients (61%) in the observa-
tion arm (p = 0.005). The median PFS was longer in the SBRT arm than in the obser-
vation arm (not reached vs 5.8 months; HR: 0.30; 95% CI: 0.11–0.81; p = 0.002).
14.3.2 Ongoing Trials for OMD with Prostate Cancer
There are several phase II trials to investigate the role of SBRT for OMD patients
with PCa although no phase III trial is currently underway that attempts to seek the
benefit of SBRT for PCa patients to the best of our knowledge. The OLI-CR-P
14 Oligomets 209
(NCT 04141709) is a prospective randomized phase II study that is comparing

metastasis-directed SBRT to observation in OMD patients with metastatic
castration-resistant PCa. The TRAP (NCT 0344303) trial is a multicenter, single-
arm, phase II study evaluating the efficacy of SBRT combined with enzalutamide or
abiraterone.
14.4 OMD with Other Primary Cancers
Several prospective trials have reported on the significance of metastasis-directed

SBRT for oligometastases in other primary cancers.
14.4.1 Clinical Trials for OMD with Other Primary Cancers
Liu et al. conducted a phase II trial to assess the safety and efficacy of SBRT for de
novo and repeat OMD in patients with esophageal cancer. OMD was defined as the
presence of up to three metastatic lesions [34]. It was also necessary for the primary
lesions to have been treated definitively, with no evidence of progression for more
than 3 months before enrollment. Thirty patients were enrolled in the study. All the
metastatic sites were treated with SBRT. The most common RT dose fractionation
was 48 Gy in six fractions (60%). Subsequently, four and six cycles of chemother-
apy were planned to be started within 2 weeks after SBRT completion although 17
patients (57%) refused to receive them after SBRT. With a median follow-up period
of 18.2 months, the median PFS was 13.3 months (95% CI: 10.7–15.9), and the 1-
and 2-year PFS were 55.9% and 33.8%, respectively. The 1- and 2-year OS rates
were 76.2% and 58.0%, respectively. The 1- and 2-year local control rates were
92.1%. Only one patient (3%) experienced grade 3 acute toxicities. The authors
concluded that SBRT, with or without chemotherapy, was a well-tolerated and effi-
cacious treatment for patients with OMD and esophageal cancer. Tang et al. con-
ducted a single-arm, phase II trial to investigate the feasibility of SBRT for all
metastatic sites after first-line systemic treatment of de novo OMD patients with
renal cell cancer. OMD was defined up to five lesions. Prescribed dose was 60–70 Gy
in 10 fractions or 52.5–67.5 Gy in 15 fractions. Patients had to stop systemic treat-
ment (TKI or immunotherapy) at least 1 month before SBRT. Thirty patients were
enrolled in the study. With a median follow-up of 17·5 months, median PFS was
22.7 months (95% CI 10.4–not reached), 1-year PFS 64% [95% CI: 48–85]). Three
(10%) patients had grade 3 or higher adverse events [35].
210 N. Imano
14.5 OMD in Mixed Primaries
14.5.1 Clinical Trials for OMD with Mixed Primaries
Stereotactic ablative radiotherapy versus standard-of-care palliative treatment in

patients with oligometastatic cancers (SABR-COMET) is a multicenter, interna-
tional, randomized phase II trial investigating the benefit of metastasis-directed
SBRT in OMD patients from a variety of primaries, including breast, colorectal,
lung, prostate, and other primary cancers [36]. In this trial, up to five metastatic
lesions in a maximum of three organs after definitive treatment of the primary lesion
were defined as OMD. A total of 99 patients were enrolled in the study. Sixty-six
were treated with SBRT and 33 were treated with standard care. The primary end-
point was OS. The median OS in the SBRT group was 41 months (95% CI: 26–not
reached), which was significantly longer than that of 28 months (95% CI: 19–33) in
the control arm (HR: 0.57; 95% CI: 0.3–1.1; p = 0.09). Median PFS was also longer
in the SBRT group compared to the control group (12 months (6.9–30.4) vs
6.0 months (95% CI: 3.4–7.1) (HR: 0.47; 95% CI: 0.30–0.76; p = 0.0012). In addi-
tion, long-term results of this trial showed an improvement in 5-year OS, 42.3%
(95% CI: 28–56%) in the SBRT arm vs. 17.7% (95% CI: 6–34%) in the control arm
(HR = 0.30; 90% CI: 0.12–0.75; p = 0.017). Grade 2 or worse adverse events
occurred in three (9%) of the 33 controls in the control arm, and in 19 (29%) of the
66 patients in the SBRT arm (p = 0.026). Treatment-related deaths occurred in three
(4.5%) of 66 patients who received SABR (radiation pneumonitis, pulmonary
abscess, and gastric ulcer), compared to none in the control group. The most com-
mon RT dose fractionations used in this trial were 35 Gy in five fractions (31%),
60 Gy in eight fractions (15%), and 54 Gy in three fractions (13%), which is a com-
monly used dose fractionation in other trials. Despite the improvement in OS, an
increase in adverse events was observed, indicating that efforts should be made to
minimize adverse events when SBRT is performed in OMD patients.
14.5.2 Ongoing Trials for OMD with Mixed Primaries
The SABR-COMET-10 trial (NCT03721341) is a multicenter, randomized, con-

trolled phase III trial for OMD patients with patients presenting 4–10 metastatic
lesions designed to evaluate the efficacy of SBRT in patients with 4–10 metastatic
cancer lesions. Participants will be randomized in a 1:2 ratio between the control
arm and the SBRT arm [37]. The recommended SBRT doses consisted of 20 Gy in
one fraction, 30 Gy in three fractions, or 35 Gy in five fractions, chosen to minimize
the risk of toxicity. A total of 159 patients will be enrolled in this study until January
2029. The SABR-COMET-3 trial (NCT 03862911) is a multicenter, prospective,
randomized, phase III trial that will include patients with 1–3 metastatic lesions
[38]. The concept of this study was similar to that of the SABR-COMET-10, except
14 Oligomets 211
for the number of metastases. The randomized phase II SABR-COMET trial showed
superiority in OS and PFS. However, to date, no phase III trial has shown an
improvement in survival. Although the SABR-COMET trial defined the number of
metastases as five or fewer, 92% of the patients enrolled in the trial had three or
fewer metastases. Although SBRT for oligometastases is becoming increasingly
popular in routine clinical practice, based on the results of SABR-COMET, this is
an important phase III study to confirm the significance of SBRT. A total of 297
participants are expected to be enrolled by December 2028. The OligoRARE (NCT
04498767) study is a multicenter, randomized, phase III superiority study conducted
by the EORTC. This study also investigates the effect of adding SBRT to the stan-
dard of care treatment on overall survival in OMD patients. This study differs from
SABR-COMET-3,10 in that the eligibility criteria for the number of metastases is
five or less. SBRT doses of 16–24 Gy/1 time, 24–33 Gy/3 times, or 25–40 Gy/5
times are almost equivalent to those in SABR-COMET3,10. Two hundred patients
will be randomized in a 1:1 ratio between the standard of care treatment and the
standard of care treatment + SBRT until August 2028, and the results will be
reported in 2030. STEREO-OS (NCT 03143322) is a multicenter, randomized,
phase III trial investigating the benefits of SBRT in combination with systemic
standard-of-care treatment [39]. Patients with OMD and breast, prostate, or non-
small-cell lung cancer with up to three bone-only metastases will be included in this
trial. Patients with bone-only metastases have been reported to have better progno-
ses than those with visceral metastases; therefore, the eligible patients in this study
were more likely to benefit from SBRT than those with OMD in other trials.
14.6 Conclusions
The detection of patients with OMD has improved over the years, due to advance-
ments in diagnostic modalities. The development of systemic therapies has also
improved the prognoses of patients with distant metastases. In this context, SBRT
techniques have improved, and metastasis-directed therapy for oligometastatic
patients has become increasingly common. Trials to examine the utility of SBRT for
the entire population of patients with OMD (SABR-COMET3,10; OligoRare) may
prove its value in wider populations of patients with OMD. It is of great interest to
determine the number of metastases that benefit from SBRT, as different trials have
adopted varying numbers of metastases in their eligibility criteria. It is possible that
the results from trials of OMD patients with all primary sites and trials by primary
site may differ (e.g., NRG LU002 study, NRG BR002 study). Furthermore, the
significance may differ depending on the site of metastasis, such as bone metastasis
versus visceral metastasis (STEREO-OS). Moreover, the significance of adding
SBRT may differ depending on the classification of OMD, as shown at the begin-
ning of this chapter. It remains to be seen whether the significance will be demon-
strated in a targeted trial or in patients with OMD as a whole. In either situation,
efforts should be made to improve outcomes while minimizing adverse events.
212 N. Imano
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Chapter 15
Other Indications
Tomoki Kimura
15.1 Stereotactic Body Radiation Therapy (SBRT)

for Prostate Cancer
15.1.1 Treatment Strategy
In addition to prostatectomy and brachytherapy, external beam radiation therapy

(EBRT) is a standard treatment for patients with localized prostate cancer. A dose-
fractionation schedule of EBRT, such as 74–81 Gy given in 37–45 fractions
(1.8–2 Gy/fraction), is the conventional approach. However, due to recent technical
advances, hypofractionation schedules, such as intensity-modulated radiation ther-
apy (IMRT) or image-guided radiation therapy (IGRT) are increasingly used.
According to the American Society for Radiation Oncology (ASTRO), American
Society of Clinical Oncology (ASCO) and American Urological Association (AUA)
guidelines, hypofractionation is usually subdivided into “moderate hypofraction-
ation” and “ultrahypofractionation” [1]. The former is defined as EBRT with each
dose between 2.4 and 3.4 Gy in these guidelines. It is recommended as the preferred
dose-fractionation schedule for patients with low to high-risk prostate cancer in the
National Comprehensive Cancer Network (NCCN) guidelines [2], based on the
largest multicenter trials comparing conventional EBRT with moderate hypofrac-
tionation [3–7]. Representative dose-fractionation schedules were 60 Gy in 20 frac-
tions (3 Gy per fraction) in the CHHip and PROFIT trials [3, 4], 70 Gy in 28
fractions (2.5 Gy per fraction) in RTOG0415 [5], 70.2 Gy in 26 fractions (2.7 Gy
per fraction) [6], and 64.6 Gy in 19 fractions (3.4 Gy per fraction) in the HYPRO
T. Kimura (*)
Department of Radiation Oncology, Kochi Medical School, Kochi University,
Nangoku-shi, Kochi, Japan
e-mail: tkkimura@kochi-u.ac.jp
Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_15
216 T. Kimura
trial [7]. Ultrahypofractionation is defined as EBRT at doses of >5 Gy per fraction

[1] delivered in 4–7 fractions. This is referred to as stereotactic body radiation ther-
apy (SBRT) which is covered by national health insurance in Japan for patients with
localized prostate cancer. The α/β ratio for prostate cancer, which is as low as
1.5–1.8 according to several reports [8–10], suggests that this hypofractionation
strategy could potentially have an advantage also for other cancers. Especially,
SBRT might improve not only the therapeutic ratio, but also patient convenience
and cost-effectiveness. On the other hand, considering that the α/β ratio for normal
organs, including rectum and bladder, is higher than for prostate cancer [10], NCCN
guidelines state that SBRT is acceptable in practices with the appropriate technol-
ogy, physics, and clinical expertise for toxicity reduction [2].
Indications for SBRT in prostate cancer are described in several guidelines and
reports [1, 2, 11]. The ASTRO/ASCO/AUA guidelines recommend schedules for
patients with low and intermediate risk [1], and the NCCN guidelines recommend
them for patients with very low and low, intermediate, high, and very high risk [2].
In addition, Zaorsky et al. suggested that during the recent COVID-19 pandemic,
5- to 7-fraction SBRT is preferred for localized prostate cancer that requires treat-
ment [11].
15.1.2 Treatment Techniques
For simulation, in many cases, prostate fiducial markers and a SpaceOAR as rectal
separation are placed under ultrasound guidance. Regarding SpaceOAR, Hamstra
et al. reported a phase III randomized trial [12]. A total of 222 patients was random-
ized 2:1 to the SpaceOAR vs control group and received 79.2 Gy in 44 fractions.
Frequencies of 3-year rectal toxicity grades ≧1 (9.2% vs 2.0%) and ≧ 2 (5.7% vs
0%) were significantly lower in the SpaceOAR group; QOL was also superior.
For treatment planning, according to the ASTRO/ASCO/AUA guidelines [1], the
clinical target volume (CTV) includes the prostate alone in low-risk patients, and
the prostate plus a variable portion (usually the proximal portion) of the seminal
vesicle in intermediate risk patients. Planning target volume (PTV) is commonly
defined as CTV + 5 mm in all directions except for 3 mm posteriorly. A dose-
fraction schedule of 35–36.25 Gy in five fractions of 7–7.25 Gy to the PTV may be
offered to low- and intermediate-risk patients with prostate sizes <100 cm3. In addi-
tion, these guidelines do not recommend consecutive daily treatments due to the
potential increased risk of late urinary and rectal toxicity.
15.1.3 Clinical Outcomes
The first publications on SBRT for localized prostate cancer were from the SHARP
trial in 2007 [13–22]. Since then, many prospective trials and several meta-analyses
have been published (Table 15.1). Most of the eligible subjects were low- or
15 Other Indications 217
Table 15.1 Prospective trials and meta-analysis of Stereotactic Body Radiotherapy (SBRT) for
prostate cancer
Dose/ Late GIc Late GUd
Number of patients Median fraction toxicity toxicity
Author/year (L/I/H %)a Study type follow-up (Gy/fr) bRFSb ≧Grade 3 ≧Grade 3
Madsen 40 (100/0/0) Phase I/II 3.42 y 33.5 Gy in 90% 0%e 0%e
(2007), USA 5 fr (4 y)
[13]
McBride 45 (100/0/0) Phase I 3.7 y 36.3– 97.7% 4.4%f 2.2%f
(2012), USA 37.5 Gy in (3 y)
[14] 5 fr
King (2013), 1100 Phase II 3y 35–40 Gy 93% N.A.g N.A.g
USA [15] (58.3/30.4/11.3) in 5 fr (5 y)
Loblaw 84 (100/0/0) Phase I/II 4.58 y 35 Gy in 5 98% 1% e, h 1%e, h
(2013), fr (5 y)
Canada [16]
D’Agostino 90 (53/37/0) Phase II 2.25 y 35 Gy in 5 L: 100% 0f 0f
(2016), Italy fr (N.A.g)
[17] I: 94.5%
(N.A.g)
Hannan 91 (33/58/0) Phase I/II 4.5 y 45–50 Gy 98.6% 6.8%h 6%h
(2016), USA in 5 fr (5 y)
[18]
Meier (2018), 309 (55.7/44.3/0) Phase II 5y 40 Gy in 5 97.1% (5 0%h 2%h
USA [19] fr y)
Jackson 6116 (45/47/8) Meta- 3.25 y 36.25 Gy in 95.3% 1.1% 2%
(2019), USA analysis 5 fr (5 y)
[20] (most 93.7%
common) (7 y)
Kishan, 2142 (55/45/0) Large 6.9 y 33.5–40 Gy L: 0.4%f, h 2.4%f,h
(2019), USA cohort in 4–5 fr 95.5%
[21] from (7 y)
phase II I: 89.8%
studies (7 y)
Widmark Si: 598 (0/89/11) Phase III 5y S: 42.7 Gy S: 84% S: 1% S: 5%
(2019), Cj: 602 (0/89/11) in 7 fr (5 y) (≧grade 2)e (≧grade 2)e
Sewden [22] C: 78 Gy in C: 84% C: 4% C: 5%
(HYPO- 39 fr (5 y) (≧grade 2)e (≧grade 2)e
RT-PC)
Abbreviations:
a
L Low risk, I Intermediate risk, H High risk
b
bRFS Biochemical recurrence-free survival
c
GI Gastrointestinal
d
GU Genitourinary
e
Toxicity was assessed according to the Radiation Therapy Oncology Group (RTOG) guidelines
f
Toxicity was assessed according to Common Terminology Criteria for Adverse Events (CTCAE)
ver. 4.0
g
N.A. Not available
h
Toxicity was assessed according to Common Terminology Criteria for Adverse Events
(CTCAE) ver. 3.0
i
S SBRT
j
C Conventional fraction
218 T. Kimura
intermediate-risk patients. Various different dose-fraction schedules were used,

such as 33.5–50 Gy in 4–7 fractions, most commonly five fractions.
Jackson et al. reported a meta-analysis of 38 prospective trials with 6116 subjects
including low (48%), intermediate (47%), and high-risk (8%) patients [20]. Median
follow-up was 3.25 years and the most common dose-fraction schedule was
36.25 Gy in five fractions. Overall, 5- and 7-year biochemical relapse-free survival
(bRFS) was 95.3% and 93.7%, respectively. Estimated late grade ≧3 genitourinary
(GU) and gastrointestinal (GI) toxicity rates were 2% and 1.1%, respectively.
Kishan et al. published a large cohort study from 10 single-institutional and two
multi-institutional Phase II studies, reporting the long-term outcomes of SBRT for
2142 patients with low (55%) or intermediate (45%) risk disease [21]. Median fol-
low-up was 6.9 years and the dose-fraction schedule ranged from 33.5 to 40 Gy in
4–5 fractions. Seven-year bRFS was 95.5% for low risk, 91.4% for favorable
intermediate-risk and 85.1% for unfavorable intermediate-risk disease, respectively.
Late grade ≧3 genitourinary (GU) and gastrointestinal (GI) toxicity rates were 2.4%
and 0.4%, respectively.
Hypo-RT-PC, a non-inferiority randomized phase III trial of SBRT vs conven-
tionally fractionated radiotherapy (CF-RT) in 589 patients receiving SBRT and 602
patients CF-RT from 12 centers in Sweden and Denmark, was published in 2019 on
intermediate (89%) and high (11%) risk patients [22]. Median follow-up was 5 years
and the dose-fraction schedule was 42.7 Gy in 7 fractions in the SBRT group and
78 Gy in 39 fractions in the CF group. Estimated 5-year failure-free survival was
84% in both groups, with an adjusted hazard ratio of 1.002 (log-rank p = 0.99).
Acute grade ≧2 GU/GI toxicity was increased in frequency in the SBRT group (158
[28%] of 569 patients in the SBRT group vs 132 [23%] of 578 in the CF group;
p = 0.057). However, there were no significant differences in late toxicities between
the groups at 5 years, with grade ≧2 GU toxicity (11 [5%] of 243 patients in the
SBRT group vs 12 [5%] of 249 in the CF-RT group; p = 1.00) or GI toxicity (3 [1%]
of 244 patients vs 9 [4%] of 249; p = 0.14). From these results, the authors con-
cluded that SBRT is non-inferior to CF-RT for intermediate-to-high risk prostate
cancer in terms of failure-free survival. Compared with the other studies in
Table 15.1, bRFS was a little lower in the Hypo-RT-PC trial. One reason for this
may be the low rate of IMRT utilization, which was only 20% (three-dimensional
conformal radiotherapy, 80%).
15.1.4 Future Directions
As described in “Clinical outcomes,” SBRT for patients with low- and intermediate-
risk cancer has been established as one of the standard radiation therapies. However,
several clinical questions remain, such as comparing SBRT in 5 fractions vs conven-
tional EBRT, SBRT vs moderate hypofractionated radiotherapy, and others.
The PACE-B trial (NCT01584258), which is a randomized phase III, non-

