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[AQ1] CHAPTER
14 Image-Guided Radiation Therapy
[AQ2] Guang Li  ■  Gig S. Mageras  ■  Lei Dong  ■  Radhe Mohan
Introduction
Most modern radiation therapy of cancer involves nonin-
vasive targeting of localized disease and conformal avoid-
ance of nontarget tissues. Radiation dose is delivered to
the volume of intended treatment without the benefit of
physically seeing the regions being irradiated. Therefore,
imaging guidance is crucial in every step of the radiation
therapy, including cancer diagnosis, staging, and delinea-
tion; treatment simulation and planning; patient setup,
tumor localization and motion monitoring; and treatment
response assessment, efficacy evaluation and strategy
refinement. In fact, most of the significant advances in
radiation oncology over the last three decades have been
made possible by preceding advances in medical imaging,
including computed tomography (CT), magnetic reso-
nance imaging (MRI), magnetic resonance spectroscopic
imaging (MRSI), positron emission tomography (PET),
single photon emission computed tomography (SPECT),
and ultrasound (US). With the aid of CT and MRI, three-
dimensional (3D) shapes of treatment regions and critical
normal structures are delineated with great precision, thus
reducing the chance for marginal misses of the tumor and
minimizing the exposure of normal tissues to high radia-
tion dose. MRI, MRSI, PET, and SPECT images provide
additional functional and metabolic information to define
and delineate the extent of the disease. Examples of image
guidance in various stages of radiation therapy are illus-
trated in Figure 14.1.
Image-guided radiation therapy (IGRT) is composed
of a multitude of major innovations to address some of
the problems arising from inter- and intra-fractional ana-
tomic variations. IGRT aims to deliver a radiation treat-
ment as it is planned based on an image acquired at
simulated treatment conditions. This simulation image
establishes a reference of 3D patient anatomy (with pos-
sible inclusion of tumor respiratory motion information)
for both image-based treatment planning and image-
guided treatment delivery. The former follows the exact
3D anatomy (both the tumor and normal tissues) for
dosimetric planning, while the latter focuses mostly on
tumor alignment between the reference image and daily
images at the treatment unit prior to and during treat-
ment, in reference to the treatment beams. Therefore,
the variations of tumor position in the image-guided
LWBK933_Ch14_p229-258.indd 229
inter-fractional setup (i.e., variation between treatment
fractions) and intra-fractional organ motion (i.e., motion
occurring within a treatment fraction) could be corrected
for more accurate delivery of the planned treatment dose
to the target. As the variation of normal tissues is usually
ignored in the current image-guided approach, dosimetric
and clinical consequences must be assessed.
Increasing evidence shows that there are substantial
inter- and intra-fractional variations in the shapes, vol-
umes, and positions of treatment targets and the interven-
ing and surrounding normal tissues, in contrast to the
“snapshot” planning anatomy of a patient. The causes of
such variations include body shift, rotation and deforma-
tion, respiration-induced organ motion, weight loss, and
radiation-induced changes such as tumor shrinkage.
These variations could have a significant impact on the
outcome of treatments, as they may result in underdosing
the target or overdosing the organs at risk (1–3). In the
current state of the art of the planning and delivery of
radiation therapy, based on the use of CT, PET, and MRI
images acquired prior to the course of treatments, it is
assumed implicitly that patient’s anatomy discerned from
initial imaging remains static throughout the course of the
radiation therapy. In the current practice, wide treatment
margins, derived from population-based studies, are used
to ensure coverage of the disease, exposing considerable
volumes of normal tissues to unwanted radiation. The use
of large margins limits the ability to safely deliver higher
tumor doses because of increased risk of normal tissue
toxicity, especially for hypo-fractioned stereotactic body
radiotherapy (SBRT), in which the high dose per fraction
exceeds the normal tissue’s capacity for sublethal repair.
Furthermore, the margin needed for some patients exhib-
iting large target variations may exceed the population-
based margin, potentially leading to marginal misses,
especially with the use of highly conformal modalities,
such as 3D conformal radiotherapy (3DCRT), intensity-
modulated radiotherapy (IMRT), volumetric-modulated
arc therapy (VMAT), and proton therapy (4–6). Treat-
ment planning and delivery techniques that do not correct
for such daily volumetric variations adequately may lead
to suboptimal treatments. These factors may, in part, be
responsible for the poor outcome and high toxicity in
radiation therapy for some cancers. IGRT has the potential
to target gross and microscopic diseases accurately, to
229
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 230 n  Treatment Planning in Radiation Oncology
Figure 14.1.  Image guidance at various stages of the radiotherapy
process.
individualize treatments to reduce margins, and to allow
radiation dose escalation to higher levels with the expecta-
tion of improving local control and reducing toxicity
(7,8). Although this rationale is supported by increasing
evidences, continuing research to further develop IGRT
methods for clinical trials is required to determine the true
clinical promise of IGRT.
[AQ3] This chapter focuses on IGRT technologies related to
treatment planning as well as treatment delivery. The
related topics are covered in the following sections: second
and third sections introduce various forms of IGRT tech-
nologies and their commercial implementations for inter-
fractional and intra-fractional imaging, respectively.