inferiority trial comparing standard-of-care conventional EBRT with moderately
hypofractionated radiotherapy vs 5-fraction SBRT for low- to intermediate-risk
localized prostate cancer, is fully subscribed (total 874 patients) and follow-up is
ongoing. Acute toxicity findings have been reported, indicating that there were no
significant differences between the two groups in terms of grade ≧2 GU toxicity (96
[23%] of 415 patients for SBRT group vs 118 [27%] of 432 for the conventional
EBRT or moderately hypofractionated radiotherapy group; p = 0.16) and GI toxicity
(43 [10%] of 415 patients vs 53 [12%] of 432; p = 0.38) [23]. The authors concluded
that although the HYPO-RT-PC trial suggested higher acute toxicity with SBRT,
these PACE-B trial results suggest that SBRT does not increase either GU or GI
acute toxicity. Long-term results are awaited. In contrast, NRG GU005
(NCT03367702) is a superiority trial comparing moderately hypofractionated
EBRT (70 Gy in 28 fractions) with SBRT (36.25 Gy in five fractions) which could
make SBRT the unequivocal standard of care if it improves disease control or qual-
ity of life.
15.2 SBRT for Pancreatic Cancer
Standard radical treatment for pancreatic cancer is surgical resection. In this regard,
tumors are categorized as resectable, borderline resectable and locally advanced,
according to NCCN guidelines [24]. “Resectable” is defined as no arterial (celiac
axis [CA], superior mesenteric artery [SMA], and common hepatic artery [CHA])
and no venous (superior mesenteric vein [SMV] and portal vein [PV]) contact, or
≦180° contact without vein contour irregularity. “Locally advanced” refers to unre-
sectable, defined as solid tumor contact with the SMA or CA >180° or invasion to
arteries, aorta, and SMV/PV with or without occlusion. For locally advanced dis-
ease, definitive radiation therapy with chemotherapy (chemoradiotherapy [CRT])
and chemotherapy alone are both standard therapies. For CRT, the recommended
dose is generally 45–54 Gy at 1.8–2 Gy per fraction [24]. Although two randomized
Phase III studies compared CRT and chemotherapy alone [25, 26], the results were
not in agreement and therefore the superiority of one therapy over the other cannot
be established. Recently, SBRT has been utilized for patients with borderline resect-
able or locally advanced pancreatic cancer. Considering that the majority of these
patients die of systemic rather than local progression, SBRT may improve local
tumor control. This is because this radioresistant tumor requires a high dose, such
as 100 Gy or more, to be biologically effective and achieve local control [27]. In
addition, SBRT also allows shorter treatment duration which could avoid delaying
delivery of chemotherapy.
220 T. Kimura
Indications for SBRT in pancreatic cancer have not been established yet, but
several guidelines and reports suggest application for the following conditions
[28–30]:
• borderline resectable or locally advanced patients as definitive or neoadjuvant
treatment
• Tumor size ≦5 cm
• No regional lymph node metastasis or distant metastasis
• Appropriate distance from critical organs, such as stomach, duodenum, and
small intestine.
15.2.2 Treatment Techniques
For simulation, respiratory motion management, daily image guidance with fiducial
markers, and contrast material administration during CT simulation is strongly rec-
ommended by the ASTRO guidelines [28].
For treatment planning, gross tumor volume (GTV) including the primary tumor,
which is usually seen as a hypodense lesion on enhanced CT, using all available
multi-modalities, such as magnetic resonance imaging (MRI), FDG-PET, endoscopy
should be employed. The concept of the tumor-vessel interface (TVI), which is a
region at high risk for recurrence in close proximity to the tumor between major ves-
sels has been utilized [29, 30]. According to the Australasian Gastrointestinal Trials
Group (AGITG) and Trans-Tasman Radiation Oncology Group (TROG) guidelines,
TVI is defined as the area where the GTV is involved or within 5 mm of the major
vessels in the upper abdomen, including the CH, SMA, CHA, left gastric artery,
SMV, portal vein, splenic vein, or aorta [29]. CTV includes GTV and TVI, internal
target volume (ITV) creation using motion information, and PTV usually adds 5 mm
to ITV. Several guidelines recommend that elective nodal regions are not routinely
included in the target volume [28, 29]. The dose-fraction schedule according to the
ASTRO guidelines is recommended as 30 to 33 Gy in five fractions of 6.0–6.6 Gy for
borderline resectable patients, 33–40 Gy in five fractions of 6.6–8 Gy [28].
Recently, SBRT using the MRI-guided adaptive radiation therapy technique has
been reported [31]. This approach makes it possible to improve target volume cov-
erage while adapting daily gastrointestinal organ motion and minimizing excessive
doses to at-risk organs.
Table 15.2 shows several treatment outcomes when using SBRT for pancreatic can-
cer [27, 31–36]. Most eligible patients had locally advanced or borderline resectable
disease. Various different dose-fraction schedules were used, such as 25–67.5 Gy in
1–15 fractions, mostly in five fractions.
Table 15.2 Treatment outcomes of Stereotactic Body Radiotherapy (SBRT) for pancreatic cancer
Dose/ Surgery
Median fraction after Local Overall GIa toxicity
Author/year Number of patients Study type follow-up (Gy/fr) Chemotherapy SBRT control survival ≧Grade 3
Hoyer 22 Phase I/II N.A.b 45 Gy in 3 N.A.b 0% 57% 5% (1y) Acute: 79%
(2005), (T1-3N0M0) fr (6 m) (grade 2)c
Denmark
15 Other Indications
[32]
Pollom 167 Retrospective 8 m 25–45 Gy Gemcitabine ± PTXd/ 0% 5 5 fr_35% 5 fr_6%
(2014), USA (locally advanced) in 5 fr CDDPe/CPT-11 (87%) fr_88% (1y) (1y)f
[33] 25 Gy in 1 (1y) 1 fr_31% 1 fr_12%
fr 1 (1y) (1y)f
fr_91%
(1y)
Herman 49 Phase II 13.9 m 33 Gy in 5 Gemcitabine (100%) 8.2% 78% 59% (1y) 6%f
(2015) USA (locally advanced) fr (1y) 18% (2y)
[27]
Park (2017), 44 Retrospective 12.9 m 30–33 Gy Gemcitabine (47.7%) 0% 65.6% 56.2% Acute: 0%f
USA [34] (stage I–III) in 5 fr FOLFORINOXg (43.2%) (1y) (1y) Late: 9.1%f
FOLFOXh (4.5) 51.3% 25.7% (GI
(2y) (2y) bleeding)
Quan (2018), 35 Phase II 15.4 m 36 Gy in 3 Gemcitabine + capecitabin 34.3% 78% 54% (1y) 0%f
USA [35] (T1-4N0-1) fr (100%) (1y) 10% (2y)j
52%
(2y)i
(continued)
221
Table 15.2 (continued)
222
Dose/ Surgery
Median fraction after Local Overall GIa toxicity
Author/year Number of patients Study type follow-up (Gy/fr) Chemotherapy SBRT control survival ≧Grade 3
Rudra 25 (locally Retrospective 17 m 40–52 Gy Gemcitabine-based/ 8.3% 77% 49% (1y) 0%f
(2019), USA advanced/ in 5 fr FOLFORINOXg/ (1y)
[31] borderline 50– FOLFOXh (91.7%)
resectable) 67.5 Gy
In 10–15
fr
Chuong 35 Retrospective 10.3 m 50 Gy in 5 FOLFORINOXg (60%) 0% 87.8% 58.9% Acute:
(2021) USA (T2-4N0–2) fr Gemcitabine-based (31%) (1y) (1y) 2.9%l
[36] (ENIk Late: 2.9%l
57.1%)
Abbreviations:
a
GI: Gastrointestinal
b
N.A. Not available
c
Toxicity was assessed according to the WHO toxicity grading system
d
PTX: Paclitaxel
e
CDDP: Cisplatin
f
Toxicity was assessed according to Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0
g
FOLFORINOX
h
FOLFOX
i
Locally advanced only
j
Non-surgical locally advanced only
k
ENI Elective nodal irradiation
l
T. Kimura
After 2010, two prospective phase II studies were published. Herman et al. reported
a multi-institutional trial of SBRT using gemcitabine for 49 patients with locally
advanced unresectable pancreatic adenocarcinoma [27]. Median follow-up was
13.9 months with three doses of GEM (1000 mg/m2) followed by a 1-week pause and
SBRT (33 Gy in five fractions). Overall, 1- and 2-year overall survival (OS) was 59%
and 18%, respectively. The 1-year local control (LC) rate (freedom from local disease
progression) was 78%, which was approaching the expected rate of 80%. Late grade
≧3 GI toxicity was observed three patients (6%), and one patient died of a GI bleed
(grade 5) 22.4 months after SBRT. Quan et al. reported a multi-institutional trial of
12-week induction chemotherapy using gemcitabine and capecitabine followed by
SBRT for 35 patients with locally advanced unresectable pancreatic adenocarcinoma
[35]. Median follow-up was 15.4 months and the dose-fraction schedule of SBRT was
36 Gy in three fractions. Overall, 1- and 2-year OS was 54% and 10%, respectively.
The 1- and 2-year local control rate (local progression-free survival) was 78% and
52%, respectively. Late grade ≧3 GI toxicity from SBRT was not observed. The authors
of these studies concluded that the results were acceptable, with minimal toxicities.
Because there are limited prospective data to support the efficacy and safety of
SBRT, it should preferably be utilized as part of a clinical trial or at an experienced,
high-volume center [24]. Further studies to define patient eligibility, optimal dose-
fraction schedules and optimal combinations of SBRT with chemotherapy are needed
to establish this approach as one of the treatment modalities for pancreas cancer.
15.3 SBRT for Adrenal Gland Tumor
Recently, several investigators reported that combined treatment with immune

checkpoint inhibitors and local therapies, including surgical resection or SBRT,
improved survival of patients with oligometastatic disease [37–39]. The adrenal
glands are a common site of metastasis from various different primary tumors. It is
well known that lung cancer is the most frequent, but also kidney, colorectal, mela-
noma, liver, breast, and others, were also reported as the primary tumors [40–43].
Although surgical resection is considered the standard treatment, SBRT is an alter-
native treatment option due to less invasiveness for patients with comorbidities or
who refuse invasive treatments.
Table 15.3 shows several treatment outcomes of SBRT for adrenal gland metastases
[41–43]. The primary tumor was lung cancer in almost one half of these patients.
Various different dose-fraction schedules were used, 35–40 Gy in five fractions
being the most common.
224
Table 15.3 Treatment outcomes of Stereotactic Body Radiotherapy (SBRT) for adrenal gland metastases
Number of Median Dose/fraction Isodose Local Overall Toxicity
Author/year patients Study type follow-up (Gy/fr) prescription Lunga control survival ≧Grade 3b
Toesca (2018), USA 35 Retrospective 37 m 40 Gy in 5 fr 75–97% 49% 92.4% 19 m 0%
[40] (median) (36/39) (median)
Voglhuber (2020), 31 Retrospective 9.8 m 35 Gy in 5 fr 60–80% 41.9% 74.1% 64% (1y) 0%
Germany [41] (median) (1y)
König (2020), 28 Retrospective 36.4 m 50 Gy in 10 fr 80–90% 46% 84.8% 32% (2y) 0%
Germany [42] (median) (2y)
Chen (2020), USA 1006 Meta- 12 m 38 Gy in 5 fr 70–100% 65.7% 63% (2y) 42% (2y) 1.8%
[43] (2009–2019) analysis (median)
Abbreviations:
a
Percentage of primary lung malignancy
b
T. Kimura
Chen et al. reported a meta-analysis of 1006 patients from 39 studies published

between 2009 and 2019 [43]. Median follow-up was 12 months and the median
dose-fraction schedule of SBRT was 38 Gy (range, 18–60 Gy) in five fractions
(range, 1–10 fractions). The pooled 1- and 2-year OS was 66% and 42%, respec-
tively. The pooled 1- and 2-year LC was 82% and 63%, respectively. Late grade ≧3
toxicity was 1.8%. In addition, a strong positive association between SBRT dose
and 1- and 2-year LC (p < 0.0001, p = 0.0002) and an association with 2-year OS
(p = 0.03) was also reported. However, most of these reports were retrospective and
on only a small number of patients, so it is hard to conclude that the efficacy and
safety, and the identification of an optimal dose-fraction schedule of SBRT have
been established. Further prospective trials are warranted in future.
15.4 SBRT for Head and Neck Cancer
From the point of view of preservation of function, radiation therapy with or with-
out chemotherapy is the standard treatment for most patients with head and neck
cancers. However, for patients with locoregional recurrence, salvage surgery is con-
sidered. Recently, SBRT is also being considered as a salvage treatment for unre-
sectable cases. Roman et al. suggested an algorithm for SBRT treatment for
re-irradiation of patients with recurrent head and neck cancers who are not candi-
dates for surgery [44]. To determine the indications for SBRT, the dose limitation
for at-risk organs should be considered first. If there is no dose limitation, then
SBRT may be a good treatment option. As described above, the most common use
of SBRT is in the setting of re-irradiation, but several prospective studies limited to
a small number of patients reported its use as a primary treatment.
Table 15.4 shows several treatment outcomes of SBRT for head and neck cancer
[45–50]. Most eligible patients had recurrent head and neck cancer, but naïve
patients are also included. Various different dose-fraction schedules were used, such
as 35–44 Gy in 5–6 fractions for patients with recurrent disease. Several phase II
studies documented efficacy and acceptable toxicities [46, 47]. Although severe
toxicities, such as carotid blow-out and fistula, should be avoided, no grade 4 or 5
toxicities were reported in these series. For naïve patients who are medically unfit
for standard treatment, several prospective studies have also reported acceptable
outcomes with relatively low toxicity. However, most of these reports were on small
numbers of patients, and again, it cannot be concluded that SBRT utility has been
established. Further prospective trials are warranted.
226 T. Kimura
Table 15.4 Prospective trials of Stereotactic Body Radiotherapy (SBRT) for head and neck cancers
Number Dose/ Toxicity
Author/ of Previously Median fraction Local Overall ≧Grade
year patients Study type treated follow-up (Gy/fr) control survival 3a
Heron 25 Phase I Yes 13 m 36 Gy in 76% 6 months 0%
(2009) 5 fr (RRb) (median)
[45] (median)
Lartigau 60 Phase II Yes 11.4 m 36 Gy in 91.8% 45.7% 30%
(2013), 6 fr (2y) (1y)
France
[46]
Vargo 50 Phase II Yes 18 m 40– 60% 40% Acute:
(2015), 44 Gy in (1y) (1y) 6%
USA 5 fr Late:
[47] 6%
Sher 29 Phase I No 43.6 m 45 Gy in 83% N.A.c 6.9%
(2019), (T1–2 10 fr (3y)
USA larynx) (median)
[48]
Kang 13 Phase I No 26.6 m 59.5 Gy 89.5% N.Ac 10.5%
(2019), (T1–2 in 17 fr (RRb)
Korea larynx) (median)
[49]
Gogineni 66 Prospective No 15 m 35– 73% 64% 3%
(2020), (various 40 Gy in (1y) (1y)
USA sites) 5 fr
[50]
Abbreviations:
a
Toxicity was assessed according to Common Terminology Criteria for Adverse Events (CTCAE)
ver. 4.0
b
RR Response rate
c
N.A. Not available
15.5 SBRT for Locally Advanced Non-Small Cell

Lung Cancer
Chemoradiation followed by immune checkpoint inhibitors for locally advanced

non-small cell lung cancer (LA-NSCLC) has improved treatment outcomes in terms
of OS and PFS [51]. Although this is important for improving cure rates, local fail-
ure remains problematic, and meta-analyses have shown that better locoregional
control can lead to improvement in survival [52]. On the other hand, in the RTOG
0617 phase III study, which randomized doses between 60 Gy in 30 fractions and
74 Gy in 37 fractions, the high-dose arm failed to improve survival, even on long-
term follow-up [53]. The reasons for this failure were suggested to be related to
several factors, such as poor radiation therapy compliance, prolonged treatment
time, use of three-dimensional radiation therapy technique, and others. To solve
these problems, several efforts, such as isotoxic IMRT individualized dose
prescription under the same normal tissue limits, adaptive radiation therapy and
SBRT boosting, are being considered. Among these efforts, SBRT boosting could
have potential advantages, as follows [54]:
• Highly conformal dose distribution delivery using immobilization, respiratory
motion management, and conformal planning techniques.
• Significant reduction of treatment time
• Biological advantage of improving tumor control using high fractional doses.
To investigate the optimal dose of SBRT boosting, several phase I studies were
initiated [54, 55]. Hepel et al. reported dose escalation using SBRT boosting to both
primary and nodal disease in two fractions after conventional radiation therapy
(50.4 Gy in 28 fractions), with concurrent chemotherapy for 12 patients with
LA-NSCLC [54]. They recommended 24 Gy in two fractions or more for local
tumor control, and in particular, the dose constraints of the proximal bronchial-
vascular tree should be considered for reasons of safety. Higgins et al. also reported
SBRT boosting after conventional radiation therapy, at 44 Gy in 22 fractions, with
concurrent chemotherapy for 19 patients with stage III NSCLC [55]. They recom-
mended 30 Gy in five fractions as the maximum tolerated dose. However, consider-
ing these limited phase I studies, further prospective trials are warranted and SBRT
boosting for patients with LA-NSCLC should be utilized as part of a clinical trial.
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Part IV
Development of Machines
Chapter 16
Vero4DRT System and Dynamic Tumor
Tracking SBRT
Takashi Mizowaki, Yukinori Matsuo, and Masahiro Hiraoka
16.1 Introduction
Stereotactic body radiotherapy (SBRT), also referred to as stereotactic ablative

radiotherapy (SABR), was developed as a new radiotherapy approach for localized,
relatively small extracranial tumors in the 1990s [1]. In SBRT, an ablative dose is
convergently irradiated in single or several fractions as radiosurgery to intracranial
tumors. Many retrospective studies and multi-institutional prospective trials have
demonstrated excellent local control with acceptable toxicity in various sites of
tumors using SBRT [2–5]. Therefore, SBRT now plays an essential role in treating
localized extracranial tumors in various locations and situations.
Current stereotactic irradiation based on modern image-guided radiotherapy
(IGRT) technique realizes enough high accuracy of a few millimeters order in beam
delivery for static targets. In contrast, additional internal motion management pro-
cedures are required for a moving target [6, 7]. In the traditional approach with
internal target volume (ITV), where irradiation fields cover the whole tumor trajec-
tory of a tumor, adjacent normal tissues are also included in the expanded irradia-
tion field. That often resulted in increasing the risk of toxicities and limiting the
indications of SBRT to a smaller tumor or a less-moving tumor. On the other hand,
new four-dimensional (4D) irradiation techniques that can deliver a high dose to a
tumor and limit the doses to normal tissues are expected to improve outcomes and
expand the indications of SBRT.
The Vero4DRT (Hitachi Ltd., Tokyo, Japan, and BrainLab AG, Feldkirchen,
Germany; Fig. 16.1), formerly called the MHI-TM2000 (Mitsubishi Heavy
Industries [MHI] Ltd., Tokyo, Japan), is a novel and innovative radiotherapy system
T. Mizowaki (*) · Y. Matsuo · M. Hiraoka

e-mail: mizo@kuhp.kyoto-u.ac.jp
Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_16
234 T. Mizowaki et al.
Fig. 16.1 Vero4DRT system
dedicated to IGRT. Two significant advantages of this system are the capabilities of
non-coplanar beam delivery without couch rotation and 4D dynamic tumor tracking
(DTT) irradiation under real-time monitoring [8]. This paper introduces the devel-
opment, physics evaluations, and clinical applications of the Vero4DRT system.
16.2 Specification of the Vero4DRT
An overview of the Vero4DRT system is shown in Fig. 16.2. The characteristic

components of this system are the O-ring-designed gantry, beam delivery subsys-
tem, imaging subsystems, and the precise robotic five-dimensional couch system.
The rigid O-ring gantry supports beam delivery and imaging subsystems allowing
accurate beam delivery and image guidance. The O-ring can also skew around the
vertical axis, which realizes non-coplanar irradiation without couch rotation,
which contributes to decreased intrafractional setup errors and shortened overall
treatment time. The details of the Vero4DRT system had already been reported
elsewhere [9].
The beam delivery subsystem comprises an ultra-compact C-band linear accel-
erator (LINAC), multi-leaf collimators (MLC), and a gimbaled mechanical head.
16 Vero4DRT System and Dynamic Tumor Tracking SBRT 235
Fig. 16.2 Internal configuration of the Vero4DRT. Abbreviations: LINAC Linear accelerator, MLC
Multi-leaf collimator, DOF Degree of freedom, FPD Flat panel detector, EPID Electric portal
imaging device
The linear accelerator produces a 6-megavolt (MV) photon beam with a 500 cGy/
min maximal dose rate. The MLC has 30 pairs of leaves of 5 mm thickness at the
isocenter and allows a maximal field size of 15 × 15 cm2. The gimbals can indepen-
dently swing the treatment beam to the two orthogonal directions (pan and tilt rota-
tions) up to ±2.4 degrees, corresponding to ±4.2 cm in each direction on the
perpendicular isocenter plane to the beam axis and allow any trajectory within the
mechanical limits. The gimbaled X-ray head also realizes high accuracy in position-
ing the static treatment beam and on DTT irradiation for a moving target.
The imaging subsystem includes two sets of kV X-ray on board imaging (OBI)
and an electronic portal imaging device (EPID). The OBI provides orthogonal
radiographs or cone-beam computed tomography (CBCT) for image-guided setup.
The ExacTrac X-ray system (BrainLab AG) is integrated with the OBI system. The
EPID visualizes a treatment field with a treatment beam through the patient body.
Both imaging subsystems also monitor the treated position during DTT in real-time.
The robotic couch system can compensate for setup errors with 5 degrees of
freedom (translations along vertical, coronal, and sagittal axes; and roll and pitch
rotations). The remaining yaw rotation is compensated with the O-ring skew. In
addition, an infrared (IR) camera system helps precise localization of the couch.
The IR camera also works for monitoring respiratory phases via markers on the
abdomen during DTT radiotherapy.
16.3 History of the Development
The project for developing of Vero4DRT started in 2000 in MHI as an intrapreneur-

ship. As MHI had already developed an ultra-compact C-band LINAC, they planned
to create a new radiotherapy machine capable of tracking and irradiating a moving
target by using the gimbals mechanism, they had also developed. Therefore, MHI
started collaborating with Kyoto University (Kyoto, Japan) and the Institute of
Biomedical Research and Innovation (IBRI; Kobe, Japan) as medical partners to
realize this objective. Machine design and concepts were discussed and decided by
the collaboration team, including functional enhancement of image guidance, high-
precision setup, and DTT. As a result, some prototype machines were made and
tested between 2002 and 2005.
The clinical version of the IGRT system was developed in 2006. The system was
first approved by the US Food and Drug Administration in August 2007 and then by
the Japanese Ministry of Health, Labor, and Welfare in January 2008 as
“MHI-TM2000.” The CE Mark certification in Europe was acquired in 2010.
Outside Japan, the unit is marketed as the “Vero” through BrainLAB AG as an origi-
nal equipment manufacturer (OEM) supply partner.
The first application of the MHI-TM2000 to clinical treatment had made in May
2008 at IBRI [10]. The clinical applications initially started in palliative cases with
symptomatic bone or the lymph node metastases. Then, the application was extended
to high-precision radiotherapy with curative intent, including SBRT for the lung
using static beams and intensity-modulated radiotherapy (IMRT) for the prostate.
Kyoto University started treatment with the system in October 2010.
Based on the initial clinical experiences and physics evaluations, DTT with real-
time monitoring was started with SBRT for the lung in September 2011 at Kyoto
University and in December 2011 at IBRI. DTT-SBRT for the liver was initiated in
2012 at UZ Brussel, followed by Kyoto University in March 2013. After the success
of DTT-SBRT, MHI changed the market name for the system in Japan from
“MHI-TM2000” to “Vero4DRT.” DTT was also combined with IMRT. Kyoto
University performed DTT-IMRT for pancreatic cancer in June 2013, the world’s
first case treated with tumor tracking IMRT [10, 11].
In 2006, we hit the idea of the possibility of three-dimensional unicursal irradia-
tion by simultaneously rotating the gantry and the O-ring utilizing the unique struc-
ture of the Vero4DRT. Because the development of DTT irradiation was prioritized
over the development of this function, the first consideration of this concept was
introduced in 2013 [11]. This approach was combined with the volumetric-modu-
lated arc technique and renamed Dynamic WaveArc (DWA). After the DWA func-
tion was supported by a commercially available treatment planning system
(RayStation, RaySearch Laboratories AB, Stockholm, Sweden) in 2015, it was

clinically implemented [12] and is currently set as a standard option of Vero4DRT.
16.4 Physics Evaluation and Clinical Application
16.4.1 Physics Evaluation
Extensive essential evaluations have been done to introduce new treatment tech-
niques to the clinics, extensive basic evaluation has been done. Table 16.1 summa-
rizes results of the physics evaluations for the Vero4DRT system. The evaluated
Table 16.1 Summary of physics evaluations of the Vero4DRT system

Evaluation Results Author (year)
Static beam Positioning accuracy 0.08 mm (pan axis), 0.10 mm (tilt Kamino (2006)
(RMS) axis) [9]
IC radius in starshot 0.12–0.43 mm (gantry), 0.01– Depuydt (2012)
0.08 mm (O-ring) [13]
MLC Field size <0.5 mm Nakamura
Leaf position 0.0 ± 0.1 mm (2010) [14]
Leakage <0.21% (interleaf), <0.12%
(intraleaf)
Image guidance Error at 50-mm 0.2 mm (kV x-ray), 1.0 mm Miyabe (2011)
offcenter (CBCT) [15]
Tracking Beam positioning <0.6 mm Kamino (2006)
error [9]
(direct tracking) Motion blurring Significantly reduced Takayama
effects (2009) [16]
System lag 47.7 ms (pan), 47.6 ms (tilt) Depuydt (2011)
Tracking error 0.54 mm [17]
(90-percentile)
Tracking error (RMS) 1.2 mm (prediction), 0.1 mm Mukumoto
(mechanical), 1.2 mm (total) (2012) [18]
Tracking Tracking error (SD) 0.55 mm (pan direction), 0.95 mm Depuydt (2013)
(tilt direction) [19]
(Model based 4D modeling error 0.1–1.0 mm (LR), 0.1–1.6 mm Akimoto (2013)
tracking) (SD) (AP), 0.2–1.3 mm (SI) [20]
Tracking error < 1 mm Mukumoto
(95-percentile) (2013) [21]
DWA Positional error 0.2° (gantry), 0.1° (O-ring), Hirashima
(RMS) 0.1 mm (MLC position) (2017) [22]
Other Commissioning Solberg (2014)
process [23]
Abbreviations: RMS Root mean square, IC Isocenter, MLC Multi-leaf collimator, CBCT Cone-
beam computed tomography, SD Standard deviation, LR Left-right, AP Anteroposterior, SI
Superoposterior, DWA Dynamic WaveArc
items include accuracy in static beam delivery [9, 13], specification of MLC [14],
accuracy in image guidance [15], errors in DTT irradiation [9, 16–21], DWA [22],
and commissioning process [23].
16.4.2 Initial Clinical Application
In the first phase of the clinical application, ten palliative treatments were performed
on patients with bone metastases or lymph node metastases at IBRI [10]. The pur-
pose of the phase was to validate the usability and reliability of the system in clini-
cal practice. The typical IGRT session for palliation took less than 10 min, including
patient setup, image guidance, verification, and beam delivery. An IGRT flow suit-
able for the system was established through the first phase. In the next step, high-
precision radiation treatments such as IMRT for the prostate and SBRT for the lung
were performed. Image-guided setup verification after couch correction demon-
strated that the setup error was generally within 1 mm. Accuracies in image guid-
ance, couch movement, and beam delivery were confirmed in various clinical
situations. In addition, DWA was established as a pretty helpful irradiation tech-
nique in SBRT for static targets such as brain, prostate, and bone tumors because
overall treatment time is significantly shorter than the conventional couch-rotation
approach despite non-coplanar beam delivery for dose concentration [12, 24].
16.4.3 Dynamic Tumor Tracking SBRT
Based on the physics and clinical evaluations described above, DTT with the
Vero4DRT was considered feasible. Our procedures for DTT were as follows.
Spherical gold markers with a diameter of 1.5 mm (FMR-201CR; Olympus Medical
Systems, Tokyo, Japan) were placed around the tumor under bronchoscope guid-
ance before treatment planning. A simulation with 4D CT was performed one week
after the marker placement. An internal target volume (ITV) for tracking was delin-
eated on a breath-hold CT at end-exhale, followed by a modification to compensate
for intrafractional variations between the fiducials and the tumor using the 4D CT
[25]. The 4D modeling, which correlates abdominal motion with tumor position
during respiration, was performed in the planning procedure and each treatment
fraction. Planning target volume (PTV) for tracking was defined as the ITV plus
additional internal margins and setup error. The additional internal margins were
defined individually for each patient to compensate for the 4D modeling errors,
baseline drift of the abdominal position, and mechanical errors of the system.
Treatment beams were delivered using the gimbaled X-ray head toward the pre-
dicted coordinate position calculated based on the 4D model and the abdominal wall
position. During the irradiation, the tumor and the fiducials were continuously mon-
itored with OBI and EPID in real time [26] (Fig. 16.3).
Fig. 16.3 Comparison of dose distributions in Patient 1 between dynamic tumor tracking (left)
and conventional static irradiation (right)
After approval from the institutional review board, we conducted a prospective

feasibility study on DTT-SBRT for the lung after approval from the institutional
review board. Sixteen out of 22 patients enrolled in the feasibility study of DTT-
SBRT for the lung were successfully treated by DTT. On the other hand, four
patients who coughed out the gold markers, one whose tumor was spontaneously
regressed, and one whose abdominal motion did not correlate with the tumor
motion, were not treated by DTT-SBRT. When comparing dose-volume metrics
between DTT plans and conventional static plans in the 16 cases, doses covering
95% of the GTV did not differ (93.4% for DTT and 93.7% for static, p = 0.323). On
the other hand, PTV volumes (39.6 mm2 for DTT and 56.2 mm2 for static, p < 0.001)
and normal lung volumes receiving 20 Gy or higher (4.4% for DTT and 5.5% for
static, p < 0.001) were significantly 8.8 min (range, 19–70 min). A propensity score-
matched study also reported that DTT-SBRT for lung tumors reduced the PTV vol-
ume by 30.3%, while DTT did not deteriorate local control at 2 years (96.3% vs.
94.5% for DTT and static, p = 0.79) [27].
Intrafractional DTT-SBRT accuracies in patients with lung tumors were vali-
dated based on orthogonal fluoroscopy images acquired during DTT irradiation and
the synchronously acquired log files of the Vero system. The averaged intrafrac-
tional errors were (left-right, cranio-caudal, anterior-posterior) = (0.1, 0.4, 0.1 mm)
for 95th percentiles of mechanical errors, (1.2, 2.7, 2.1 mm) for 95th percentiles of
prediction errors, and (1.3, 2.4, 1.4 mm) for 95th percentiles of overall targeting
errors, respectively. In addition, we confirmed similar accuracy in DTT delivery and
adequacy in PTV margin settings at different centers based on each specific local
workflow [28].
The success in DTT for lung SBRT drove us to apply this technique to liver
SBRT. The procedures for the liver were almost the same as in the lung, except that
a linear fiducial marker (Visicoil; IBA Dosimetry GmbH, Schwarzenbruck,
Germany) was used as the implanted marker. Based on the analyses of the initial ten
patients with 11 successfully treated liver lesions by DTT-SBRT, the mean value of
35% could reduce the PTV volumes in DTT plans relative to the static plans, which
resulted in a 16% reduction in the average liver dose with DTT. In addition, The
average 95th percentiles of intrafractional prediction errors were 1.1, 2.3, and
1.7 mm in the left-right, cranio-caudal, and anterior-posterior directions, respec-
tively [29]. We also started hypofractionated DTT IMRT for locally advanced pan-
creatic cancer in 2013 [30], which is out of the scope of this book.
In 2015, four Japanese institutions initiated multi-institutional phase II studies of
DTT-SBRT for lung (UMIN Clinical Trials Registry number: 000016547) and liver
tumors (UMIN000017886) to evaluate and confirm the safety and efficacy of DTT-
SBRT approach (Table 16.2). The primary endpoint is the 2-year local control rate
for both studies. Forty-eight patients had registered in both studies as designed. In
the lung study [31], 47 tumors in 47 patients were successfully treated by DTT-
SBRT. In the remaining patient, DTT was switched to the conventional static SBRT
because the abdominal wall motion was poorly correlated with internal marker posi-
tions. With a median follow-up period of 32.3 months (range: 3.0–53.8 months), the
2-year local control rate was 95.2% (lower limit of the one-sided 85% confidence
interval [CI]: 90.3%), which met the predefined threshold value for the primary
endpoint. No grade 4 or 5 toxicity was observed. The incidence of radiation pneu-
monitis of grade 2 or worse was 8.3% (95% CI: 2.3%–20.0%). On the other hand,
48 tumors in all 48 cases were successfully treated by DTT-SBRT in the liver study
[29]. With a median follow-up period of 36.5 months (range: 3.0–62.4 months), the
2-year local control rate was 98.0%, which also satisfied the predefined threshold
value. No grade 4 or higher toxicity was observed. Grade 3 hepatobiliary enzyme
elevation, hyponatremia, and thrombocytopenia occurred in 5, one, and one
Table 16.2 Summary of the multi-institutional phase II studies of dynamic tumor tracking SBRT
for lung and liver tumors
n Median f/u 2-Year local Grade 3 adverse Grade 3 adverse
Region n (DTT-SBRT) (months) control (%) event (%) event (%)
Lung [31] 48 47 32.3 95.2 2.1 0
Liver [29] 48 48 36.5 98 14.6 0
Abbreviations: n Number of patients, n (DTT) Number of patients successfully treated by dynamic
tumor tracking stereotactic radiation therapy, f/u Follow-up period
patient, respectively. As a result, these two trials have proved the safety, efficacy,
and feasibility of the multi-institutional dissemination of DTT-SBRT.
16.5 Summary
The Vero4DRT system has two unique advantages in SBRT. One is the gyratory
O-ring structure, which enables non-coplanar beam delivery without any couch
rotation. The other is gimbaled mechanical head, which allows for tracking a mov-
ing target. Those features are translated into clinical practices such as DTT and
DWA irradiation and have validated the system’s usefulness in various aspects.
Although the benders terminated the system’s marketing due to a commercial deci-
sion [8], a much-improved successor was launched in July 2003.
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Chapter 17
Real-Time Tumor-Tracking Radiotherapy
(RTRT), SyncTraX
Naoki Miyamoto, Norio Katoh, Hiroshi Taguchi, Kentaro Nishioka,

and Hidefumi Aoyama
17.1 Introduction
The real-time tumor-tracking radiotherapy system (RTRT system) was developed in

1998 at Hokkaido University Hospital with support of the Education Ministry Grant-
in-Aid for Scientific Research [1]. As of 2022, the most recent version of the RTRT
system (SyncTraX, SHIMADZU, Japan) has been installed in 20 institutions in Japan
and the number of institutions has doubled since 2017. From the first clinical usage to
the present, we have reported the clinical results of stereotactic body radiation therapy
(SBRT) for non-small cell lung cancers (NSCLC), hepatocellular carcinomas (HCC),
adrenal tumors, and spinal schwannomas [2–8]. The analysis of the marker motion
was also performed and several interesting findings were reported [9–17].
N. Miyamoto
Department of Medical Physics, Hokkaido University Hospital, Sapporo, Japan
Division of Applied Quantum Science and Engineering, Hokkaido University Faculty of
Engineering, Sapporo, Japan
e-mail: noriwokatoh@med.hokudai.ac.jp
N. Katoh (*) · H. Aoyama
Department of Radiation Oncology, Hokkaido University Faculty of Medicine,
Sapporo, Japan
H. Taguchi
Department of Radiation Oncology, Hokkaido University Hospital, Sapporo, Japan
K. Nishioka
Department of Radiation Oncology, Hokkaido University Hospital, Sapporo, Japan
Global Center for Biomedical Science and Engineering, Hokkaido University Faculty of
Medicine, Sapporo, Japan
Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_17
244 N. Miyamoto et al.
In this chapter, we describe the physical aspects and clinical application of the
RTRT system, experience with gold marker insertion, clinical results of SBRT using
the RTRT system, analysis of marker movements, and the future developments pos-
sible for the RTRT system.
17.2 Physical Aspects and Clinical Application

of the RTRT System
The appearance of the latest RTRT system installed in Hokkaido University

Hospital is shown in Fig. 17.1. The system consists of external radiation therapy
equipment (TrueBeam, Varian Medical Systems, USA) and real-time imaging
equipment (SyncTraX, SHIMADZU, Japan). The SyncTraX consists of four sets
of X-ray fluoroscopes as with the first system [18]. Flat panel detectors (FPDs) are
used to acquire two-dimensional images. Two sets of fluoroscopes are automati-
cally selected based on the geometrical position of the gantry and couch in order to
acquire two X-ray images for both of the patient setup and real-time monitoring. A
photo of the software arrangement of SyncTraX is shown in Fig. 17.2. Internal
fiducial markers are identified in both images by means of template pattern match-
ing at a maximum of every 0.033 s [19], and then the three-dimensional position of
the markers can be calculated within an accuracy of 1 mm [20]. The SyncTraX
system has several setting options for the frequency of the X-ray fluoroscopy.
When an internal fiducial marker inserted in a patient is outside the range of the
gating window, the linac stops the irradiation. When a marker is inside the range of
the gating window, in relation to the planned position, treatment beam is delivered.
In this way, precise “gating” irradiation to the mobile target is realized [21]. The
gating irradiation method is a more precise method than hitherto available for mov-
ing targets by measuring the marker location during beam delivery from a synchro-
nized linac [18]. The dose distribution on X-ray films on a moving phantom with
the RTRT system has been shown to be comparable to the dose distribution on a
static phantom [18]. Photon beams with high dose rates like a maximum dose rate
of 1400 MU/min at 6 MV and 2400 MU/min at 10 MV with flattening filter-free
(FFF) can be used in the latest RTRT system. Compared with the first system where
the dose rate was about 300 MU/min, presently four or more times higher irradia-
tion efficiencies have been achieved and treatment time has been significantly
reduced.
For slowly moving targets, such as the prostate, it would not be proper to continu-
ously generate diagnostic X-rays during treatment. In such a case, we may use a
different option, that of consulting a single exposure at the start of every treatment
beam portal and intermittently during the beam delivery [22]. The 3D coordinates of
the markers were measured with the RTRT system, and the patient table position is
corrected to locate the marker to the planned position. The position of the patient
17 Real-Time Tumor-Tracking Radiotherapy (RTRT), SyncTraX 245
Fig. 17.1 Appearance of the RTRT system installed in Hokkaido University. Blue arrows indicate
FPD attached to the ceiling. Red arrows indicate kilo-voltage X-ray sources placed under the floor.
The cover is removed for this picture. Another two X-ray sources are located under the opposite
side floor across the linac
Fig. 17.2 Snapshot of the software arrangement of the SyncTraX. The planned and identified
marker positions are displayed on the X-ray image. Planned three-dimensional position, tolerance
(shown as Delta in this figure) and actual three-dimensional position of the marker are shown in
the lower panel
table can be continuously corrected so as not to diverge from the planned posi-
tion [19].
17.3 Method of Gold Marker Insertion
A “Disposable gold marker” manufactured by Olympus Corp. (Tokyo, Japan) was

invented as the marker kit which made it possible to follow a moving lung tumor by
the RTRT system. This kit consists of a pusher unit, a sheath unit, and the marker.
The marker is made of pure gold, spherical and diameter 1.5 mm. It can be implanted
near the targeted lung tumor by bronchoscopy. The method of implantation of the
gold marker into the lung is described by Harada et al. [23] and Imura et al. [24].
The gold marker is inserted and wedged into small bronchi near the tumor. The
location of the bronchoscope, catheter, and markers are visualized by fluoroscopy
[23, 24].
Imura et al. reported that 94% of markers that were seen in the CT for radio-
therapy planning were detected throughout the radiotherapy delivery [24]. They
also reported that 95% of the distance variation between implanted markers was
within 2 mm. The identified fixation rate in the left upper lobe was lower than in the
other lobes, and a learning curve for the placement was suggested.
Imura et al. reported histological changes after the marker insertion. They found
that fibrotic changes were observed 5–7 days after the marker insertion [25] and
suggested that radiotherapy should be started 5 or more days after the gold marker
insertion because marker dislocation then tended not to occur due to fibrotic changes
around the marker.
Katoh et al. reported clinical outcomes of 286 non-small cell lung cancer (NSCLC)
patients in a multi-institutional retrospective study [3]. One thousand markers were
implanted, and 918 markers were present at the start of treatment. There were three
cases requiring replanning due to inter-fractional migration of gold markers during
the treatment period. Complications associated with gold marker implantation
included pneumothorax in three cases (Grade 1: one patient, Grade 2: two patients)
and Grade 2 tachycardia in 1 case, but no cases of Grade 3 or higher were observed.
17.3.2 Liver and Prostate
It has been reported that true-spherical gold markers can be inserted into the liver
and prostate [22, 26]. Implantation of the markers into the liver through the skin was
performed using ultrasound and/or CT. The implantation kits for the liver and pros-
tate were manufactured by MEDIKIT Co. Ltd. (iGold™, Tokyo, Japan). Morita et al.
evaluated 116 procedures of true-spherical gold marker implantation into the liver
in 100 patients [26]. The technical success rate of the gold marker implantation was
92.2% (107/116). Migration was identified in 9 of 116 markers. No Grade 3 or
higher complications due to marker implantation occurred.
Hanazawa et al. of Yamaguchi University reported that one of 17 patients devel-
oped pneumothorax after percutaneously implantation of 1.1 × 5.0 mm coiled fiducial
markers (VISICOIL™, IZI Medical Products, Owings Mills, MD, USA), into the liver
and that no marker migration after implantation was observed in the 17 patients [27].
Shimizu et al. inserted gold markers into the prostate using a transperineal
approach guided by transrectal ultrasound observations. They reported no apparent
complications during or after the insertion, with a median follow-up period of
6 months [22].
17.4 CT Acquisition and Treatment Planning
In the case of lung tumors, considering the high rate of gold marker migration
immediately after the implantation [24], treatment planning CT is generally per-
formed 3 days after the implantation. In the case of liver tumors, CT is performed
the day after the implantation. Patients are asked to hold their breath at the exhale
phase during the CT acquisition. The slice thickness is 2.0 mm or less in principle.
Gross tumor volume and clinical target volume (CTV) was determined as with
other SBRT methods without an RTRT system. Markers were also contoured. The
gating window was usually 2 mm, but this was changed to 3 mm by respiratory
irregularities in actual treatment. The PTV was created by adding the margin of the
gating window and other uncertainties to the CTV, the margin was usually 5 mm. If
there is a displacement of the marker coordinates of 5 mm or more in one direction
compared to those at the time of the planning CT, a CT scan is made and replanning
may be done if thought necessary.
17.5 Clinical Results
Inoue et al. reported the results of stereotactic body radiation therapy (SBRT) using
the RTRT system for NSCLC [2]. They used a superposition algorithm for inhomo-
geneity corrections and 48 Gy in four fractions at the isocenter or 40 Gy in four
fractions at D95 of PTV. The 5-year local control rate (LC) was 78% (95% confi-
dence interval (CI), 68–90%) and the 5-year overall survival rate (OS) was 64%
(95% CI, 53–78%), respectively. The 5-year overall survival (OS) in patients with
T1a was 75%. The 5-year OS in patients with T1b or T2 was 56%, which was sta-
tistically poorer than that of patients with T1a (P < 0.01). Inoue et al. also reported
that the maximum amplitude of the marker movement in the lower lobe was signifi-
cantly larger than that in the upper lobe; however, there was no significant differ-
ence in LC between the lower lobe and the other lobes.
Katoh et al. reported clinical outcomes of 286 NSCLC patients in a multi-
institutional retrospective study [3]. A total dose of 35–60 Gy was administered in
4–9 fractions. The calculated biologically effective dose (alfa/beta = 10) at the iso-
center using the linear-quadratic model was from 66 to 126 Gy with a median of
106 Gy. The 3-year LC in T1a + T1b and T2a + T2b were 79% and 64% and the
3-year OS in stage 1A and 1B + 2A were 70% and 50%, respectively. There were
no differences between the clinical outcomes among the four institutions included.
As reported by Inoue et al., there was no significant difference in LC between the
lower lobe and the other lobe. The absence of any difference in LC between the
lower and the other lobes shows that the RTRT system allows accurate treatment of
moving tumors.
In the above two reports, radiation pneumonitis occurred in about 10% of patients
with Grade 2, about 3% with Grade 3, and in no patients with Grade 4 or higher.
These results are comparable to those reported for SBRT without an RTRT system.
17.5.2 Hepatocellular Carcinomas
Taguchi et al. reported the initial clinical outcomes of SBRT using an RTRT system
for 15 patients with 18 lesions of the HCC. The local control rate of 83% at 2 years
[4]. Uchinami et al. retrospectively analyzed 63 patients with 74 lesions treated with
SBRT using an RTRT system [5]. The dose-fractionation schedule was selected
according to the location of the tumor: 40 Gy in four fractions for tumors more than
2 cm away from both the hepatic hilum and the gastrointestinal tract and 40–48 Gy
in eight fractions in other cases. Doses were prescribed to a reference point or 95%
of the volume of the PTV enclosed by the 67–83% isodose line of the dose at the
reference point. The 2-year OS and LC were 71.1% (95% CI, 57.8–81.6%) and 92%
(77.5–97.5%), respectively. Classic radiation-induced liver diseases (RILD) was
observed in one patient and non-classic RILD in one patient within 3 months of the
treatment. There was no late Grade 3 or higher adverse event. In that study it was
concluded that SBRT using an RTRT system for HCC showed favorable outcomes
with lower incidences of toxicities.
17.5.3 Other Tumors
Katoh et al. reported the results of SBRT for adrenal metastases using an RTRT
system [6, 7]. They evaluated the clinical outcomes of 13 lesions in 12 patients
treated with RTRT and 8 lesions in 8 patients treated without RTRT (general SBRT,
g-SBRT). In the RTRT group, all 13 lesions were treated with 48 Gy in 8 fractions
prescribed at the isocenter and in the g-SBRT group, 8 lesions treated with 40–70
Gy in 5–10 fractions prescribed at the isocenter or D95 of the PTV [7]. Although
there was no statistically significant difference in the OS between the RTRT (83%
at 1-year) and g-SBRT (53.8% at 1-year) groups (p = 0.60), the LC was statistically
significantly higher in the RTRT group (100% at 1-year) than in the g-SBRT group
(50% at 1-year). No Grade 3 or higher acute or late reactions were observed in both
groups. The study concluded that SBRT using an RTRT system was more effective
than g-SBRT in local control of adrenal metastasis.
Onimaru et al. reported on the experience of radiotherapy treatment for spinal
schwannomas using the RTRT system [8]. They calculated the rotation using three
markers. It was found to be important to consider the rotation and the deformation
of the target; however, the strategy of the rotation and the deformation is still to be
investigated.
17.6 Marker Movement Analysis
The RTRT system records log files of the marker motion. The log file is very valu-
able because it is the exact data obtained during irradiation delivery. The analysis of
RTRT log files has shown valuable and important results.
Seppenwoolde et al. developed a system of analysis and reported the marker
motion in the lung. This report showed that respiratory movement of the marker
shows hysteresis. This was the first report of a baseline shift during the radiation
delivery and intra-fractional errors based on data during irradiation delivery [9].
Takao et al. have examined the frequency and amplitude of the baseline shift of lung
tumors in detail [14]. They showed that the incidence of baseline shift/drift exceed-
ing 3 mm was 6.0%, 15.5%, 14.0%, and 42.1% for the LR, CC, AP, and for the
square-root of the sum of three directions, respectively, within 10 min of the start of
treatment, and 23.0%, 37.6%, 32.5%, and 71.6% within 30 min.
Onimaru et al. reported the relationship between the marker location and the
amplitude of the marker movement in NSCLC, they showed that the marker move-
ment in the craniocaudal direction was smaller in the anterior and the cranial parts
of the lung [10]. Nishioka et al. reported exhalation fluctuations by using synchro-
nized internal/external position data. The exhalation fluctuation, which was defined
as the phenomenon in which the lowest point of the external wave crossed down-
ward past the pre-determined baseline, occurred in 18.4% of all of the data measure-
ments during the entire course of treatments, and the fluctuation magnitude was up
to 12.2 mm in the left–right, 12.7 mm in the craniocaudal, and 9.7 mm in the ante-
rior–posterior direction [11]. Onodera et al. evaluated the relationship between lung
parenchymal findings on CT and the amplitude of marker movement, they found
that fibrosis and pleural tumor contacts were weakly associated with marker motion,
but there was no correlation between lung fibrosis and marker motion in the lower
lung, nor was there any between emphysema findings and marker motion in the total
lung [12]. Harada et al. compared the marker amplitude obtained from 4DCT with
the actual amplitude during SBRT, the average of the maximum amplitude during
SBRT was significantly larger than that obtained by 4DCT in all directions [13].
Marker movement in the liver was evaluated by Nishioka et al. [15]. The mean
craniocaudal total movements were 15.98 ± 6.02 mm. They reported that the fluc-
tuations from the baseline position in liver tumors were smaller than that in lung
tumors. This result suggested that liver tumor motion was stable in amplitude com-
pared with lung tumor motion. The reason for this phenomenon is unclear.
The RTRT system can continuously observe the movement of the target during
radiation therapy. It is possible to evaluate non-respiratory organ motion such as of
the prostate and bladder. Shimizu et al. evaluated the intra-fractional motion of the
prostate and reported that inter-portal adjustment of the table position was required
in more than 10% of portal irradiations during the 10-min period after initial setup
to maintain treatment accuracy to within 2.0 mm [16]. Nishioka et al. evaluated the
inter-fractional and intra-fractional motion of the bladder wall and reported that the
cranial and anterior bladder wall showed larger uncertainties in position than the
opposite side in the cranial-caudal direction [17]. In both reports, the variance of
intra-fractional movement increased over time and the data indicate that optimal
internal margins should be chosen or employment of a precise intra-fractional target
localization system is required depending on the target organ and treatment delivery
time in the setting of highly conformal radiotherapy.
As shown here, the finding from log files of the RTRT system contribute to the
understanding of tumor or organ movement. Understanding the movement of
tumors or organs will help to set margins appropriately, leading to improved out-
comes and reduced toxicity of SBRT.
17.7 Future Directions
Owing to the high dose rate of a linac, treatment time of RTRT has been signifi-
cantly reduced from the first generation system. Furthermore, the latest systems can
implement volumetric modulated arc therapy (VMAT) combined real-time tumor
tracking techniques to conduct beam gating. Real-time image-guided VMAT will be
one of the best options for future SBRT to reduce treatment time further while main-
taining or improving dose distributions.
Research to improve the tumor localization accuracy has also been reported.
Ukon et al. have proposed a new tumor localization technique by using multiple
fiducial markers and shown that gated irradiation accuracy could be improved when
compared with the conventional tumor localization method based on the use of one
marker [28]. Hayashi et al. have proposed a real-time volumetric imaging technique
which could be applied in the next-generation motion management [29].
Although more than 20 years have passed in the development of the RTRT sys-
tem, clinical outcomes of SBRT using the RTRT system have mostly been reported
as single-center, retrospective studies; now that the RTRT system has been installed
in 20 institutions, evaluations in multicenter prospective clinical studies would be
expected.
17.8 Summary
We have described the physical aspects of the RTRT system, the clinical results, and
marker movement analysis of various organs using the RTRT system. The RTRT
system can provide precise radiation delivery and provide valuable information
about intra-fractional organ motion. Analysis of log files obtained from SyncTraX,
a modern RTRT system, has already resulted in the development of techniques such
as the prediction of tumor location using multiple markers, and further technologies
are expected to be developed.
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Chapter 18
CyberKnife®
Satoshi Kito
18.1 Introduction
The CyberKnife® Robotic Radiosurgery System (Accuray Incorporated, Sunnyvale,

CA, USA) is a dedicated device for performing frameless stereotactic radiosurgery
(SRS) and stereotactic radiotherapy (SRT) [1]. The CyberKnife® system was initi-
ated as an alternative to the existing SRS systems, such as the Gamma Knife (Elekta
AB, Stockholm, Sweden) or conventional linear accelerator (LINAC) systems, as
described in a series of technical papers in the late 1990s. Although the basic con-
cept of CyberKnife® has not changed, major system modifications and technical
improvements have continued [2, 3], and papers focusing on quality assurance have
also been reported [4]. Task Group 135 of the American Association of Medical
Physics detailed the technical quality assurance of CyberKnife® prior to the G4™
version [5]. A detailed overview of the technical system was published previously
[6], where the CyberKnife® system (version 8.0) was first described in 2008 and
then updated in 2009 (version 8.5) and 2010 (CyberKnifeVSI™) [7]. The latest ver-
sion of CyberKnife®, which was released in 2020, is the S7™ system [8].
CyberKnife® is a small magnetron LINAC with six free-joint axis arms.
CyberKnife® can irradiate the target from multiple directions and possibly reduce the
dose to normal tissues, while concentrating the dose on the target better than the
conventional LINAC. In addition, the CyberKnife® system has two X-ray tube sys-
tems and can perform three-dimensional image-guided radiotherapy by various
tracking methods. It is possible to calculate the patient’s setup error from the radio-
graphic images taken intermittently at 5–150 s intervals during the patient’s
S. Kito (*)
Division of Radiation Oncology, Department of Radiology, Tokyo Metropolitan Cancer and
Infectious Diseases Center Komagome Hospital, Tokyo, Japan
e-mail: satoshi_kitou@tmhp.jp
Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_18
256 S. Kito
treatment and automatically correct the irradiation position. This allows the
CyberKnife® to minimize setup errors during treatment, unlike other LINAC systems.
In treatment planning, planners can choose a 5–60 mm circular tungsten collima-
tor, depending on the size of the target. However, in the earlier versions of
CyberKnife®, therapists had to manually replace the appropriate collimator during
the irradiation procedure. Since the G4 version, the Xchange® Robotic Collimator
Changer has been implemented to enable therapists to automatically change the col-
limator without entering the irradiation room during treatment [4]. In addition, the
Iris™ Variable Aperture Collimator, which can automatically change the size of the
circular collimator, was installed in G4 [9]. This has made it possible to reduce the
time required to replace the collimator. Moreover, a six-axis RoboCouch® Patient
Positioning System was implemented, which has made it possible to correct the
patient’s position by translating and rotating the three axes.
There are two traditional CyberKnife® planning techniques: isocentric planning
and sequential optimization planning. The isocentric planning technique concen-
trates beams from a maximum of 180 nodes arranged on a spherical surface toward
the center of the target. The other, the sequential planning technique uses inverse
planning to achieve a more conformal dose distribution to the target by irradiating
beams of various collimator sizes from 180 nodes in 32 directions.
The M6™ version has the InCise™ installed, a multileaf collimator (MLC) system
consisting of 41 leaf pairs with widths of 2.5 mm, forming a maximum field size of
120 mm × 102.5 mm. By using InCise™, the treatment planning for stereotactic body
radiotherapy (SBRT) for prostate [10] and vertebral lesions [7] with complicated shapes
has improved. For example, Iris™-based planning requires multiple beams to create a
conformal dose distribution in a spinal vertebral lesion (Fig. 18.1a), which results in
longer treatment times [11]. However, InCise™-based planning has made it possible to
achieve shorter treatment times without compromising treatment outcomes [12].
The CyberKnife® system has tracking options for each treatment site. For exam-
ple, the brain stereotactic radiosurgery/stereotactic radiotherapy has made it
a b
Fig. 18.1 An example of (a) position registration by X-sight® Spine tracking and (b) dose distri-
bution in vertebral body stereotactic body radiotherapy. The blue square in (a) is the region of
interest for the registration. Each grid of the green mesh is called a node. The X-sight® Spine
algorithm searches for similar positions between the live image and the digitally reconstructed
radiograph in each node and calculates the shift that matches the best on an average in all the nodes
18 CyberKnife® 257
possible to irradiate the tumor with high accuracy using skull tracking, which
focuses on the skull shape characteristics on the two orthogonal radiographic
images. The following sections describe the various extracranial tracking options
used for CyberKnife® stereotactic body radiotherapy.
18.2 Xsight® Spine Tracking
Xsight® Spine Tracking is an image registration technique that specializes in vertebral

bone structure. The tracking algorithm searches for match points on live images for
each point placed in a mesh on digitally reconstructed radiographs (DRR), and the
optimum registration is calculated by averaging all positional errors at each node [13]
(Fig. 18.1a). Furthermore, the registration accuracy of Xsight® Spine Tracking is
improved by using an image filter that removes pixel signals from the anatomy other
than the vertebra for both DRR and live images [7]. Xsight® Spine Tracking is used
for vertebral bone SBRT (Fig. 18.1b). It may also be used for targets connected to the
vertebrae, such as the rib or for tumors with unchanged positional relationship with
the vertebrae. Xsight® Spine Tracking is also a basic technique used for bone collation
in the Xsight® Lung Tracking system used for lung SBRT as described in Sect. 18.5.
18.3 Fiducial Marker Tracking
Fiducial marker tracking is a position-matching technique for targeting radio-

opaque fiducial markers implanted in or near a tumor. This tracking method enables
highly accurate positioning using fiducial markers toward a target that cannot be
visualized with radiographic images. Fiducial marker tracking can be used in vari-
ous areas including the lungs.
Usually, cylindrical gold seeds with a diameter of 0.8–1.2 mm and a length of
3–6 mm are used as radio-opaque fiducial markers. Fiducial markers are placed per-
cutaneously or via bronchoscopy in the lungs [14]. Generally, 3–5 fiducial markers
are implanted. Then, a computed tomography scan for treatment planning is per-
formed at least 1 week after implantation to stabilize the position of the fidu-
cial marker.
In Fiducial Marker Tracking, registration is performed based on the position of
the fiducial markers identified in the DRR and those extracted from the live image
[15]. Marker migration is evaluated automatically by determining the deviation of
the individual fiducial markers after registration. Fiducial markers with large migra-
tions can be excluded from registration if necessary. However, if fiducial markers
are placed too close together, the rotational error may not be evaluated correctly [16].
A 5-year follow-up study of CyberKnife® SBRT using Fiducial Marker Tracking
in stage I-II prostate cancer reported that CyberKnife® SBRT was equivalent to
conventional intensity-modulated radiotherapy [17]. A hypofractionated radiother-
apy study reported that the CyberKnife® treated group had a significantly reduced
258 S. Kito
incidence of grade 2 or higher acute urinary toxicity than the general LINAC-treated
group [18].
18.4 Synchrony Respiratory Motion Tracking System
The Synchrony system comprises a real-time tracking technique (RTTT) with the
CyberKnife®. The RTTT can minimize the irradiation volume to normal tissue by
dynamically moving the irradiation port following the tumor motion. Generally, the
RTTT is used for sites with large respiratory motions, such as lung and liver can-
cers. The technical concept of the Synchrony systems has been defined previ-
ously [19].
The Synchrony system processes the following steps to track the target motion in
real-time (Fig. 18.2).
Fig. 18.2 Overview of the Synchrony system. (a) The system monitors the motion of the LED
markers attached to the body surface in real-time with a Synchrony camera. (b) The CyberKnife®
head constantly moves to aim at the target based on the correlation model, which is the relation
between the positions of the LED markers and the target in various respiratory phases. The hori-
zontal axis shows the average position of the LED markers, and the vertical axis shows the target’s
position in inferior-superior, left-right, and anterior-posterior axes. Abbreviations: LED Laser
light-emitting diode
18 CyberKnife® 259
1. The position and orientation of the patient are registered based on the bone struc-
ture by Xsight® Spine Tracking and corrected by moving the couch.
2. The motion of the laser light-emitting diode (LED) sensor placed on the abdomi-
nal body surface is monitored in real-time using an infrared camera.
3. While monitoring the motion of the LEDs, the three-dimensional positions of
the radio-opaque markers are obtained by intermittently taking–8–15 pairs of
orthogonal radiographic images.
4. A model that correlates the relationship between the positions of the LED and
radio-opaque markers in various respiratory phases is created. There are three
types of correlation models depending on how the target moves: “Linear,” in
which the motion fits in a straight orbit; “Curved Poly,” in which the motion fits
in an arc; “Dual Poly,” which fits when the target moves along different paths
during the expiratory and inspiratory phases. The optimal model is automatically
selected according to the acquired respiratory waveforms of the patient.
5. The robotic arm moves according to the correlation model, and the LINAC head
dynamically aims at the target.
6. The correlation model is updated if the infrared camera system detects a change
in respiration during irradiation.
However, a total delay of 115 ms occurs owing to the communication delay and
inertia of the robot manipulator. Therefore, the system incorporates a predictor to
quickly respond to changes in the breathing patterns and target movements to elimi-
nate delays. Further details have been reported by Sayeh et al. [20].
Changes in intra- and inter-respiratory motion are common problems in radio-
therapy [21]. Lischalk et al. reported that the 5-year local control for stage I non-
small cell lung cancer in 61 cases treated with CyberKnife® SBRT was 87.6% [22].
In the case of SBRT for liver cancer, Yoon et al. reported that the dose to normal
tissues could be reduced using the Synchrony system [23].
18.5 Xsight® Lung Tracking
Xsight® Lung Tracking is a reliable option for RTTT in lung cancers without radio-
opaque markers [7, 24]. Xsight® Lung Tracking uses a technique to identify the
three-dimensional position of the target by automatically detecting the shadow of
the target in orthogonal radiographic images (see Fig. 18.3a).
If the target’s shadow is detected from two views, complete RTTT can be per-
formed by the 2-view tracking mode. Fu et al. reported that 2-view tracking could
irradiate with an accuracy of 1.5 mm or less [24]. If the shadow of the target is
detected from only one view, a 1-view tracking mode can be used to perform the
RTTT. The dose to the target is guaranteed by expanding the asymmetric internal
margin for the direction in which the target motion cannot be evaluated (see
Fig. 18.3b). If the shadow of the target cannot be detected from either of the two
directions, the RTTT is not performed. In this case, the planning target volume that
260 S. Kito
Fig. 18.3 An illustration of lung optimized treatment. (a) The three-dimensional position of the
target is detected from the two orthogonal radiographic images by the automatic analysis of the
X-sight® Lung system. (b) An optimum internal target volume for the target is created depending
on the number of directions in which the target’s shadow can be detected from the radiographic
images. If the target can be identified from only one direction, an internal margin is added to the
direction that cannot be tracked
thoroughly covers the tumor motion is irradiated using the Spine Tracking tech-
nique (0-view tracking).
The Lung Optimized Treatment system proposes an optimum tracking mode for
the user from the above three tracking modes. The planner can determine the opti-
mum tracking mode by acquiring the patient’s respiratory waveform and radio-
graphic images during simulation in the CyberKnife® room before treatment
18 CyberKnife® 261
planning. However, Chan et al. recommended using a method that can reduce the
target motion when performing 0-view tracking [25].
18.6 Summary
The CyberKnife® is a reliable system for frameless SRT. The latest version inte-
grates the robotic arm, automated couch, variable collimator, precise MLC, two-
orthogonal radiographic imaging system, and the Synchrony system for RTTT. The
CyberKnife® system can accurately irradiate various tumors.
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doi.org/10.4103/0973-1482.138220.
Chapter 19
Tomotherapy
Hidetoshi Shimizu
19.1 General
The concept of tomotherapy had initially been proposed by Dr. Mackie in 1993 [1],
the basic concept of which involved placing a linear accelerator into a computed
tomography (CT)-like ring gantry configuration and delivering therapeutic radiation
using a rotating fan beam that was modulated by a multileaf collimator system
while the patient moves through the gantry in the longitudinal direction [1]. A pro-
totype was installed at the University of Wisconsin-Madison in 2003. Currently,
many units are working clinically worldwide. We can observe details of the devel-
opment process that Dr. Mackie reviewed in a previously published paper [2].
TomoTherapy® has undergone a major structural evolution over the decades since
the prototype had been introduced at the University of Wisconsin-Madison. After
having been placed on the market, the Hi-Art® system could initially only perform
the TomoHelical™ mode, which delivers the dose with the treatment couch moving
with the gantry rotation, which has been available since the TomoTherapy® was first
released. This was followed by the TomoHD® system with the TomoDirect™ mode,
which delivers the dose from the fixed gantry with the couch moving for breast
cancer and palliative cases that do not require high-precision radiotherapy, in addi-
tion to the TomoHelical™ mode. Subsequently, the TomoHDA™ system was released
equipped with the TomoEDGE™, which was a dynamic jaw technology with a
dynamic adaptation of field width at the cranial and caudal edges of a target for both
delivery modes. The low-priced Onrad® system was also released as part of the
marketing process, which supported only the TomoDirect™ mode. The latest sys-
tem, called Radixact®, can equip Synchrony®, which is an optional technology for
respiratory synchronization. Figure 19.1 shows the exterior of a Radixact® system
[(a) with a cover and (b) without a cover]. There are megavoltage (MV) image
H. Shimizu (*)
Department of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_19
264 H. Shimizu
a b LINAC
kV source
Fig. 19.1 The exterior of a Radixact® system [(a) with a cover and (b) without a cover, image
provided courtesy of Iwata city Hospital]. Megavoltage (MV) image detectors are present on the
opposite side of the 6 MV linac, whereas a kilovoltage (kV) tube was present at the orthogonal
direction to the linac, with the kV image detector on the opposite side
a b
Y Y
X X
Fig. 19.2 Beam collimators used to form the field size [(a) jaw and (b) binary MLC]
detectors on the opposite side of the 6 MV linac and a kilovoltage (kV) tube at the
orthogonal direction to the linac, with the kV image detector on the opposite side.
The source to axis distance is 85 cm, which differs from the 100 cm in conventional
linacs. TomoTherapy® or Radixact® does not have a flattening filter, and their dose
rate is 850 or 1000 cGy/min, respectively, which enables efficient dose delivery.
Figure 19.2 shows the beam collimators used to form the field size, which is first
formed by the primary collimator and then by the subsequent jaw position in the
International Electrotechnical Commission (IEC)-Y direction (Fig. 19.2a). The
selectable jaw sizes include 1.0, 2.5, and 5.0 cm at the isocenter. Considering that
the jaw is composed of very thick tungsten, the leakage dose is quite small [3]. The
multileaf collimator (Fig. 19.2b) made of 10-cm thick tungsten is set under the jaw.
TomoTherapy®/Radixact® utilizes a binary MLC not operated by mechanical
motors. Each leaf opens and closes at high speed within 20 ms through highly pres-
surized air, which enables complicated dose distributions. Each leaf has a width of
0.625 cm at the isocenter, with the MLC covering an area of 40 cm with 64 leaves
in the IEC-X direction. Megavoltage CT (MVCT) can be used as image-guided
radiotherapy (IGRT) technique. Although MVCT is inferior to treatment planning
19 Tomotherapy 265
Fig. 19.3 Computed tomography images of a patient treated for (a) lung or (b) prostate cancer
[left: computed tomography (CT) simulation, center: ClearRT™ kVCT, and right: megavoltage
(MV) CT, image provided courtesy of Anjo Kosei Hospital]. The ClearRT™ scan for lung or pros-
tate was acquired with thorax or pelvis medium settings in normal mode, respectively
CT in soft-tissue resolution, it has sufficient resolution for determining patient anat-

omy alignment. The resolution of soft tissues can also be improved using an itera-
tive reconstruction (IR) algorithm implemented from Radixact®. IR has been known
to reduce noise, produce a smooth image as a whole, and promote excellent soft-
tissue matching (e.g., certain head-and-neck, thoracic, mediastinal, and abdominal
cases) [4]. Conversely, the conventional filtered back-projection algorithm promotes
superior bone matching (e.g., cranial as well as head-and-neck cases) [4]. The user
can choose a proper algorithm depending on treatment cases. While the dose for
MVCT is much lower than that for cone-beam CT equipped in other linacs [5], its
scanning time tends to be longer than other linacs. To overcome this, the latest
Radixact® system utilizes helical kilovoltage CT (kVCT) imaging, ClearRT™, which
allows for a very short scanning time with good image quality [6]. Figure 19.3
shows comparisons between CT simulation (left), ClearRT™ kVCT (center), and
MVCT (right) of a patient treated for (a) lung or (b) prostate cancer. ClearRT™ pro-
vides visibly better images compared to MVCT with considerably less noise and
improved soft-tissue contrast, whereas MVCT images have the advantage of
decreased metal and air artifacts [7]. The user can choose MVCT or kVCT as an
image-guided radiotherapy strategy.
19.2 Beam Model
The beam model of the TomoTherapy®/Radixact® consists of common and machine-

specific models. The common model includes energy spectral distribution, beam
profiles, and Energy Fluence per Ideal Open Time (EFIOT), whereas the
266 H. Shimizu
machine-specific model includes Jaw Fluence Output Factors (JFOF) and Leaf
Fluence Output Factors (LFOF), leaf filter, and MLC latency. Details regarding
these models will be described later.
19.2.1 Common Model
The average energy spectral distribution and beam profiles of several facilities have
been modeled [8]. The energy spectrum distribution is adjusted so that the PDD10 of
the entire field size matches [8]. The lateral and longitudinal beam profiles are mod-
eled at a depth of 1.5 cm and are normalized at the maximum value in some jaw
sizes (1.0, 2.5, and 5.0 cm) [8]. The EFIOT is defined as the energy fluence in the
air under conditions of the field size of 5 × 40 cm2 [8]. Given that the EFIOT is
calculated using the ideal open time of MLC, the tongue-and-groove, leaf penum-
bra, and leaf velocity that contribute to the fluence were not included.
19.2.2 Machine-Specific Model
The machine-specific model in each facility needs to be measured or tuned finely to

the default value. The JFOF is a factor for correcting energy fluence due to differ-
ences in jaw size and is defined as the jaw size energy fluence normalized by the
5.0 cm jaw size energy fluence [8]. At the commissioning phase, the factor is
adjusted to bridge the error between the measured and calculated doses using some
simple plans even for different jaw sizes.
The binary MLC has unit-specific geometric characteristics, which greatly affect
dose distribution calculation and dose delivery. The LFOF is a parameter for reflect-
ing the characteristics of MLC fluence and corrects the fluence difference due to the
opening and closing of adjacent MLCs as follows [8].
F ( i ∪ i − 1)
LFOFi | lower leaf = (19.1)
F ( i ) + F ( i − 1)
F ( i ∪ i + 1)
LFOFi | higher leaf = (19.2)
F ( i ) + F ( i + 1)
F ( i ∪ i − 1 ∪ i + 1)
LFOFi | both leaves = (19.3)
F ( i ) + F ( i − 1) + F ( i + 1)
where, the F and i indicate the fluence and leaf number, respectively. The leaf filter
is a parameter that reflects the shape of the MLC dose profile [8]. Given that the
TomoDirect™ mode does not accompany gantry rotation during dose delivery, the
19 Tomotherapy 267
edges of the MLC dose profile must be modeled more accurately. However, in the
TomoHelical™ mode, the edges are not as important as that in the TomoDirect™
mode due to the blurring by gantry rotation although the dose calculation accuracy
can be improved by introducing the leaf filter.
Although the binary MLC opens and closes at high speed within 20 ms through
highly pressurized air, it has a slight latency due to the electronic control [8]. Given
that dose delivery is performed through 51 projections per gantry rotation, the pro-
jection time can vary between 231 and 1176 ms (gantry rotation period: 11.8–60 s).
The smaller the projection time, the greater the effect of the leaf latency on the
projection time. This effect can be eliminated by MLC latency correction coeffi-
cient of each machine. MLC latency adjusts the programmed leaf open time consid-
ering the transit time in order to apply the required fluence during the treatment
plan [8].
OTprogrammed = m × OTactual + c (19.4)
Here, OTprogrammed and OTactual indicate the programmed leaf open time and actual
leaf open time, respectively, whereas m and c indicate the slope and intercept values
of an approximate straight line, respectively. Considering that m and c do not depend
much on the leaf number but depend heavily on the projection time, they are defined
in multiple projection times. Using continuous feedback from the optical sensor, the
latest MLC adjusts the timing of each leaf during treatment.
19.3 Treatment Planning
Accuray Precision® is one of the treatment planning systems that can design treat-
ment plans for TomoTherapy®/Radixact®. There are three important treatment plan-
ning parameters (field width, pitch, and modulation factor) in Precision®. Field
width represents the jaw size and is defined using the full width at half maximum of
the dose profile in the IEC-Y direction. Although a smaller jaw size increases the
delivery time, it allows for a finer dose distribution in the IEC-Y direction, which
improves dose distribution [9–11]. There is a tradeoff between delivery time and
dose distribution in the IEC-Y direction. The dynamic jaw technology can work,
except for cases that have a jaw size of 1.0 cm, provided that there is a TomoEDGE™
license. Generally, the dose delivered to at-risk organs adjacent to the IEC-Y direc-
tion of the target outside the dose delivery range is reduced due to sharpened dose
distribution in the IEC-Y direction; however, the dose within that does not reduce.
As a clinical example, choosing a one-step increase in jaw size (e.g., from 2.5 cm
jaw width without the dynamic jaw technology to 5.0 cm width with the technol-
ogy) might reduce the dose to organs at risk, such as the rectum and bladder, with
the reduction of the dose delivery time [12]. Next, the pitch is defined as the couch
movement per gantry rotation. Reports have shown that some pitch values cause
ripples in the dose distribution along the IEC-Y direction. These ripples are called
268 H. Shimizu
the “thread effect” [13]. To alleviate this effect theoretically, the values obtained by
dividing 0.86 by an integer (0.43, 0.287, 0.215, etc.) had been used in the past based
on the report of Dr. Kissick [13]. However, the pitch value reported by Kissick et al.
was effective only for the on-axis target. Later, Chen et al. found that the effect
depends on the jaw size and target offset [14]. The study published by Chen et al.
presented pitch values suitable for each condition in a table [14]. For instance, they
showed that the optimal pitch values were 0.446, 0.303, and 0.233 for a target with
a 5-cm offset when 2.5-cm jaw size was used. Finally, the modulation factor is an
indicator of the complexity of MLC modulation. The modulation factor is defined
as the ratio of the maximum leaf opening time to the average leaf opening time of
all non-zero leaves [15]. When a user sets a value of 2 as the modulation factor, the
maximum leaf open time will be twice the average leaf open time. In other words,
if the modulation factor setting is 2.0 with an average leaf open time of 200 ms, the
maximum leaf open time becomes 400 ms at maximum. Generally, targets with a
complex shape are known to need a large modulation factor. Conversely, increasing
the modulation factor allows a longer maximum leaf open time, resulting in a longer
delivery time [15].
Given the high dose per fraction required in SBRT treatment plans, the gantry
rotation period is sometimes lengthened to achieve the adequate target dose.
Considering that the gantry rotation period is limited to a maximum of 60 s, this
limitation may be violated depending on the settings of the above treatment plan-
ning parameters. In such cases, it can be solved by adopting a small MF and/or pitch.
19.4 Quality Assurance
For quality assurance (QA) of TomoTherapy®/Radixact®, in addition to reports from

the American Association of Physicists in Medicine (AAMP) task group (TG)-40,
142, and 198 that have summarized the tolerance and procedure related to QA items
of medical accelerators [16–18], reports by TG-148 and the Netherlands Commission
on Radiation Dosimetry specializing in TomoTherapy®/Radixact® have been help-
ful [19, 20]. The basic concept of QA for TomoTherapy®/Radixact® is similar to that
for conventional linacs, with some peculiar QA items in the former. One of these
items is the synchrony test. The dose delivery for TomoTherapy®/Radixact® requires
synchronization between the gantry rotation and couch movement. The ability of
the system to identify gantry angles and synchronize the couch position with the
beam delivery needs to be assessed periodically [19, 21], together with the synchro-
nization between couch translation and gantry rotation [19, 21]. Additional QA rec-
ommendations for technology implemented after TG-148 had been published are
ongoing, as can be observed in AAPM TG-306.
Regarding dosimetry, TomoTherapy®/Radixact® unfortunately does not allow for
the creation of a 10 × 10 cm2 field, which has been commonly used as the reference
condition for conventional linacs. This explains why standard dosimetry, as well as
an 85-cm source axis distance and flattening filter-free beams, cannot be utilized.
19 Tomotherapy 269
The AAPM TG-148 report [19], published in 2010, introduced the following new
reference conditions defined by the International Atomic Energy Agency study
group into dosimetry for TomoTherapy®/Radixact®:
Dwfmsr f msr
( f msr , f ref
, Qmsr = M Qmsr ⋅ N D ,W , Q0 ⋅ kQ , Q0 ⋅ kQmsr , Q ) (19.5)
f
Dwpcsr
f
pcsr
( f msr , f ref f
, Qpcsr = M Qpcsr ⋅ N D ,W , Q0 ⋅ kQ , Q0 ⋅ kQmsr , Q ⋅ kQpscr , Qmsr
pcsr msr ,f
) (19.6)
Equations (19.5) and (19.6) show machine-specific and plan-class-specific refer-

ences, respectively. First, the machine-specific reference field used in TomoTherapy®/
Radixact® has a field size of 5 × 10 cm2. The factor kQ ,Q0 can be obtained by convert-
ing the PDD10 under machine-specific conditions to that obtained under reference
conditions based on previous reports [19, 22]. The factor kQ ,Q0 can be also converted
from the value calculated by multiplying the TPR20,10 obtained under machine-
specific conditions by 1.027 [23]. Apart from the conventional standard dosimetry
formalism, another k-factor (kQfmsr , f ref
msr , Q
) is required. This factor was calculated by
Monte Carlo simulation and was reported to be 0.997 (1.000 with 0.5% uncertainty)
f , f msr
[23]. Next, the plan-class-specific reference is added as one more k-factor (kQpcsr pscr , Qmsr
)
in addition to the machine-specific reference. This plan-class-specific reference
field is as close as possible to a final clinical delivery scheme but delivers a homo-
geneous absorbed dose to an extended and geometrically simple target volume [19].
The AAPM TG-148 report recommends generating a treatment plan that delivers a
uniform dose of 2 Gy to a target with an 8-cm diameter and 10-cm length in a 30-cm
diameter water-equivalent phantom that has a minimum length of 15 cm [19].
Evidence has recommended the use of a 5 cm treatment slice width and a pitch of
f , f msr
0.287 [19]. Thereafter, the value of kQpcsr pscr , Qmsr
was experimentally reported to be
1.000 [19].
19.5 Synchrony®
Radixact® Synchrony® is an intrafraction motion management technique that traces

target motion by adjusting the collimation of the radiation in real-time during treat-
ment. A light-emitting diode (LED) camera mounted on the ceiling monitors the
LED positions on the patient’s chest and the couch. A correlation model between
tumor movement by kV images and the LED signal is then created, and the jaw and
MLC track the tumor according to the model. The jaws move to compensate for
superior-inferior target motion and the planned leaf patterns shift left and right
along the binary MLC to compensate for anterior–posterior and mediolateral
motions [24]. There are three methods for creating the correlation model: fiducial
tracking with non-respiratory motion (FNR, e.g., prostate), fiducial tracking with
respiratory modeling (FR, e.g., lung, liver, and pancreas), and fiducial-free tracking
with respiratory modeling (FFR, e.g., lung). Chen et al. measured the target motion
270 H. Shimizu
detection accuracy during motion tracking using Synchrony® phantom plans of the
three tracking methods [25]. They delivered the plan with respiratory motion cor-
rection using a sine wave motion trace with a period of 3 s and an amplitude of
10 mm. Tracking accuracy was measured using the root mean square (RMS) of the
difference between the tracked and driven motion of the phantom positions. The
RMSs were 0.84, 1.13, and 0.48 mm for FNR, FR, and FFR, respectively, within the
1.5 mm recommended tolerance. Ferris et al. delivered the plan for 13 patients
(liver, lung, and pancreas cases) using patient-specific modeled motion trace [26].
The RMS error between the tracked and driven motion of the phantom positions
was <1.5 mm for all Synchrony® deliveries with the LEDs on the Delta4® Phantom+
mounted on a Hexamotion® stage. Thus, the target motion detection accuracy dur-
ing motion tracking using Synchrony® was quite high.
During treatment planning, the use of Synchrony® is limited to the TomoHelical™
mode. Although the jaw size projected to the isocenter is 5 cm at maximum; how-
ever, this is not available for Synchrony® since there would be little dynamic range
for plan modulation in the IEC-Y direction. Eric et al. reported the accuracy of
delivering treatment plans to a robotic phantom on the experimental motion man-
agement system [24]. By adding motion correction for the phantom with an ampli-
tude of 15 mm, they found that the dose difference within the target can be reduced
from 30% to <2% in film measurement. They reported that the dose difference was
also improved for the non-respiratory motion, such as the gradual drift and unpre-
dictable shifts that can occur in prostate treatments. William et al. measured dose
distributions with the motion that was modeled using an equation proposed by
Lujan et al. [27] using a Delta4® Phantom + mounted on a Hexamotion® stage for
13 plans [26]. All 13 of the phantom motions with Synchrony®-measured doses had
gamma pass rates of >90% on a criterion dose difference of 3% and distance to
agreement of 2 mm with a dose threshold of 10%, whereas only two of the phantom
motions without Synchrony®-measured doses had gamma pass rates >90%.
Figure 19.4 compares the two-dimensional dose and profile distributions measured
with films for the FNR plan deliveries [25]. When motion compensation is imple-
mented, we can observe a dramatic improvement in the plan agreement. Given that
the Radixact® system uses an unflattened beam, the use of off-axis beams during
jaw swing can change the beam characteristics. However, the change in dose inten-
sity due to the correction of the jaw and binary MLC positions cannot be considered
in the dose calculation of treatment planning. With the motion (<1 cm) typically
observed in most clinical situations, this off-axis effect is small (<2%) [25]. For
rare, extremely large motions, such as 2–4 cm in the IEC-Y direction, the off-axis
effects can exceed 2% [25]. Therefore, confirming the dose distribution during
actual measurement verification is imperative.
Synchrony® utilizes kV radiographs to track target motion and synchronize the
delivery of radiation with the motion. Proper management of this imaging dose
requires accurate quantification. Chen et al. reported that the measured CTDIw for
a single radiograph with a 120 kVp and 1.6 mAs protocol was 0.084 mGy, implying
a low imaging dose of 8.4 mGy for a typical Synchrony® motion tracking fraction
19 Tomotherapy 271
a b
c d
Fig. 19.4 Comparison of the dose distributions and profiles measured with films in fiducial-free
tracking with respiratory modeling [(a) No motion compensation vs. no motion, (b) Motion com-
pensation vs. no motion, (c) IEC-X profiles, and (d) IEC-Y profiles]. The IEC-X and Y profiles are
indicated using solid green and dot-dashed cyan lines, respectively. The three profiles for Synchrony
with a 10-mm irregular target motion, non-Synchrony and non-Synchrony with a 10-mm irregular
target motion are shown in (c) or (d). (Reproduced from Ref. [25] with permission)
with 100 radiographs [25]. Ferris et al. used Monte Carlo simulation to quantify
organ-specific patient doses from 100 images on the Radixact® with tube potentials
between 100 and 140 kVp for various patient anatomies [28]. Patient median doses
to soft tissue and bony structures ranged from 2.0 to 4.6 mGy and 4.7 to 25.4 mGy,
respectively. The dose from 100 radiographs on Radixact® is expected to be slightly
less than that from typical kV-CBCT scans or a Tomo MVCT setup scan, according
to imaging doses from other image guidance procedures used in radiotherapy from
the AAPM TG-180 report [29].
The evaluation of kV imaging quality and imaging dose parameters, dose deposi-
tion accuracy, target detection coincidence, and target position detection accuracy
are needed as additional QA procedures for Synchrony®. Goddard et al. proposed
QA testing of the Radixact® Synchrony® system with tolerance levels and frequen-
cies ([30], Table 19.1). They designed the testing protocol to allow for continuous
assessment of system performance and ensure the accuracy of target detection and
motion correction. Designing and conducting appropriate QA programs based on
the literature is necessary for performing SBRT safely using Synchrony®.
272 H. Shimizu
Table 19.1 Proposed quality assurance testing of the Radixact® Synchrony® system with tolerance
levels and frequencies (Reproduced from Ref. [30] with permission)
Test Description Tolerance Frequency
System Ensure system can detect fiducials/ Functional Daily/weekly
functionality dense target and LED functionality
Planar kV Measure the below parameters for a
imaging range of imaging protocols:
(i) Imaging and treatment (i) ≤2 mm Monthly
coincidence (non-
(ii) Scaling SRS/SBRT),
(iii) Spatial resolution ≤1 mm (SRS/
(iv) Contrast SBRT)
(v) Uniformity and noise (ii) ≤2 mm
(non-
SRS/SBRT),
≤1 mm (SRS/
SBRT)
(iii) Baseline
(iv) Baseline
(v) Baseline
Dose A 2D detector array or film shall be Tolerance limit: Monthly
deposition placed on a motion platform capable g-pass rate ≥ 95%,
accuracy of creating a 2D motion. Motion Action limit: g-pass
deliveries that if not corrected would rate ≥ 90%,
result in ≤75% of points passing γ 3%/2 mm 10% dose
criteria should be utilized. DQA shall threshold
be delivered with synchrony motion
correction enabled.
The same criteria as above should be 3% Annual/major
utilized, and absolute dose component
measurements performed change
MV/kV target Place the cheese phantom and ≤1 mm in any Annual/major
detection precisely align the isocenter to a direction component
coincidence fiducial within the phantom. With the change
phantom stationary but the LED
markers in motion deliver a DQA to
the phantom. Analyze detected target
position graphs to determine offset
between detected position and MV
isocenter.
Planar kV Measure the below parameters for a
imaging range of imaging protocols:
(i) Beam quality/energy (i) Baseline Annual/major
(ii) Imaging dose (ii) Baseline component
change
Measured Measured target positions for a known ≥90% of points Commissioning/
target position motion delivery should be extracted within 2 mm 3D annual
accuracy and compared to the ground truth offset
motion
DQA Delivery quality assurance, SRS Stereotactic radiosurgery, SBRT Stereotactic body radia-
tion therapy
19 Tomotherapy 273
19.6 Practicality of SBRT
In TomoTherapy® without Synchrony®, the target motion for providing safe SBRT
treatment has been examined [31–34]. In 2010, Kissick et al. proposed the follow-
ing important technical approaches for the target with the motion [33]: choosing
planning parameters to increase the number of breathing cycles averaged into the
treatment for each voxel, attempting to coach the patient for steady shallow breath-
ing, using a movement-suppressing device such as the BodyFIX™ (Medical
Intelligence, Munich, Germany) to make the breathing shallower, low-frequency
breathing cycle with less drifting, and performing a patient-specific motion QA test
with a good 4D motion phantom. Clinical outcomes based on these technical
approaches have been also reported [35–44], which have included the liver [39],
kidney [40, 41], prostate [42], and spine [43, 44]. However, most of them have
involved the lungs [35–38]. Nagai et al. investigated the outcomes of lung tumor
patients treated by SBRT using helical tomotherapy with a fractionation schedule of
48 Gy in four fractions or 50–60 Gy in 5–8 fractions [35]. In the mentioned report,
grade 2 radiation pneumonitis was observed in 5% of the patients in both groups. At
2 years, the local control rate for all 72 patients was 86%, with no difference between
the two groups. In addition, Neha et al. reported outcomes of lung SBRT with main
fractionation schedules of 48 Gy in four fractions and 50 Gy in five fractions [36].
In their report, local control rates for all patients at 1, 2, and 5 years were 94.6%,
83.4%, and 74%, respectively. Adverse effects were minimal, with only 2 (3%)
patients reporting chest wall pain and 6 (8%) patients recorded as having radiation
pneumonitis (RP) (4 had grade 1–2 RP, 1 had grade 3 RP, and 1 had grade 5 RP).
Although both studies were conducted at a single institution, their adverse events
were comparable to those in a phase II SBRT for stage I non-small cell lung cancer
[45–48].
In recent years, the technology of Synchrony®, which was preceded by
CyberKnife®, has been incorporated into the Radixact® system. Figure 19.5 com-
pares conventional and Synchrony® treatments for the lung and liver cases [(a) and
a Lung case b Liver case
Conventional plan Synchrony plan Conventional plan Synchrony plan
Fig. 19.5 Comparisons between conventional and Synchrony® treatments for lung and liver cases
[(a) and (b), respectively; image provided courtesy of Takarazuka City Hospital]. The area within
the red dot lines shows the target region in a conventional plan. Through Synchrony®, it is possible
to reduce the target volume
274 H. Shimizu
(b), respectively]. The area within the red dot lines shows the target region in a
conventional plan. Through Synchrony®, it is possible to reduce the margin for the
target motion, thereby contributing to dose reduction in normal tissues. Several
clinical experiences using Radixact® Synchrony® have been reported. Notably,
Okada et al., who reported a case report for lung and liver cancers, demonstrated
clinical feasibility [49]. Chen et al. reported that 10 lung cancer (fiducial-free) and
5 prostate cancer (fiducial-based) cases showed good QA results with radiation
doses <0.5% of that prescribed [50]. Nonetheless, available clinical reports are still
few in number. However, with the spread of Radixact®, more clinical results will be
published in the future. Further technological innovations on the Radixact® system,
such as the practical development of adaptive radiotherapy, are expected.
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Chapter 20
MR-LINAC: Elekta Unity
Noriyuki Kadoya, Shohei Tanaka, Yoshiyuki Katsuta, Kiyokazu Sato,

Noriyoshi Takahashi, and Keiichi Jingu
20.1 Introduction
Magnetic resonance imaging (MRI) provides excellent soft-tissue visualization,

thereby increasing the sensitivity for detecting tumor and normal tissue boundary
[1, 2]. The role of MRI in radiotherapy has largely been relegated to the initial radio-
therapy planning stages (e.g., before treatment). Recently, hybrid MR scanners and
linear accelerators (MR-Linac) have been developed, including the MRIdian
(ViewRay, Oakwood, USA) and Unity (Elekta, Stockholm, Sweden). These sys-
tems are capable of performing MR-guided radiotherapy (MRgRT). MRgRT is a
novel treatment technique that acquires real-time MR images (e.g., during treat-
ment), allowing for the tracking and monitoring of target and organ at risk (OAR)
movements during the period of beam delivery. Daily MR imaging can improve
target and OAR visualization compared to cone-beam computed tomography
(CBCT), allowing for plan adaptation (i.e., online adaptive radiotherapy [ART]),
potentially resulting in improved PTV coverage and dose escalation or reduction for
isotoxicity in SBRT [3–5]. This chapter discussed the features of MR-Linac Unity
and our clinical workflow for online ART.
N. Kadoya (*) · S. Tanaka · Y. Katsuta · N. Takahashi · K. Jingu

Department of Radiation Oncology, Tohoku University Graduate School of Medicine,
Sendai, Japan
e-mail: kadoya.n@rad.med.tohoku.ac.jp
K. Sato
Radiation Technology, Tohoku University Hospital, Sendai, Japan
Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_20
278 N. Kadoya et al.
20.2 History of Unity
In 2000, Lagendijk et al. at Medical Centre Utrecht (UMCU) proposed the basic
concept of MR-Linac, which utilizes a low field magnetic field (0.2–0.3 T) and a
low energy accelerator (4–6 MV) [6]. Then, in collaboration with Elekta and Philips
(Amsterdam, The Netherlands), UMCU developed a hybrid 1.5-T MR-Linac [7–9],
and the proof of concept of this system was presented by Raaymakers et al. [9]. This
system has evolved into the Elekta Unity system and has been clinically introduced
for the treatment of oligometastatic lymph nodes in 2018 (Fig. 20.1) [10].
Fig. 20.1 Landscape of setup and online adaptive treatment planning using the Unity system
20 MR-LINAC: Elekta Unity 279
20.3 Characteristics of Unity
The Unity MR-Linac is comprised of a 1.5-T MRI and a 7-MV Linac without flat-
tening filter. The Linac triode electron gun enables the radiation beam, which
instantaneously pauses and unpauses, and the dose rate is 425 MU/min. The MRI is
based on the 1.5 T Philips Ingenia wide bore system that has been modified to
accommodate the perpendicular Linac configuration. The Linac, along with all
beam generating components, is mounted on a gantry around the MRI cryostat
using a slip-ring design, enabling continuous rotation around a patient at a maxi-
mum rate of six revolutions per minute. The radiation-generation system is equipped
with a 160-leaf multileaf collimator (MLC) similar to the Agility MLC found on
standard Elekta Linacs. The maximum field size in the isocenter plane is 57.4 cm
(crossplane) by 22.0 cm (inplane). Collimator rotation is disabled in this design, and
the MLC leaves move in the superior/inferior direction with respect to the patient
anatomy with a leaf width of 7.175 mm at the isocenter plane [11]. The Unity has a
source to isocenter distance of 143.5 cm and an inner-bore diameter of 70 cm. The
system is currently only capable of delivering step-and-shoot Intensity Modulated
Radiotherapy (IMRT) and 3D conformal treatments [12].
The purpose of the combination of MR and Linac is to enable real-time soft-
tissue contrast MR imaging on the couch to visualize anatomical changes of the
tumor and OARs prior to and during the beam delivery. MRI can be used to capture
both inter-fractional motion and intra-fractional motion, providing the input for
ART [13]. Anatomical and functional MRI can both be used to assess treatment
response [14, 15]. It was clear that for MR-Linac to ensure normal operation of
Linac and the MLC, the MR system had to be as close as possible to the mainstream
MR scanner [16]. Philips scientists modified the active shielding of the MRI to cre-
ate a low field annulus in which the Linac and its associated components could
move. They accomplished this without jeopardizing their magnet specification for
imaging. Additionally, this approach successfully preserved the MR scanner’s short
wide bore for maximum patient comfort. This decreases in coupling between the
primary B field and Linac also occurs in the opposite direction, implying that the
Linac has no effect on the MR imaging. Concerning the main clinical advantages,
Unity has the following three advantages:
1. Soft tissues, which are often difficult to distinguish on CT images, can be clearly
distinguished on MRI, thereby allowing image-guided radiotherapy (IGRT) to
achieve higher image-guided registration accuracy compared with the conven-
tional linac system.
2. Real-time image acquisition is possible during the beam delivery without addi-
tional X-ray exposure.
3. Functional MR images can be acquired, each being described in more
detailed below:
Fig. 20.2 Comparison of CT and MRI images from the same patient
1. As illustrated in Fig. 20.2, the CT and MR images are two distinct images. The
MR images are excellent in the depiction of soft tissues, and soft tissues that
were difficult to depict on CT images can be imaged well on MR images, and
even tumors with unclear boundaries on CT can be clearly confirmed on MRI. As
a result, it has now become possible to perform MR-based IGRT with greater
accuracy than CT-based IGRT. In line with this, online ART can be accurately
performed with an MR-Linac.
2. Due to the fact that MR imaging does not use radiation at all, it is possible to
acquire images both before and during treatment without additional radiation
exposure, thereby allowing us to confirm in real time whether the target and/or
OAR are being irradiated as planned. Additionally, we expect that gated delivery
may be performed more safely in the future. We also anticipate that tracking
irradiation for respiratory moving tumors, such as a pancreatic cancer, will be
possible without the use of a fiducial marker [11].
3. With a help of functional MRI techniques such as diffusion-weighted imaging
(DWI) and dynamic contrasted-enhanced imaging, functional changes can be
analyzed during the course of radiotherapy and possibly during beam delivery.
The apparent diffusion coefficient (ADC) maps, which represent a quantitative
measure of water diffusivity in tissues, can be generated from DWI images that
are proportional to the amount of cellularity present in a tissue. Higher cell den-
sity in tumors restricts the diffusion of water and induces a lower ADC value. In
the aftermath of successful antitumor therapy, a decrease in cell density caused
by tumor cell death and apoptosis can be observed, which results in a significant
increase in ADC value [17]. Several studies have suggested that ADC may be a
promising tool for tumor response evaluation and prognosis prediction among
NSCLC patients [18, 19] Pasquier et al. demonstrated that ADC value can be
used as an early predictor of tumor response of prostate SBRT in a laboratory
setting [20].
4. Online Adaptive Radiotherapy with Unity
Unity can employ two different adaptive planning strategies: one is “adapt-to-
position” (ATP) and the other is “adapt-to-shape” (ATS) (Fig. 20.3). ATP resem-
bles conventional cone-beam CT based IGRT, but the treatment filed is displaced
instead of the patient couch to compensate for daily change of the tumor posi-
Fig. 20.3 Schematic of the “adapt to shape (ATS)” and “adapt to position (ATP)” methods. In the
ATS, deformable registration is performed between pre-treatment CT and daily MRI, thereby
enabling online contour adaptation and daily dose optimization. In the ATP, rigid registration is
performed between pre-treatment CT and daily MRI, thereby displacing the treatment fields
instead of moving the patient couch [21]
tion. For ATS, the structures on daily MRI is recontoured to create the treatment
plan of the day [21]. The ATS is close to the general method called ART. The
detailed workflow of ATS is explained in the next section. The MOMENTUM
study, which was designed to facilitate evidence-based implementation of the
world’s first comedically available high-field MR-Linac Unity and capture its
initial experience, reported that a total of 943 patients participated in this study
(February 2019–October 2020 at seven institutions in four countries). A total of
40% of the patients had prostate cancer, 17% had oligometastatic lymph node
cancer, 12% had brain cancer, and 10% had rectal cancer. The median number of
fractions administered was 5 (range 1–35); 64% used the ATS and 29% used the
ATP [4].
5. Our Initial Clinical Experience with SBRT for Prostate Cancer
Unity was employed to initiate prostate SBRT treatment in our hospital. The
prescription dose was 36.25 Gy/5 Fr (for low-risk and intermediate-risk patients)
and 40 Gy/5 Fr (for high-risk patients). The 9-field step and shoot IMRT tech-
nique was utilized. Figure 20.4 depicts a schematic overview of our clinical
workflow for ATS. First, a T2-weighted offline simulation MRI scan is obtained
in ~2 min. To calculate the dose distribution on the MR image, we also obtain the
simulation CT image. In both MR and CT simulations, patients are instructed to
have their bladder half full (200 cc of water 20–30 min before the session). For
low-risk prostate cancer, the CTV comprises the prostate gland only, whereas for
intermediate-risk and high-risk prostate cancer, the CTV comprises the prostate
and the partial/whole of the seminal vesicles. The CTV to PTV margin of 5 mm
Fig. 20.4 The schematic overview of our clinical workflow for adapt-to-shape (ATS) in pros-
tate SBRT
is used in each direction. As OARs, the rectum, the bladder, the urethra, and the
femoral heads are delineated.
Prior to each fraction, an online T2-weighted MRI scan (pre-MRI) is per-
formed and rigidly registered to the simulation MR. Through deformable regis-
tration, the original set of contours is propagated onto the daily pre-MRI and,
manually edited by the radiation oncologist as necessary. The medical physicist
re-optimizes the plan by starting from fluence optimization, and during the sec-
ond optimization phase (i.e., the field segmentation phase), a position verifica-
tion MRI scan is acquired to determine whether the target has been displaced. If
displaced, we employ ATP (e.g., we only change the isocenter position of the
ATS plan). If no displacement is found, the patient receives treatment beams
while the target and OARs are continuously monitored in real time using 2D cine
MRI, typically acquired on the axial and sagittal planes.
Immediately after the delivery is completed, a post-MRI scan is performed, to
estimate the intra-fraction organ motion. The dose distributions overlaid on the
simulation and pre-MR image at each fraction are shown in Fig. 20.5. As can be
seen, the ATS treatment plan on each day was adapted to the anatomy of each
pre-MR image.
6. Technologies Expected to Improve the Performance of SBRT on Elekta Unity
At present, Unity can only provide the step and shoot IMRT, despite the fact
that VMAT is the most extensively used irradiation technique. Kontaxis et al.
evaluated the feasibility of VMAT on Unity and concluded that VMAT was fea-
Fig. 20.5 Treatment planning using a daily magnetic resonance image in each fraction
sible on Unity. Additionally, they conducted preliminary MR imaging tests dur-

ing dynamic therapy, revealing that the impact of radiation and moving gantry/
collimator components had a negligible impact [11]. At present, Unity does not
provide respiratory-gating functionality. Keiper et al. investigated the efficacy of
real-time organ motion tracking based on MR image intensity registration per-
formed by a research software on Unity [22]. Uijtewaal et al. published a first
experimental demonstration of the technical feasibility of MRI-guided MLC
tracking for lung SBRT using a research tracking interface on Unity [23].
References
1. Chung NN, Ting LL, Hsu WC, et al. Impact of magnetic resonance imaging versus CT on
nasopharyngeal carcinoma: primary tumor target delineation for radiotherapy. Head Neck.
2004;26:241–6.
2. Mitchell DG, Snyder B, Coakley F, et al. Early invasive cervical cancer: tumor delineation
by magnetic resonance imaging, computed tomography, and clinical examination, veri-
fied by pathologic results, in the ACRIN 6651/GOG 183 Intergroup Study. J Clin Oncol.
2006;24:5687–94.
3. Noel CE, Parikh PJ, Spencer CR, et al. Comparison of onboard low-field magnetic resonance
imaging versus onboard computed tomography for anatomy visualization in radiotherapy.
Acta Oncol. 2015;54:1474–82.
4. de Mol van Otterloo SR, Christodouleas JP, Blezer ELA, et al. Patterns of care, tolerability,
and safety of the first cohort of patients treated on a novel high-field MR-linac within the
MOMENTUM study: initial results from a prospective multi-institutional registry. Int J Radiat
Oncol Biol Phys. 2021;111:867–75.
5. Alongi F, Rigo M, Figlia V, et al. 1.5 T MR-guided and daily adapted SBRT for prostate cancer:
feasibility, preliminary clinical tolerability, quality of life and patient-reported outcomes dur-
ing treatment. Radiat Oncol. 2020;15:69.
6. Lagendijk J, Bakker C. MRI guided radiotherapy: a MRI based linear accelerator in
ESTRO-2000: Abstracts Istanbul European Society for Therapeutic Radiation Oncology; 2000.
7. Lagendijk JJ, Raaymakers BW, van Vulpen M. The magnetic resonance imaging-linac system.
Semin Radiat Oncol. 2014;24:207–9.
8. Raaymakers BW, Jurgenliemk-Schulz IM, Bol GH, et al. First patients treated with a 1.5 T
MRI-Linac: clinical proof of concept of a high-precision, high-field MRI guided radiotherapy
treatment. Phys Med Biol. 2017;62:L41–l50.
9. Raaymakers BW, Lagendijk JJ, Overweg J, et al. Integrating a 1.5 T MRI scanner with a 6 MV
accelerator: proof of concept. Phys Med Biol. 2009;54:N229–37.
10. Werensteijn-Honingh AM, Kroon PS, Winkel D, et al. Feasibility of stereotactic radiother-
apy using a 1.5 T MR-linac: Multi-fraction treatment of pelvic lymph node oligometastases.
11. Kontaxis C, Woodhead PL, Bol GH, et al. Proof-of-concept delivery of intensity modulated arc
therapy on the Elekta Unity 1.5 T MR-linac. Phys Med Biol. 2021;66:04lt1.
12. Snyder JE, St-Aubin J, Yaddanapudi S, et al. Commissioning of a 1.5 T Elekta Unity MR-linac:
a single institution experience. J Appl Clin Med Phys. 2020;21:160–72.
13. Kleijnen JP, van Asselen B, Burbach JP, et al. Evolution of motion uncertainty in rectal cancer:
implications for adaptive radiotherapy. Phys Med Biol. 2016;61:1–11.
14. van der Heide UA, Houweling AC, Groenendaal G, et al. Functional MRI for radiotherapy
dose painting. Magn Reson Imaging. 2012;30:1216–23.
15. van Rossum PS, van Lier AL, van Vulpen M, et al. Diffusion-weighted magnetic resonance
imaging for the prediction of pathologic response to neoadjuvant chemoradiotherapy in esoph-
ageal cancer. Radiother Oncol. 2015;115:163–70.
16. Brown K, Goldwein J, de Vries L. Elekta unity for magnetic resonance radiation therapy (MR/
RT). White paper of Elekta; 2018.
17. Galbán CJ, Hoff BA, Chenevert TL, et al. Diffusion MRI in early cancer therapeutic response
assessment. NMR Biomed. 2017;30
18. Weiss E, Ford JC, Olsen KM, et al. Apparent diffusion coefficient (ADC) change on repeated
diffusion-weighted magnetic resonance imaging during radiochemotherapy for non-small cell
lung cancer: a pilot study. Lung Cancer. 2016;96:113–9.
19. Wang D, Qiu B, He H, et al. Tumor response evaluation by combined modalities of chest mag-
netic resonance imaging and computed tomography in locally advanced non-small cell lung
cancer after concurrent chemoradiotherapy. Radiother Oncol. 2022;168:211–20.
20. Pasquier D, Hadj Henni A, Escande A, et al. Diffusion weighted MRI as an early predic-
tor of tumor response to hypofractionated stereotactic boost for prostate cancer. Sci Rep.
2018;8:10,407.
21. Winkel D, Bol GH, Kroon PS, et al. Adaptive radiotherapy: The Elekta Unity MR-linac con-
cept. Clin Transl Radiat Oncol. 2019;18:54–9.
22. Keiper TD, Tai A, Chen X, et al. Feasibility of real-time motion tracking using cine MRI dur-
ing MR-guided radiation therapy for abdominal targets. Med Phys. 2020;47:3554–66.
23. Uijtewaal P, Borman PTS, Woodhead PL, et al. Dosimetric evaluation of MRI-guided multi-
leaf collimator tracking and trailing for lung stereotactic body radiation therapy. Med Phys.
2021;48:1520–32.
Chapter 21
ViewRay MR-Linac
Hiroyuki Okamoto, Takahito Chiba, Junichi Kuwahara, and Hiroshi Igaki
21.1 Machine Specification
The MRIdian®-Linac (Viewray, Oakwood Village, OH, USA) is a cancer treatment

system that combines a magnetic resonance (MR) scanner with a radiotherapy system
mounted on a ring-type rotating gantry (Fig. 21.1) [1–3], offering MR-guided (MRg)
online adaptive radiotherapy (ART) as well as gated radiotherapy by real-time tumor
tracking in cine MR imaging (MRI) during treatment. The MR scanner in MRIdian®
has a horizontal solenoidal superconducting superior–inferior magnetic field of 0.35 T
and a gantry with a 6 MV flattening filter free (FFF) linear accelerator (linac) at the
28-cm gap between the two magnet halves. There are six compartments (buckets) on
the ring-type gantry to shield linac components, such as the magnetron, from the mag-
netic field. The radiofrequency (RF) pulse necessary for linac operation is shielded by
layers of RF absorbing carbon fiber and RF reflecting copper as it can degrade the
quality of MR images. The inner bore has a diameter of 70 cm. It is possible to perform
step-and-shoot intensity-modulated radiation therapy (IMRT) and three-dimensional
conformal radiotherapy (3DCRT) with a maximal dose rate of 600 cGy/min at a
source-to-axis distance of 90 cm. The position of treatment couch is remotely adjusted
in superior–inferior, right–left, and anterior–posterior directions with reference to the
results of daily patient setup. The radiation field is defined by a double stack and dou-
ble-focus multileaf collimator (MLC) without the collimator jaws. The MLC consists
H. Okamoto (*) · T. Chiba

Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
e-mail: hiokamot@ncc.go.jp
J. Kuwahara
Department of Radiological Technology, National Cancer Center Hospital, Tokyo, Japan
H. Igaki
Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_21
286 H. Okamoto et al.
Fig. 21.1 MRIdian® (ViewRay, Oakwood Village, OH, USA). Image courtesy of ViewRay Inc
Fig. 21.2 (a) Irradiation is allowed as long as the tracking volume is within the boundary. (b) The
boundary is defined from the tracking volume in treatment planning. “Beam-off” and “Beam-on”
is automatically controlled in each frame
of 138 tungsten leaves, the height of the MLC in each stack is 5.5 cm, and the total
height in a double stack MLC is 11 cm. The leaf width is 0.83 cm at isocenter. However,
the effective width achieved by a double stack MLC is 0.415 cm. The minimum and
maximum field size sizes are 0.2× 0.415 cm2 and 27.4×24.1 cm2, respectively.
21 ViewRay MR-Linac 287
During irradiation, cine MRI can be acquired in several planes at 4–8 frames per
second, and the target can be automatically tracked in real time to control delivered
beam to the target (Fig. 21.2). The field of view (FOV) has a diameter of 50 cm. The
MR images have higher contrast in image quality for soft-tissue materials such as
muscle and adipose compared to CT images, while no imaging dose for acquiring
MRI is an attractive prospect. A low magnetic field of 0.35 T presents reduced
image distortion of 2 mm over a 35 cm diameter sphere volume (DSV) FOV and
1 mm over a 20 cm DSV FOV. The image sequence in MRIdian® is a True Fast
Imaging with Steady State Precession (TRUFI, T2/T1 weighted). A TRUFI sequence
is used for routine planar and volumetric imaging. The obtained daily MR images
prior to treatment can be used for online ART including patient positioning, treat-
ment planning, and gated irradiation (planar images). Moreover, safety and opera-
bility of MR and treatment system in MRIdian® is beneficial for more efficient and
safer online and offline ART.
21.2 Patient Positioning
In general, CT scans are required when performing heterogeneous correction in

dose calculation based on CT images, and patient immobilization is created as in
ordinary RT, and both CT and MR images are acquired on the same day. Regarding
patient immobilization, the vacuum cushion is generally used in order to maintain
patient’s position taking into consideration the comfort and high reproducibility of
patient positioning. In particular, specific attention should be focused on patient
comfort, as overall treatment period for online ART tends to be longer compared to
conventional RT. Importantly, the carbon material which is generally used as part of
immobilization in radiotherapy should not be used in MRgRT, as it generates heat
by RF pulse. A similar patient poisoning with the vacuum cushion is suggested,
even if deformable image registration for CT and MR images in treatment planning
systems (as presented below). The shortest scan time in MR image sequences is
17 s, and breath-hold necessary for lung cancer is possible.
21.3 Gated Radiotherapy
MRIdian® has a gated radiotherapy system available for controlling beam timing
based on the relative location of the tracking volume (corresponding to tumor vol-
ume) to the boundary in cine MRI. As presented in Fig. 21.2, irradiation is allowed
as long as the tracking volume is within the boundaries. The MRIdian® system
automatically monitors the tracking volume in each frame of cine MRI by image
processing techniques. In general, the boundary is generated with an expansion of
3–5 mm geometrical margins from GTV. Moreover, the tracking volume can be
determined to a different area from the irradiated region as a surrogate signal, as
long as the surrogate motion is similar to that of tumor motion. The CTV-PTV mar-
gin is 3–5 mm by considering other various uncertainties. By employing a commu-
nication system between the patient and the therapist, patient respiratory is managed
as in conventional RT.
21.4 Online Adaptive Radiotherapy
Online ART allows immediate modification of the treatment plan prior to daily
treatments, while a patient is on the treatment couch during treatment. Other defini-
tions of the online ART include “plan library” [4]. The plan library enables the
selection of the optimum treatment plans among several treatment plans prepared in
advance with reference to the results of IGRT. The MRIdian® is available also for
the plan library approach. Figure 21.3a presents the typical process map in online
ART. The position of the treatment couch can be adjusted remotely according to the
IGRT results using MR images. Generally, the tumor alignment in patient position-
ing is achieved. The MR images are also used when preparing adaptive treatment
plans, i.e., the physician delineates tumor and organs at risk by reference to the daily
MR images. Since delineation on daily MR images is very time consuming, deform-
able image registration (DIR) technique is effective in reducing physician’s delinea-
tion burden. In the DIR approach, the original contours are propagated to new daily
MR images, and minor corrections are manually performed. When a physician
would like to assess tumor shrinkage, original shapes can be maintained by apply-
ing rigidly copy to the targeted volume. In this process, a function called “Rule” is
useful to efficiently prepare PTV and other structures such as a ring structure used
for constraints in optimization. Boolean operations or expansions by predefined
geometrical margins like PTV can be registered in the “Rule.” Once rules are regis-
tered, the associated structure is automatically generated by clicking a button and
enabling efficient delineations procedures even for offline ART. The electron den-
sity map is also applied to the new daily MR images by using DIR techniques. After
optimization and dose calculations on new MR images, comparison of DVH and
dose distributions among original and new adaptive treatment plans can be con-
ducted (Fig. 21.3b), and it is possible if either treatment plans can be adopted for
treatment according to institutional protocol and DVH criteria. In principle, there
are two optimization approaches in online ART. In the first approach, optimization
is executed without modifying other parameters in treatment plans such as the num-
ber of beams and gantry angles, while only delineations are updated. The optimiza-
tion parameters are adjusted if necessary, allowing immediate preparation of
adaptive treatment plans and prompt treatment initiation. On the other hand, if the
organ locations of interest or tumor shapes vary significantly, there is a limitation in
adjusting dose distribution without modifying the treatment parameters. Improved
treatment plans could be generated by modifying other parameters in treatment
plans including addition of beams or by modification of beam gantry angle as well
as by adjusting the optimization parameters. This approach is time consuming and
Fig. 21.3 (a) Treatment process map in online ART. All procedures are performed on the same
day. (b) Comparison between original and adaptive plan dose distribution
requires experienced skills and modifying parameters in treatment plans. The

approach of applied prescribed dose can be modified when necessary. D95 to PTV
can be for instance intentionally adjusted in each treatment. Furthermore, if the
maximum dose to organs at risk exceeds the tolerated dose, it can be easily reduced
below the tolerated dose by rescaling the whole dose distribution. Online ART can
be promptly modified to a safer treatment plan by referring dose distribution and
DVH criteria prior to treatment. After approval of treatment plans, the medical
physicist and the radiation technologist perform pretreatment quality assurance
(QA) via the specialized checklist (as mentioned below) to online ART and the
independent dose verification system, which is used to independently ensure dose
calculation accuracy for the adaptive treatment plans. After pretreatment QA, cine
MRI is acquired to finally verify anatomical changes do not occur during that time.
The patient should be monitored during modification of treatment position and
treatment plan. In addition, radiation technologists carefully monitor cine MRI for
proper patient respiratory management during treatment. A nurse should be assigned
for prompt response to an emergency or to a patient’s request. All of treatment infor-
mation is recorded in the system, which is available for offline ART.
21.5 Offline Adaptive Radiotherapy
Offline ART implies a change in the usual treatment plan. The MRIdian® enables
more efficient modifications in the treatment plan without specialized procedures.
In conventional IMRT, for instance, replanning requires 1–2 weeks as well as new
CT scans for the preparation of a new treatment plan. In MRIdian®, the planner can
select any treatment data from the calendar in the system to create a new treatment
plan with the new MR images from the selected date. In this case, new CT scans are
not required as the electron density map is applied to new MR images. When con-
tours are redrawn for treatment plan evaluation in daily treatments, replanning does
not require redrawing, and optimization and dose calculation are performed as in
online ART. The “Rule” function is useful for delineation efficiency as previously
described, and the same Boolean operations as in the original treatment plans can be
applied in offline ART. When systematic organ displacement due to daily treatments
is observed, offline ART is actively selected to allow performing online ART within
limited working time.
21.6 Commissioning
General quality control and QA procedures according to the American Association

of Physicists in Medicine task group 142 [5] can be performed in the MRIdian®
system. For instance, consistency of two coordinates in radiotherapy system and
image-guided system (MR scanner) should be maintained [6]. Although the mea-
surements of beam data for modeling in TPS is not required as performed in a com-
mon linac, dose verification with homogeneous and heterogeneous phantoms using
an MR compatible chamber should be performed. The MR compatible motion
phantom (CIRS, Norfolk, VA, USA) can evaluate gated radiotherapy accuracy [7],
while the boundary and tracking volume on the phantom can be defined, as pre-
sented in Fig. 21.4. The typical water-equivalent phantom is invisible on MR
images, and the verification phantom should be filled with water in order to be vis-
ible on MR images. Maintenance of image quality of MR images is essential, as
deterioration of the image quality influence tracking accuracy of the target on cine
MR images. In regularly QA of machine performance, the uniformity and signal-to-
ratio should be confirmed by the dedicated phantom [8]. In particular, the influence
of treatment environment (monitor, room lighting, devices related to radiotherapy)
on image quality should also be validated for a long period [9]. Additionally, the
Fig. 21.4 MR compatible motion phantom (CIRS, Norfolk, VA, USA). The mimicking tumor
(blue) and the predefined boundary (red) on cine MR images
attenuation of the surface coil and patient couch should be measured and correction
of the attenuation in TPS should also be validated.
21.7 Stereotactic Body Radiation Therapy (SBRT)

in Lung Cancer
The MRIdian® system enables real-time tumor tracking in cine MRI with marker-
less respiratory-gated SBRT in lung cancer. Particularly, in lung cancer, gated radio-
therapy can reduce the internal target volume, potentially resulting in reduced
toxicity and improved treatment outcome. Other treatment instruments require fidu-
cial markers inside or near the tumor, or they may not be able to effectively track
cases in which the contrast near the tumor is not clear. MRIdian® on the other hand,
enables tracking in the vast majority of cases. Cine MRI can also be acquired during
treatment, and the beam is automatically stopped in coughing or other breathing
disturbances events. In addition, even when baseline shifts of patient’s respiration
occur, the treatment couch can be remotely adjusted for corrections of baseline
shift. Nevertheless, the superior–inferior and anterior–posterior directions are avail-
able. In general, tumor rarely moves laterally and even if such movements occur, the
differences may be detectable in different sagittal planes of cine MRI. The extra MR
scans after treatment for specific reasons such as assessment of body movement or
intrafractional motion is easily achieved without concerns for the imaging dose.
After treatment, overall trajectory of the tracking volume during treatment can be
evaluated. As presented in Fig. 21.5, dose profile in smaller field sizes has shorter
penumbra and undesirable dose in the surrounding tumor is effectively reduced. The
MRIdian® is thus suitable for lung cancer SBRT.
The magnetic field causes alterations in the trajectory of scattering electron by
the Lorentz force. This phenomenon is commonly known as the electron return
effect (ERE) [10–17]. Especially at the tissue–air boundaries, a large dosimetric
effect may be stimulated due to the ERE. Other phenomena, such as the electron
a b
Fig. 21.5 (a) Dose profiled for a field size of 0.2 × 0.415 cm2. (b) An example of SBRT treat-
ment plan in MRIdian® system
streaming effect in which scattered electrons stream outside the irradiated field, and
some facilities use a bolus to reduce the increasing dose in the surface [18]. In the
lungs, the use of a bolus is being considered near the thyroid gland and other areas
as needed, depending on the treatment site. The dosimetric changes by ERD depend
on the strength of the static magnetic field, the direction of radiation (scattering
electron), and the density of the medium. Particularly, in low-density regions, the
trajectory change has a wide range because of the long range of the electrons. The
MRIdian® system implements a Monte Carlo simulation that takes into account the
ERE in dose calculation.
For dose verification in SBRT for lung cancer, heterogeneous phantom can be
used as in a conventional linac. Nevertheless, when performing IGRT and other
imaging processes are involved in the dose verification, a typical water-equivalent
phantom is not appropriate due to its invisibility on MR images. A dedicated water-
filled phantom should thus be prepared for visibility on MR images, as described
above. For IMRT dose verification, MR compatible multi-detectors are available
and IMRT dose verification such as gamma analysis can be performed [19, 20].
21.8 Safety Control and Quality Management
Table 21.1 presents a representative checklist used for online ART. Japanese guide-
lines also recommend the clinically implementation of the checklists comprehen-
sively covering pretreatment QA [8]. The guidelines suggest that confirmation items
should involve delineation accuracy, Boolean operation for delineations, electron
density used for dose calculation, dose prescription (D95%, etc.), dose distribution
and DVH evaluation, comparison of planned information between original and
Table 21.1 An exmple of online ART checklist

Online ART 1Fr 2Fr 3Fr 4Fr 5Fr
Treatment Date
Registration accuracy
Skin definition
Electron density (including override density)
Apply rules
Target/OAR delineation (Smoothing or clean up dust)
Adaptive plan? (Yes or No)
(i) Reoptimize without adjusting parameters
(ii) Reoptimize with adjusting parameters
0. Nothing 1. Beam 2. Delineation 3. Optimize parameter 4.
Normalize
Treatment time
Beam direction (collision to patient couch)
Normalization (tumor or risk organ)
Dose evaluation
Save as correct plan name (e.g., 1-1-2 FrX Adapt 180101)
Passing rate (>95%)
Signature
revised treatment plans. Since online ART is ongoing during the treatment session,
confirmation results should be recorded in all fractions (Table 21.1). The MRIdian®
system obtains electron density map from deformed CT images to daily MR images
using the DIR approach, which is used for dose calculation. Registration accuracy
should be thus carefully verified. In particular, missing a part of the body on the
deformed CT images resulting in significant dosimetric error in dose calculations
should be avoided. As previously mentioned, delineation accuracy, DVH criteria,
and dose distribution should be independently assessed. Dose calculation accuracy
in adaptive treatment plan should be verified by independent dose verification which
is available for different dose calculation engine from that of MRIdian® system. The
passing rates in the independent dose verification system are used to determine
approval of adaptive treatment plan. After verification, cine MRI is acquired prior to
treatment to finally confirm unexpected displacements of tumor and OARs does not
occur for that time.
In the presence of a QA tool, peripheral equipment or devices with ferromagnetic
materials in the treatment room, ferromagnetic materials should be excluded by fer-
romagnetic material detector in order to prevent projectile or missile events. Patient
transfer devices such as wheelchairs and stretchers should be MR compatible. In
addition, practical procedures in emergency should be established at the department
of radiation oncology before clinical implementation.
Online ART is primarily performed in cases of hypofractionation with high doses
to the for improved treatment outcome. Importantly, inaccurate online ART may
lead to undesired severe toxicities. In addition, online ART presents a safety control
limitation, and dose verification through measurements cannot be accomplished

during treatment. Furthermore, the radiation oncology team should have additional
knowledge and experience of the MR system. Undoubtedly, the essential key toward
safe online ART is the establishment of an implementation system in the radiation
oncology department before clinical implementation. Appropriate assignment of
staff exclusively in charge of online ART and development of an education system
are also essential. Practical procedures and operations should not be complicated,
and mock trials covering the overall procedures should be performed to develop the
institutional policies for online ART. Additionally, risk assessment is recommended
to identify risk characteristics in online ART [22] .
21.9 Machine Installation
Approximately 18,000 patients have been treated with MRIdian, 48 MRIdian sys-
tems are installed at hospitals around the world [21]: Siteman Cancer Center at
Washington University and Barnes-Jewish Hospital, UCLA Jonsson Comprehensive
Cancer Center, Miami Cancer Institute, and Henry Ford Cancer Institute, etc., in the
United States; Seoul National University Hospital, National Cancer Center Japan,
etc., in the Asia pacific; Amsterdam UMC, Gemelli ART, and Heidelberg University
Hospital, etc., in Europe; Sheikh Khalifa Specialty Hospital and Assuta Medical
Centers in Middle East.
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Part V
Future Perspectives
Chapter 22
Future of SBRT with AI
(Artificial Intelligence)
Daisuke Kawahara
Abbreviations
3DCRT 3-Dimensional conformal RT

AI Artificial intelligence
ART Adaptive radiotherapy
cGAN Conditional generative adversarial network
CNN Convolution neural network
cyckeGAN Cycle-consistent generative adversarial network
DM Distant metastases
IGRT Image-guided radiation therapy
IMRT Intensity-modulated radiotherapy
MC Monte Carlo simulations
QA Quality assurance
22.1 Introduction
The treatment technique of radiation oncology has been developed with technologi-
cal innovation in the hardware and software. Especially, it has been progressed
acceleratory by two technological innovations; these are intensity-modulated radio-
therapy (IMRT) and Monte Carlo simulations (MC). Especially, the treatment tech-
niques have moved from three-dimensional conformal RT (3DCRT) to
D. Kawahara (*)
Department of Radiation Oncology, Institute of Biomedical & Health Sciences, Hiroshima
University, Hiroshima, Japan
e-mail: daika99@hiroshima-u.ac.jp
Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_22
300 D. Kawahara
intensity-modulated radiotherapy (IMRT) with the advent of image-guided radia-

tion therapy (IGRT). IMRT can safely deliver more effective radiation dose to
tumors with fewer side effects compared with conventional radiotherapy techniques.
MC simulation provides a high accurate dose distribution, and which leads to the
improvement of the treatment outcome.
With the development of computer science such as machine learning and deep
learning, artificial intelligence (AI) has a great potential to be improve the clinical
workflow of radiotherapy by automation and optimization [1–3]. Many economic
forecasts predict the impact of the healthcare and the global economy by AI in the
coming years. Recent analysis predicts that AI in the healthcare market will grow
from approximately 2 billion USD in 2018 to 36.1 billion USD in 2025 [4]. Recently,
the necessary of the automation and labor-saving is more enhanced by the introduc-
tion of adaptive radiotherapy (ART). Moreover, the AI is expected to be a tool for
the prediction of the treatment outcome and side effect by the improvement of deep-
learning technique and development of radiomics which can characterize tumor
phenotypes quantitatively from medical images. In this chapter, the utility and
future prospects of the AI for SBRT.
22.2 Application of AI for SBRT
A general workflow in SBRT is shown in Fig. 22.1: (1) determination of the immo-
bilization and breath control method and treatment planning CT or MRI image scan,
(2) the target delineation and OAR segmentation, (3) the beam arrangement, optimi-
zation, and dose calculation, (4) treatment quality assurance (QA) by comparing the
measurement and calculation, and (5) daily treatment with IGRT. Recently, AI has
applied as an auto-segmentation tool in contouring, auto-planning tool in the treat-
ment planning, a synthetic image tool in the contouring and treatment planning, and
an automated QA tool in the treatment QA and treatment delivery. These AI tools
were partially developed by radiation oncology vendors. On the other hand, clinical
decision support systems based on prediction models of treatment outcome have
Fig. 22.1 The application of AI in the SBRT workflow

22 Future of SBRT with AI (Artificial Intelligence) 301
been developed by research sectors, but such tools have not yet been widely adopted
into clinical practice. This section introduces the role of AI in the SBRT workflow.
22.2.1 Auto-segmentation
Auto-segmentation technique has been improved with the progress of computer

vision and medical image processing. Until to today, four epochs of auto-
segmentation technique have driven transitions: intensity analysis and shape model-
ing, atlas-based methods, early (non-deep) machine-learning techniques, and
deep-learning approaches, as shown in Table 22.1 [5]. For the research topic for
auto-segmentation, atlases and shape models have been investigated before 2016;
thereafter, it was shifted to deep learning. The number of submissions using neural
networks increased over 10 times from 2012 to 2018 for brain tumor segmentation
[6]. For SBRT, the auto-segmentation model of gross tumor volume region using
deep learning and deep fully convolutional networks have been investigated [7, 8].
Another study proposed the deep learning-based auto-segmentation model for organ
Table 22.1 Auto-segmentation technique: intensity analysis and shape modeling, atlas-based
methods, early (non-deep) machine-learning techniques, and deep-learning approaches [10]
Epoch Algorithmic basis Benefits Weaknesses
Intensity Thresholding, Computationally simple, Dependent on image quality
analysis and edge detection, explainable, and consistent. and clear definition of organ
shape active contours, Minimal data requirements. boundaries. Lacks
modeling active shape Clear failure modes. anatomical context.
models Limited use in soft-tissue
segmentation.
Atlas-based Deformable Can be performed on a single Limited capability to adapt
image registration workstation. or vary anatomy and
Require 20 or more cases to geometry.
build a set of atlases.
Leverages existing workflow
for deformable image
registration.
Non- Random forests, Geometric context included Limited gains from larger
deepmachine support-vector in model. Can be trained on training sets. Initial feature
learning machines, 50–120 cases. selection is not
k-means straightforward. Failure
clustering modes may be poorly
defined.
Deep learning Convolutional Greatest capability to learn Need powerful computers
neural networks, anatomical context in a (GPU clusters) to train
includingU-nets robust manner. Scalable to models. Millions of
extremely large datasets. Use parameters per model.
democratized by open-source Difficult to optimize model
tools from machine-learning performance. Hard to
community. explain model workings.
302 D. Kawahara
Table 22.2 A commercial solutions offer deep learning-based auto-segmentation tool

Algorithmic basis Benefits Weaknesses
DLC Expert Mirada Medical, UK Multiple sites
Mvision Mvision AI, Finland Multiple sites
Limbus.ai Limbus.ai Inc, Canada Multiples sites
ART-Plan Therapanacea, Paris Multiple sites
CNN
at risk, which was improved the performance than atlas-based model [9]. Recently,
several commercial solutions offer deep learning-based auto-segmentation tools,
valid for a large number of organs across multiple body sites, as shown in Table 22.2.
22.2.2 Auto-Planning and Synthetic Image
Radiotherapy treatment planning process is complexity and requires advanced

skills. It caused a large user variability [11]. AI helps to beam arrangement and
optimization process, which decreases human intervention and workload, improves
plan quality and consistency [12].
Many commercial-based auto-planning system has been implemented. The auto-
planning system, which RapidPlanTM in Eclipse® treatment planning software,
has provided since 2014. The concept called knowledge-based planning, which uti-
lize various anatomical and geometrical features such as distance to target struc-
tures, volumes of target, and OAR structures to build a mathematical or statistical
model that is then used to predict various dosimetry features [13]. RayStation uses
the machine learning based auto-planning system learns from historical patient and
plan data and infers a 3D spatial dose on a new patient geometry. University Medical
Center Groningen (UMCG) has conducted a clinical study on the method for Head
and Neck cancer VMAT cases, showing promising results [14]. Another auto-
planning system was implemented by Pinnacle [15]. It is a protocol-based method
that performs iterative optimization steps to reach a final plan compared to using the
machine learning-based method is available.
For the research area, the convolution neural network (CNN)-based algorithms
with large numbers of hidden layers making image-based AI applications a domi-
nant topic. The prediction of the dose distribution by deep learning remains the
focus to improve the dose prediction accuracy. Recently, the prediction of spatial
dose distribution has been proposed to provide guidance for humans in decision-
making during the manual treatment planning process for potentially improved effi-
ciency and quality. Previously, various deep-learning technique in addition to the
CNN were used: these were the U-net architecture, fully convolutional volumetric
dose prediction neural network, ResNet, and DenseNet [16–19]. For SBRT,
Campbell et al. proposed the prediction of dose distributions for pancreatic SBRT
using artificial neural network. They showed that the predicted dose distribution
was excellent agreement with dose distribution on the treatment planning system,
and accuracy was substantially improved by considering the other physician’s treat-
ment planning [20]. However, the dose prediction with AI has been used to improve
the individual difference of the treatment planning. Artificial intelligence would
eventually change the paradigm of radiotherapy treatment planning practice. The
development and research of the auto-planning tool have been progressed.
Moreover, image synthesis has been implemented into the treatment planning.
CT images are the standard for radiotherapy dose calculations. Thus, CT image
synthesis from MRI image has been often performed to obtain accurate electron
density. The traditional models were statistical modeling [21], traditional machine
learning [22], and multi-atlas-based methods [23–31]. Nowadays, AI-based models
such as deep convolutional neural network (CNN) [32–42], conditional generative
adversarial network (cGAN) [43–47], and cycle-consistent generative adversarial
network (cycleGAN) [48–54] are proposed. The image synthesis technique could
reduce the scan time and increase accuracy of the dose calculation.
22.2.3 Automated QA
Generally, radiotherapy QA workflow requires a complete evaluation of the treat-

ment plan of every patient. AI has been implemented to predict the passing rate of
QA procedures, to predict error in image-guided modalities, and to assess the per-
formance of Linac [55]. The plan complexity metrics and machine parameters and
CNN approach based on fluence map to predict gamma passing rate can be used as
feedback into the treatment planning process [56–61]. Moreover, AI algorithms
have been applied for preventive maintenance of machine data, they may help to
avoid technical failures and reduce machine downtime [62–71]. Ultimately, this
should lead to a better understanding of the underlying function and relationship
between measurements and help to take preventive actions [72].
22.2.4 Outcome Prediction
Despite SBRT has demonstrated excellent local control, overall survival, and
cancer-specific survival, some patients still develop distant metastases (DM)
(13–23%) and local recurrence (4–14%) [73–79]. Identification of these patients
prior to treatment would allow augmentation of their therapeutic approach with
addition of systemic therapy and/or radiation dose intensification to reduce
304 D. Kawahara
disease relapse rates and increase OS [80]. Therefore, outcome prediction after
radiotherapy contributes to physicians for the decision support. The hand-crafted
radiomics approach exported the numerical data. After the dimension reduction,
the prediction model is built with machine learning. Many approaches have been
considered for modeling including decision trees, support vector machines, artifi-
cial neural networks, and ensemble methods [81–85]. Another approach with deep
learning, which is named as deep radiomics, is also introduced. It performs the
process from the feature extraction to the outcome prediction was performed auto-
matically [86, 87]. Several studies have also demonstrated that hand-crafted
radiomics and deep radiomics are excellent independent biomarkers for estimat-
ing prognostic results of lung cancer patients [87–91]. However, these models are
complexity, thus the methods for interpreting the predictions is required. Moreover,
the accuracy and reliability of the prediction model depended on the amount of
data. The accuracy and reliability of the outcome prediction would be improved
by increasing data availability and variation. Recently, the approach to identify
radiation sensitivity parameters with a deep-learning framework was introduced
[92]. It showed a possibility to represent an innovation in personalized medicine.
Although there are some problems with the AI-based outcome prediction model,
it has a possibility to improve the treatment outcome innovatively. Therefore, out-
come prediction after radiotherapy contributes to physicians for the decision sup-
port (Figs. 22.2 and 22.3).
Fig. 22.2 Treatment outcome prediction with hand-crafted radiomics and deep radiomics
Fig. 22.3 An approach to identify radiationSBRTArtificial intelligence sensitivity parameters with

a deep-learning Outcome predictionframework [92]. (a) The flowchart of the prediction(Deep
Profiler) for optimal dose (iGray) and outcome from the medical image and clinical data using the
regression model. The predictive performance of Deep Profiler was assessed on the basis of a
nested five-fold cross-validation. (b) Deep Profiler is built of an encoder for extracting imaging
features and building a task-specific fingerprint, a decoder for estimating handcrafted radiomic
features, and a task-specific network for generating an image signature for therapy outcome pre-
diction. The blue arrows indicate the training mode, where classical radiomics are calculated using
predefined formulas; estimated radiomics and risk scores are the outputs of Deep Profiler model
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2019 Jun 27.
Chapter 23
Future of SBRT with Photon and Charged
Particles
Tadamasa Yoshitake, Akira Matsunobu, and Yoshiyuki Shioyama
23.1 FLASH Radiotherapy (FLASH-RT)
In recent years, irradiation at extremely high dose rates (>40 Gy/s), 1000 times
higher than conventional irradiation dose rates (around 0.03 Gy/s), is expected to
lead to safer radiation therapy, with side effects more suppressible than conven-
tional therapy, while providing the same effect as conventional therapy with regard
to tumors [1–4]. This radiotherapy, called FLASH radiotherapy (FLASH-RT),
which refers to ultra-high dose rate irradiation, has attracted a great deal of attention
worldwide for its damage-reducing properties. FLASH-RT was first reported in the
1960s and confirmed in cell and animal experiments [5, 6]. Advances in treatment
equipment have made it feasible, and 2019 the first clinical cases have been reported
[1]. In the report, cutaneous lesion of T-cell lymphoma was irradiated at a dose of
15 Gy in 90 milliseconds (ms) using FLASH-RT with electron beam. The tumor
response was rapid, complete, and durable with a short follow-up of 5 months, and
a grade 1 epithelitis (CTCAE v 5.0) along with a transient grade 1 edema (CTCAE
v5.0) in soft tissues surrounding the tumor were observed as acute adverse events.
The increase of the differential effect between tumors and normal tissues appeared
to be very promising, and might significantly enhance the radiotherapy therapeutic
index. Therefore, it overturns the conventional concept of radiotherapy and has the
potential to be a paradigm shift in the field of radiotherapy if it can be applied clini-
cally. In addition, respiratory movement during irradiation has been one of the
T. Yoshitake
Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University,
Fukuoka, Japan
A. Matsunobu · Y. Shioyama (*)
Ion Beam Therapy Center, SAGA HIMAT Foundation, Tosu, Japan
e-mail: shioyama-yoshiyuki@saga-himat.jp
Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7_23
312 T. Yoshitake et al.
problems with SBRT because a large dose is administered at one time, but
FLASH-RT may facilitate irradiation under breath-hold.
This technology delivers the radiation dose almost instantaneously in ms which
is thought to induce a massive oxygen consumption and a transient protective
hypoxia in normal tissue [2–4], as opposed to conventional RT delivering the same
dose in minutes. The FLASH effect has been validated primarily, using 4–18 MeV
energy electron beams [1, 2, 7], but has also been found with photon and proton
beams [8–10]. However, irradiation at ultra-high doses is not the only condition for
the FLASH effect [11], and its mechanism is not yet fully elucidated.
23.2 Combination with Systemic Therapy
Dose prescriptions for SBRT for stage I-IIA non-small cell lung cancer (NSCLC)
vary, with 60 Gy/3–8 fractions often used in the United States and Europe [12]. On the
other hand, in Japan, 48 Gy/4 fractions are often used, and a clinical study (JCOG0403)
conducted by the Japanese Clinical Oncology Group (JCOG) has shown its efficacy
and safety [13]. They reported that the 3-year OS was 76.5%, and the 3-year PFS,
LPFS, and EFS were 54.5%, 68.6%, and 51.4% of the 64 operable patients, respec-
tively. They also reported distant metastasis was observed in 21 of 69 patients.
Therefore, further improvement of local and systemic disease control was desired.
While few clinical trials have been conducted on the concurrent use of chemo-
therapy and SBRT, many trials have been conducted on the concurrent use of immu-
notherapy and SBRT because radiation therapy may enhance the efficacy of
immunotherapy to inhibit PD-L1 through multiple mechanisms [14, 15].
The PACIFIC trial, a phase III study of the efficacy of adding durvalumab as
sequential therapy after chemoradiotherapy (CRT) in Stage III NSCLC, compared
durvalumab with placebo in patients with locally advanced unresectable Stage III
NSCLC who had completed at least two cycles of concurrent chemotherapy and
radiation therapy. The OS analysis also showed a statistically significant OS benefit
with clinically meaningful improvement in the durvalumab group compared to the
placebo group (hazard ratio: 0.68; p = 0.0025) [16].
On considering the combination with immunotherapy, a radiotherapy protocol
that maximizes the immune response must be established to aim at the local and
systemic disease control. Specifically, it will be useful to elucidate how DNA dam-
age signaling affects the immune response after radiotherapy. Furthermore, the elu-
cidation of the optimal radiotherapy method premised on the combined therapy,
such as the irradiation dose, the number of fractions and the timing of the combined
use of immune checkpoint inhibitors (ICIs), is necessary. The survival was signifi-
cantly longer in mice that started the anti-PD-L1 antibody during fractional radio-
therapy compared with those that received sequential administration after the
completion of radiotherapy [14]. In another mice study, the timing of 20 Gy × 1
fraction and anti-CTLA4 antibodies reported that the best tumor control and
23 Future of SBRT with Photon and Charged Particles 313
survival advantage was observed in the group that started the anti-CTLA4 antibod-
ies before radiotherapy, compared with the group that started it after radiotherapy
[17]. In clinical practice, a retrospective analysis of the timing of palliative radio-
therapy and ipilimumab for metastatic melanoma reported that the median OS was
9 months in patients who received radiotherapy during induction of ipilimumab and
39 months in patients who received radiotherapy while continuing ipilimumab [18].
These results suggest that ICIs should be initiated prior to or concurrently with
radiotherapy, rather than after radiotherapy, although accurate evaluation requires
comparison by prospective clinical trials due to differences in dosages and ICI used
in these studies. Regarding the irradiation field, when it includes the draining lymph
nodes, it can suppress the radiotherapy-induced immune response, as shown in pre-
clinical studies [19]. Therefore, the radiotherapy method used in the combination
treatment with immunotherapy may differ from the conventional radiotherapeutic
treatment strategies. Taken together, these results imply that ICI may be preferable
prior to or concurrent with radiotherapy in a single 10 Gy fractionated dose that
avoids draining lymph nodes.
The significance of local therapy will become more important in the future as
systemic therapy improves to control systemic disease with multiple metastases. In
the SABR-COMET phase II randomized trial, including patients with five or fewer
lesions, SBRT was associated with an improvement in overall survival [20].
23.3 Assessment of Recurrence Risk
In the future, the identification of factors that can predict the risk of recurrence may
help in determining treatment strategies such as adjuvant therapy based on risk.
Radiomics, which is obtained by analyzing radiological images, is expected to be
applied to the determination of benign and malignant lesions and to prognosis after
treatment [21]. Radiomics is a noninvasive, fast and low approach for solving the
issues of precision medicine. Huang et al. developed a radiomics signature from 282
consecutive patients with stage IA-IIB NSCLC and the radiomics signature is an
independent biomarker for the estimation of DFS in patients with early-stage
NSCLC [22]. Coroller et al. described that the phenotype of the primary tumor was
quantified on pre-treatment CT-scans using 635 radiomic features and radiomic fea-
tures capturing detailed information of the tumor phenotype can be used as a prog-
nostic biomarker for clinically-relevant factors such as distant metastasis [23].
Liquid biopsy by the analyzing circulating tumor cells (CTCs) and circulating
cell-free tumor DNA (ctDNA) is another factor expected to be associated with prog-
nosis in the future. CTCs and cfDNA are minute numbers of cells and fragments of
DNA derived from the primary tumor in the bloodstream of cancer patients, respec-
tively. While many papers have been published on the role of CTCs in chemother-
apy [24], to date, few have been published on radiotherapy and CTCs. Tay RY et al.
reported the prognostic value of baseline CTC count in an exclusive limited-stage
small cell lung cancer (LS-SCLC) population at thresholds of 2, 15 and 50 CTCs.

Specific to LS-SCLC, ≥15 CTCs was associated with worse PFS and OS indepen-
dent of all other factors and predicted ≤2 years survival, and the results may improve
disease stratification in future clinical trial designs and aid clinical decision making
[24] Wen YF et al. reported that the association between serum CTC level and clini-
copathological parameters was examined in 99 patients with locally advanced cervi-
cal cancer ([FIGO] stage IIB-IVA) undergoing radiotherapy or concurrent
chemoradiotherapy, and elevated CTC levels were significantly associated with
poor disease-free survival [25].
23.4 New Indications for SBRT
Currently, SBRT is used primarily for the curative treatment of non-metastatic

malignancies, but its indications may be expanded in the future. A joint consensus
document from the European Society for Radiotherapy and Oncology and American
Society for Radiation Oncology discussed several of these criteria, including the
site of metastases, feasibility of definitive local therapy, and systemic therapy
options, all of which should be considered when defining oligometastatic disease
and identifying appropriate candidates for aggressive local therapies [26]. SBRT
has also been reported to provide excellent pain control for patients with bone
metastases. Nguyen et al. conducted a prospective phase 2 trial comparing single-
fraction SBRT versus conventional multifraction radiotherapy for predomininantly
nonspinal bone metastases and reported non-inferiority of SBRT for pain relief in
160 patients [27]. SBRT is considered effective for patients undergoing palliative
irradiation, with shorter treatment times and fewer adverse events in normal organs.
Future advances in treatment equipment will solve the problem of long treatment
time per treatment, and its use in palliative care is expected to expand.
SBRT has been suggested as a potential new indication for benign conditions
such as refractory ventricular tachycardia [28]. Cuculich et al. reported that they
combined noninvasive mapping (electrocardiographic imaging) and SBRT (25 Gy
in a single fraction) to treat five patients with refractory ventricular tachycardia
(VT) and a marked reduction in the burden of VT was achieved.
23.5 Charged Particle: Proton and Carbon
Charged particle beams like proton and carbon ions share certain unique physical
properties compared with photon beams such as X-ray and gamma-ray. In particu-
lar, after penetrating into the body, they emit only a low dose of radiation along their
travel path; they then deliver their maximum dose at the end of their range, beyond
which the radiation dose drops sharply (so called Bragg peak). The depth-dose
profile of protons and carbon ion beams make it possible to deliver an optimal dose
to the tumor while delivering a lower doses to the critical organs surrounding the
tumor. On the other hand, photon beams apply their maximum dose near the surface
of the body, and the dose decreases with increasing depth into the body (Fig. 23.1).
Therefore, naturally, charged particle therapy thus can provide superior dose distri-
bution compared with photon radiotherapy. Dose concentration and escalation to
the tumor without increase of risk of normal tissues is the most basic and important
principle in radiotherapy. The physical property of charged particles described
above thus constitutes a distinct advantage over photons.
A distinctive property of carbon ion beams distinguished from photon and proton
is their high biological effectiveness. Carbon ion beams deliver a larger mean energy
per unit length of their trajectory [i.e. higher linear energy transfer (LET)] to body
tissues than photon and proton beams. Furthermore, the LET of carbon ion beams
increases steadily from the initial value at the entrance point as it passes through the
body, reaching its maximum value at the end of its range. Double-strand DNA
breaks are induced with increasing frequency according to the increase of the LET
of their trajectory. Therefore, LET is well correlated with the biological effects of
radiation. In addition, high-LET radiations can also be effective because of the
reduction of the oxygen enhancement ratio and differences in radio-sensitivity
related to the cell cycle of the tumor. These biological characteristics of high-LET
radiations like carbon ions offer theoretical advantages for the control for radio-
resistant type of tumors and larger tumors. Charged particle therapy has already
been used for solid tumors in various organs including diseases for which SBRT
Fig. 23.1 Depth-dose distribution of photon beams and charged particles

with photon beams is indicated, and has demonstrated efficacy and safety. Here the
clinical benefits of charged particle therapy in the treatment for lung cancer, hepa-
tocellular carcinoma and lymph node oligometastases, and technology develop-
ments in progress will be presented.
Non-Small Cell Lung Cancer: Surgical resection is the standard treatment for
early-stage non-small cell lung cancer (NSCLC). However, like SBRT with photon
beams, hypofractionated charged particle therapy using proton or carbon ions has
also been used for patients who are diagnosed inoperable because of severe comor-
bidity or poor pulmonary function or refuse surgery. In the treatment for early-stage
NSCLC, especially Stage I NSCLC, charged particle therapy with improved dose
distribution allow higher dose to the lung tumor while minimizing the dose of sur-
rounding organs at risk, for example, lung, spine, esophagus, and heart. In particu-
lar, it is a very important advantage of charged particle therapy to minimize the
expansion of low to medium dose volume to the lung tissue compared to SBRT with
photon beams. Ebara et al. reported the results of dosimetric comparison analysis
between carbon-ion radiotherapy and photon SBRT in 13 consecutive patients with
stage I lung cancer; mean lung dose, and Lung V5 through V40 with increments of
5 Gy in carbon-ion radiotherapy were significantly lower than that in photon SBRT
[29]. Therefore, charged particle therapy is suggested to be theoretically able to
reduce the risk of radiation pneumonitis. This characteristic could prove beneficial
in lung cancer patients with compromised pulmonary function and/or with larger
tumors. The results of prospective clinical trials for Stage I NSCLC in Japan are
summarized in Table 23.1. The local control rates were reported 73–96% with pro-
ton radiotherapy of 10–20 fractions, 80–98% with carbon radiotherapy of 1–4 frac-
tions, while those with SBRT of 4 fractions were 85–87% [13, 30–35]. Despite the
inclusion of tumors larger than 3 cm (Stage IB), the local control rate with charged
particle therapy was comparable to that of SBRT. On the other hand, the rates of
severe toxicities more than grade3 with charged particle radiotherapy were reported
0–2%, while those with SBRT were 10% [13, 30–35]. The lung toxicities with
charged particle therapy have been less than those of SBRT. Moreover, charged
particle therapy has been suggested to be a relatively safe treatment for NSCLC
patients with interstitial pneumonia [36, 37]. A case of stage I NSCLC who were
treated with carbon-ion radiotherapy shown in Fig. 23.2. Because low to medium
dose volume to the lung tissue is not expanded, the area of radiation pneumonitis is
localized.
Hepatocellular Carcinoma: For inoperable hepatocellular Carcinoma (HCC)
cases radiotherapy is a treatment option. The tolerance of the liver to irradiation is
generally poor, charged particle therapy like proton and carbon ions have advan-
tages over SBRT with photon beams in HCC. Abe et al. performed dosimetric com-
parison of carbon-ion radiotherapy and SBRT with photon beams for 10 consecutive
patients with HCC, and documented that carbon-ion radiotherapy provides an
advantage in both target conformity and normal liver sparing compared with SBRT
with photon beams [38]. In their report, mean liver dose and V5, V10 and V20 of
23
Table 23.1 Prospective clinical trial for stage I NSCLC in Japan

Author Institute Toxicity
Method Year Year No of Patient Stage Dose/fraction 5y-LC 5y-OS (≥ Garde3)
Photon Nagata [13] JCOG0403 100(inoperable) IA 48 Gy/4 Fr 87% 76% 10%
2015 2004–2008 64(operable) (3y) (3y)
85% 59%
(3y) (3y)
Hata [30] Tsukuba 21 IA, IB 50.0–60.0 Gy(RBE)/10 Fr 95% 74% 0%
2007 2002–2005 (2y) (2y)
Proton Iwata [31] Hyogo 57 IA, IB 80.0 Gy(RBE)/20 Fr 73% 81% 2%
2010 2003–2007 60.0 Gy(RBE)/10 Fr (3y) (3y)
Nakajima [32] Nagoya 55 IA, IB 72.6 Gy(RBE)/22 Fr 96% 87% 0%
2018 2013–2017 66.0 Gy(RBE)/10 Fr (3y) (3y)
Future of SBRT with Photon and Charged Particles
Miyamoto [33] QST 79 IA, IB IA:52.8 Gy(RBE)/4 Fr IA 98% 45% 0%

2007 2000–2003 IB:60.0 Gy(RBE)/4 Fr IB 80%
Iwata [31] Hyogo 23 IA, IB 52.8 Gy(RBE)/4 Fr 86% 86% 0%
2010 2003–2007 (3y) (3y)
Carbon Yamamoto [34] QST 20 IA, IB 48.0–50.0 Gy(RBE)/1 Fr 95% 69% 0%
2017 2003–2012
Saitoh [35] Gunma 37 IA, IB IA:52.8 Gy(RBE)/4 Fr IA 86% 74% 2%
2019 2010–2015 IB:60.0 Gy(RBE)/4 Fr IB 90%
317
a b c d
Fig. 23.2 A case of stage I NSCLC patient treated with carbon-ion radiotherapy (RT). (a) CT
image before carbon-ion RT. (b) Isodose distribution of carbon-ion RT with 54Gy(RBE) in 4 frac-
tions. The red arrows indicate the irradiated beam direction. (c) CT image at 7 months after treat-
ment. (d) CT image at 6 years after treatment
liver were significantly lower in carbon-ion radiotherapy than SBRT with photon
beams, and the differences were particular in the patients with larger tumors than
4 cm in diameter. The results of prospective clinical trial for HCC in Japan are sum-
marized in Table 23.2. The local control rates were reported 87–92% with proton
beam therapy of 10–22 fractions, 76–91% with carbon-ion radiotherapy of 2–4 frac-
tions at 4 or 5 years, while those with photon SBRT of 5 fractions was 90% at
3 years [39–44]. Despite the treatment of large tumors, charged particle therapy has
good local control rates and appears to be comparable to photon SBRT for small
tumors. Furthermore, the incidence of serious toxicity (grade 3 or higher) with
charged particle therapy has been low, ranging from 0–5%, compared to a reported
11% with photon SBRT [39–44]. A case of HCC with 5 cm in diameter who were
treated with carbon-ion radiotherapy shown in Fig. 23.3. Large liver tumors like this
patient can be treated safely by using charged particle therapy.
Lymph node Oligometastases: In a variety of cancers, the prognosis of patients
with oligometastatic disease has been relatively good compared to wide-spread
metastatic disease. Recently, the treatment of oligometastatic disease with curative
intent, including photon SBRT, has been gaining increasing acceptance. In such
cases, charged particle therapy is also indicated, and particle therapy has been often
used for oligometastases in the lung, liver, or lymph nodes. Here the results of
charged particle therapy for oligo lymph node metastases will be presented. Okonogi
et al. reported a 2-year local control rate of 85% and 2-year overall survival rate of
63% as a result of carbon-ion radiotherapy with 48 Gy (RBE) in 12 fractions as the
most common dose fraction in 323 patients with oligo lymph node recurrence of
various cancers [45]. It is expected that further evidence will be accumulated on
charged particle therapy and photon SBRT for oligometastatic disease, and their
clinical roles will be established in the future.
23
Table 23.2 Prospective clinical trial for HCC in Japan

Author Institute Tumor size(cm) Toxicity
Method Year Year No of Patient Median(range) Dose/fraction 5y-LC 5y-OS (≥ Garde3)
Photon Kimura [39] STRSPH 36 2.3 (1.0–5.0) 40 Gy/5 Fr 90% (3y) 78% 11%
2021 2014–2018 (3y)
Proton Fukumitsu [40] Tsukuba 51 2.8 (0.8–9.3) 66.0 Gy(RBE)/10 Fr 87% 38% 0%
2009 2001–2004
Iwata [41] Nagoya 45 2.5 (1.0–10.0) 72.6 Gy(RBE)/22 Fr 92% 70% 2%
2021 2013–2016 66.0 Gy(RBE)/10 Fr
Future of SBRT with Photon and Charged Particles
Carbon Kasuya [42] QST 44 3.7 (1.2–8.6) 52.8 Gy(RBE)/4 Fr 91% 25% –
2017 2001–2003
Yasuda [43] QST 57 3.3 (1.3–9.5) 45.0 Gy(RBE)/2 Fr 91% 45% 4%
2019 2008–2013
Shibuya [44] Gunma 35 3.5(1.2–7.7) 52.8–60.0 Gy(RBE)/4 Fr 76% (4y) 69% 5%
2021 2010–2016 (4y)
319
a b c
Fig. 23.3 A case of HCC treated with carbon-ion radiotherapy (RT). (a) CT image before carbon-
ion RT. (b) Isodose distribution of carbon-ion RT with 60Gy(RBE) in 4 fractions. The red arrows
indicate the irradiated beam direction. (c) CT image at 1 year after treatment
23.6 Future Perspectives on Charged Particle

Therapy Technology
In recent years, charged particle therapy technologies have advanced greatly such as
pencil beam scanning irradiation, intensity-modulated particle therapy (IMPT), but
further development of new treatment technologies is also steadily progressing. One
is the ultra-high dose rate irradiation called FLASH-RT using proton beams
described above. Another is the LET distribution optimization therapy. This is an
attempt to optimize not only the conventional dose distribution but also the LET
distribution. If the LET can be optimized so that the LET is higher inside the tumor
and lowered from the margins to the surrounding normal tissue, it will be possible
to both further improve the anti-tumor effect and reduce side effects. Intensity
Modulated Composite Particle Therapy (IMPACT) is a new therapeutic technique
of charged particle therapy under development at National Institutes for Quantum
Science and Technology (QST) in Japan that combines multiple ion species such as
protons, helium, oxygen and neon in addition to carbon ions in one treatment ses-
sion. By combining multiple ion species, the degree of freedom of LET optimiza-
tion further increase. Thus, IMPACT enables the optimization of the dose and the
LET distributions in a patient, which will maximize the potential of charged-particle
therapy by expanding the therapeutic window. Further studies and developments
will enable this therapeutic technique to be used in clinical practice [46].
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Index
A E
Adrenal gland, 223, 225 Effect(s), 15–17, 20, 23–25, 36, 37, 42–44, 47,
Anti-tumor immunity, 24 58, 64, 65, 69, 71, 73, 79, 83, 92,
Artificial intelligence (AI), 64, 299–304 97, 98, 103–105, 126, 142, 143,
Automated QA, 300, 303 145, 153, 156, 158, 163, 171, 172,
Auto-planning, 64, 300, 302, 303 177–179, 192–193, 237, 267, 268,
Auto-segmentation, 300–302 270, 273, 279, 291, 292, 300, 311,
312, 315, 320
Energy deposit of high-energy
B photon, 39
Brachial plexus, 125, 128, 139–142, 147, 187 Epidural spinal cord compression, 183, 184
Breast cancer, 140, 199, 205–207, 211 Esophagus, 125, 126, 128, 133, 139, 140, 143,
144, 147, 190, 192, 316
Excellent local control, 156, 165, 233, 303
C
Carbon-ion radiotherapy, 316, 318, 320
Centrally located lung tumors (CLTs), 125, F
126, 144 Fiducial marker(s), 78, 240, 244, 247, 251,
Chest wall, 100, 137, 139, 145–147 257, 258
Child-Pugh class B7 or below, 158 5Rs, 25–27
Clinical trial(s), 5, 56, 59–65, 91–92, 105, FLASH radiotherapy (FLASH-RT), 65, 311,
116, 117, 119, 121, 122, 125, 137, 312, 320
162, 175, 199, 201–208, 40–50 Gy in 3–5 fractions, 157
312–314, 316–319
CyberKnife, 72, 173, 255–261
G
Great vessels, 139, 144, 147
D
Dose constraint(s), 5, 92, 132, 133, 139–147,
156, 158–160, 174–176, 179, H
187–190, 192, 193, 203 Heart, 125, 126, 128, 139–141, 147
Dose kernel of high-energy photon, 47, 51, 86 Hemoptysis, 114, 126, 128, 132, 142, 144
Dynamic tumor tracking, 233–241 High safety, 160
Dynamic WaveArc irradiation, 236–238, 241 Hypoxia-inducible factor (HIF-1 α ), 16
© The Editor(s) (if applicable) and The Author(s), under exclusive license to 323
Springer Nature Singapore Pte Ltd. 2023
https://doi.org/10.1007/978-981-99-3978-7
324 Index
I Motion management, 55, 57, 58, 60, 62, 70,

Image-guided radiotherapy (IGRT), 55, 57, 76–79, 98, 133, 220, 227, 233, 251,
59–61, 69–75, 173, 176, 215, 233, 269, 270
234, 236, 238, 255, 264, 265,
279, 280
Image synthesis, 303 O
Imaging, 56, 57, 59, 64, 69–72, 78–80, 98, Oligometastases, 184, 187, 201, 206, 209, 211,
100, 102, 138, 155, 158, 163, 164, 316, 318
173, 174, 185, 192, 199, 201, 202, Oligometastatic disease, 199, 201, 223,
234, 235, 244, 251, 261, 265, 314, 318
270–272, 277, 279, 280, 283, 285, 1–3 HCCs within 3–5 cm, 157
287, 291, 292 Organ motion, 65, 70, 77, 99, 220, 250, 251,
Immunotherapy, 24, 25, 201, 209, 312, 313 282, 283
Indirect cell death, 19, 20, 23, 27, 28 Outcome prediction, 303, 304
Intensity modulated composite particle therapy
(IMPACT), 320
Intensity-modulated particle therapy P
(IMPT), 320 Pain palliation, 188
Intensity-modulated radiotherapy (IMRT), Pancreas, 97, 101, 223, 269, 270
215, 218, 226, 236, 257, 299, 300 Patient immobilization, 55, 57, 70, 74, 76, 287
Interactions of high-energy photon, Patient positioning accuracy, 75
36–39, 41–43 Peripheral lung cancer, 113, 119–122
Inter-fractional motion, 279 Prostate, 72, 75, 210, 211, 215, 216, 218, 236,
Intra-fractional motion, 279 238, 244, 247, 250, 256, 257, 265,
Irradiation position error, 70, 71 269, 270, 273, 274, 280, 281
Prostate cancer, 4, 5, 207, 208, 215–218, 257,
265, 274, 281
L Proton beam therapy, 318
Linear quadratic (LQ) model, 27, 28, 30 Proximal bronchi, 139, 147
Liquid biopsy, 313 Proximal bronchial tree, 125, 227
Locally advanced non-small cell lung cancer
(LA-NSCLC), 226, 227
Lung, 3–5, 75, 84, 86–93, 97, 99–101, 104, Q
113, 114, 116–121, 125, 126, 132, Quality assurance (QA), 55–65, 70, 255, 268,
137–147, 201, 202, 207, 210, 211, 269, 289, 300
226, 227, 236, 238–240, 243, 246,
247, 250, 257–260, 265, 269, 270,
273, 274, 283, 287, 291, 292, 304, R
312, 314, 316, 318 Radiomics, 300, 304, 313
Lung cancer, 3–5, 58, 64, 73, 89, 91, 113, 114, Radixact®, 72, 263–265, 267–273
116–122, 125, 126, 137, 140, 141, Real-time tracking radiotherapy, 243,
146, 201–205, 211, 223, 226, 227, 244, 246–251
243, 246, 247, 287, 291, 292, 304, Real-time tumor-tracking, 243, 244, 246–251
312, 314, 316 Recurrent head and neck cancer, 225
Renal cell cancer, 171–173, 175–179, 209
Reporting, 90, 92, 93, 105, 106, 158, 218
M Respiratory motion, 4, 55, 58, 60, 62, 65, 70,
Marker-less, 291 73, 75–79, 97–99, 106, 113, 133,
220, 227, 259, 269, 270
Index 325
Respiratory motion management, 55, 58, 60, SyncTraX, 72, 243, 244, 246–251
62, 70, 76–79, 98, 133, 220, 227
T
S Targeting, 101, 102, 239, 257
SABR see Stereotactic ablative radiotherapy Technique, 3, 4, 55, 56, 58, 60, 62, 69, 76, 77,
SBRT see Stereotactic body radiotherapy 83, 92, 98, 101, 105, 147, 155,
Simulation, 51, 57, 58, 62, 84, 86, 89, 104, 173–175, 183, 203, 220, 226, 233,
190, 216, 220, 238, 260, 265, 269, 236–238, 240, 251, 256–260, 264,
271, 281, 282, 292, 300 269, 277, 281, 282, 288,
Skin, 17, 18, 70, 76, 132, 139, 146, 293 299–303, 320
Small field dosimetry, 55, 58 Tomotherapy, 263–271, 273, 274
Spinal metastases, 183, 189, 192, 193 Toxicity(ies), 3–5, 76, 117–119, 125, 126,
SRS see Stereotactic radiosurgery 128, 132, 133, 137–147, 158–160,
Stereotactic ablative radiotherapy (SABR), 192, 203, 206, 208, 209, 216, 218,
13–16, 18–20, 23–28, 30, 139, 219, 223, 225, 233, 251, 291, 293,
144–146, 210, 211, 233 316, 318
Stereotactic body radiotherapy Treatment planning, 55, 57–65, 69, 73, 74,
(SBRT), 3–5, 35–49, 51, 53, 55–65, 76–78, 83, 84, 97–100, 102–106,
69, 73–77, 79, 83, 84, 88–93, 97, 113, 132, 133, 160, 176, 185, 216,
98, 101, 102, 104–106, 113–117, 220, 236, 238, 247, 248, 256,
119–122, 125, 126, 128, 132, 133, 260–261, 264, 267, 268, 270, 278,
137–147, 155–160, 162–165, 287, 300, 302, 303
171–174, 176–180, 183–193,
203–211, 215–223, 225–227,
233–241, 243, 244, 247–251, 256, U
257, 259, 268, 271–273, 277, 280, Ultra-centrally located lung tumor, 125, 126
281, 283, 291, 292, 299–304,
311–316, 318, 320
Stereotactic radiosurgery V
(SRS), 3, 4, 13, 29, 58, 59, 255, 256 Vascular damage, 15, 18–20, 24, 27–30
Synchrony®, 258, 259, 261, 263, 269–273

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Stereotactic Body Radiation

ISBN 978-981-99-3977-0 ISBN 978-981-99-3978-7 (eBook)

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Hiroshima, Japan Yasushi Nagata

Part II Basic Principles

Part III Clinical Applications

10 Lung: Toxicities���������������������������������������������������������������������������������������� 137

Part IV Development of Machines

Part V Future Perspectives

© The Author(s), under exclusive license to Springer Nature Singapore Pte 3

1.3 Principles and Methods

To extend the intracranial radiosurgery technology to extracranial tumors, two prob-

1.4 Dose Fractionation and Normal Tissue Dose Constraints

The name of SBRT was introduced by Timmerman in 2002. He originally used

1.6 Survey of SBRT in Japan and Its Current Status

Fig. 1.1 Accumulated number of SBRT cases in Japan

Fig. 1.2 Accumulated ɼ

1. Lax I, Blomgren H, Näslund I, et al. Stereotactic radiotherapy of malignancies in the abdomen.

Chang W. Song, Sun Ha Paek, Mi-Sook Kim, Stephanie Terezakis,

High-dose hypofractionated stereotactic body radiotherapy (SBRT) and stereotactic

C. W. Song (*) · S. Terezakis · Y. Watanabe · L. C. Cho

© The Author(s), under exclusive license to Springer Nature Singapore Pte 13

2.2 More Than DNA Damage Is Involved in The Cell Death

The number of clonogenic cancer cells in 1–10 g of malignant tumors is as many as

Fig. 2.1 Radiation

mean surviving cell

2.3 Effect of High-Dose Hypofractionated Irradiation

Tumor vasculatures are formed initially by angiogenesis, which involves sprouting

2.4 Vascular Damages by High-Dose

Fig. 2.2 (continued)

2.5 Indirect Cell Death Due to Vascular Damages

unrealized until SABR became an established modality for cancer treatment in

Fig. 2.3 (continued)

2.6 Immunologic Effects of SABR

SABR acts as a double-edge sword in antitumor immunity: it activates the antitu-

Irradiation-induced vascular damage and the resultant increase in tumor hypoxia

2.7 The 5Rs and Fractionation in SABR

2.7.1 Reoxygenation of Hypoxic Cells

Varying fractions of clonogenic cells in tumors are radiobiologically hypoxic. In

2.7.2 Repair of Sublethal Radiation Damage in Tumor Cells

2.7.3 Redistribution of Cells in Cell Cycle Phase

2.7.4 Repopulation of Tumor Cells

2.7.5 Radiosensitivity of Tumor Cells

The intrinsic radiosensitivity of a tumor cell varies considerably depending on the

2.8 The Linear Quadratic Model in SABR

69. Kawahara D, Wu L, Watanabe Y. Optimization of irradiation interval for fractionated stereo-

3.1 Electromagnetic Wave: X-Rays, Gamma Rays

c [ m / s] = λ ⋅ν = 3.0 × 108. (3.1)

© The Author(s), under exclusive license to Springer Nature Singapore Pte 35

Fig. 3.1 Release of X-rays

3.2 Interactions of Photons with Matter

Fig. 3.2 Interactions of incident photons with matter

Compton scattering is a scattering phenomenon between a photon and an electron

Ein 2 ⋅ Ein ⋅ γ ⋅ cos2 φ

Fig. 3.4 The Compton

σ comp ( Ein ) = σ s ( Ein ) + σ a ( Ein ) , (3.9)

Pair production is the phenomenon of the creation of a pair of an electron and a

3.3 Photon Flux in Matter

I out = I in ⋅ exp ( − µ ⋅ d ) , (3.12)

Fig. 3.7 Schematic of the photon flux passing through matter

µ ( E ) = ∑µi ( E )  µ phot ( E ) + µcomp ( E ) + µ pair ( E ) . (3.13)

3.4 Energy Deposition by Incident Photons to Matter

An incident photon deposits kinetic energy Ee on an electron by interactions, such

Hiroshima, Japan Yasushi Nagata

Part II Basic Principles

Part III Clinical Applications

10 Lung: Toxicities�� 137

Part IV Development of Machines

Part V Future Perspectives

1.3 Principles and Methods

1.4 Dose Fractionation and Normal Tissue Dose Constraints

1.6 Survey of SBRT in Japan and Its Current Status

2.2 More Than DNA Damage Is Involved in The Cell Death

2.3 Effect of High-Dose Hypofractionated Irradiation

2.4 Vascular Damages by High-Dose

2.5 Indirect Cell Death Due to Vascular Damages

2.6 Immunologic Effects of SABR

2.7 The 5Rs and Fractionation in SABR

2.7.1 Reoxygenation of Hypoxic Cells

2.7.2 Repair of Sublethal Radiation Damage in Tumor Cells

2.7.3 Redistribution of Cells in Cell Cycle Phase

2.7.4 Repopulation of Tumor Cells

2.7.5 Radiosensitivity of Tumor Cells

2.8 The Linear Quadratic Model in SABR

3.1 Electromagnetic Wave: X-Rays, Gamma Rays

3.2 Interactions of Photons with Matter

3.3 Photon Flux in Matter

3.4 Energy Deposition by Incident Photons to Matter

3.5 Energy Spectrum and Dose Distribution of Therapeutic

4.2.1 Staffing and Equipment

4.2.2.6 Third Parity Evaluation

4.2.3.1 Physical QA in Clinical Trials

4.3 Perspective of Physics QA for SBRT

5.1 Image-Guided Radiation Therapy (IGRT)

5.1.3 IGRT Devices and Methods

5.2.1 Objective of Patient Immobilization

5.2.3 Setup Accuracy Using Immobilization Devices

5.2.4 Influence on Dose Distribution

5.3 Respiratory Motion Management

5.3.1 Objective of Respiratory Motion Management

6.1 Basics of Dose Calculation Algorithm

6.1.1.2 Analytical Anisotropic Dose Calculation Algorithm

6.1.2 MC and GBBS

6.1.3 Medium of Dose Deposition and Radiation Transport

6.2 Comparison of Dose Calculation Algorithms for SBRT

6.2.1 Issues in Clinical Cases with Low-Density Material

6.2.2 Issues in Clinical Cases with High-Density Material

6.2.3 Impact of Dose Prescription

6.2.4 Impact of Dose Grid Size