Fourth section reviews requirements and considerations
for IGRT, including quality assurance (QA). Various pos-
sible IGRT strategies, margin assessment and reduction,
and clinical implications are described in fifth section.
Finally, sixth section attempts to look into the future and
speculate on new processes coming into this field.
Inter-Fractional Igrt
Imaging Modalities
In this section, we focus on in-room IGRT imaging
modalities for daily patient setup. Images acquired imme-
diately prior to treatment are used to reposition the
patient so as to align the target or its surrogate (such as
implanted radio-opaque fiducial markers in or near the
tumor) with the planned radiation beams. This is the
simplest form of image-guided radiotherapy without
modification of the original treatment design. A couch
positional adjustment is typically used to realign the
patient. The inter-fractional imaging modalities may be
classified as follows.
LWBK933_Ch14_p229-258.indd 230
2D Radiographic Imaging
Two-dimensional (2D) radiographic (projection) imaging
is typically used in treatment rooms to align the patient
relative to the radiation beams. Megavoltage (MV) elec-
tronic portal imaging (EPI) is the most commonly used
form of radiographic imaging (9,10). MV imaging uses
therapy x-ray beams and an amorphous-silicon (a-Si) flat-
panel imager to verify patient’s setup, defined as the posi-
tion of the skeletal anatomy. Other uses of MV imaging
are to verify treatment beam apertures prior to treatment
(11,12) and in vivo dosimetry during treatment (13).
Because the same therapy MV x-ray beam is used for ver-
ification, it provides direct in-field verification of treat-
ment delivery, and therefore serves as a “gold standard” for
validating new IGRT techniques. Disadvantages of MV
imaging include higher radiation dose to the patient from
the procedure (typically 1–5 cGy) and poorer image qual-
ity due to a large Compton scattering contribution from
the higher x-ray energies. Recently, in-line low-energy
(∼4 MV), with a low atomic number (Z), target (e.g., car-
bon) without beam flattening filter has become available,
which produces portal images of improved soft-tissue
contrast with lower imaging dose (14).
Two general categories of 2D kilovoltage (kV) x-ray
imaging are frequently used for IGRT. One is a gantry-
mounted kV imaging system on a linear accelerator (linac)
that is orthogonal to the therapy MV x-ray beam. The
x-ray source and flat-panel imager are mounted on
retractable arms. Kilovoltage x-ray imaging provides near-
diagnostic quality images. With either kV or MV imaging,
determination of the correction to patient position com-
monly uses orthogonal image pairs that are matched to
digitally reconstructed radiographs (DRRs) derived from
the planning CT as a reference. The second category of kV
imaging is ceiling-mounted systems (15). These systems
provide an oblique orthogonal image pair for stereoscopic
imaging at a wide range of treatment couch angles. Most
kV x-ray radiographic imaging systems have a companion
fluoroscopic imaging mode, which is useful for observing
motion of the internal anatomy or implanted fiducial
markers.
Kilovoltage radiographs are often not sufficient for
detecting soft-tissue targets but are more successful in
aligning skeletal landmarks or implanted radio-opaque
fiducials as target surrogates. In-room kV x-ray imaging
represents a major improvement over MV imaging due to
its superior image quality and its low imaging dose. The
different appearance of kV and MV images, as shown in
Figure 14.2 (thorax), results from the higher proportion of
Compton scattering and high-energy electrons in MV
x-ray beams relative to kV x-rays.
As the kV imaging beam lines are not aligned with MV
beam line, the kV-MV isocenter discrepancy must be
established within a clinical tolerance through initial and
periodic QA processes. The radiation dose from kV imag-
ing is low, typically in the range of 0.01 to 0.1  cGy per
6/1/11 6:43 PM

[Au:
Please
check
figures of
this chapter
for better
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Figure 14.2.  The appearance of anatomy kV (top row) and MV (bottom row) radiographs can be quite different. At kV
x-ray energies, the bony structures are enhanced; at the therapeutic (MV) energies, the air cavity is enhanced. Direct
comparison of kV DRRs with MV portal images can be difficult.
image, which facilitates its use for daily image-guided
patient setup.
3D Tomographic Imaging
CT imaging inside the treatment room provides 3D ana-
tomical information and improved soft-tissue visibility,
thus providing advantages over radiographic imaging. In-
room CT images may potentially be used to reconstruct
dose distributions based on anatomy captured at treat-
ment; its application to adaptive radiation therapy, in
which a patient’s treatment plan is modified in response to
changes in anatomy, is an active area of investigation. In
the following sections, we describe various forms of in-
room CT-based on x-ray systems.
kV Helical CT
Helical single- or multiple-slice CT systems have been
widely used in diagnostic imaging and radiation treatment
planning for many years. The first integrated clinical sys-
tem, which combined a linac unit and conventional CT
unit in the same room was developed by Uematsu et al. at
the National Defense Medical College, Saitama, Japan
(16). The system was designed for noninvasive, frameless
LWBK933_Ch14_p229-258.indd 231
Image-Guided Radiation Therapy  n 231
stereotactic radiotherapy of brain and lung cancers, to
reduce the uncertainty in multi-fractional frame-based
stereotactic radiotherapy. A combination of single-slice
Philips CT scanner and Varian Clinac 2100EX, which used
a rail system to transport the patient between treatment
and CT couches, was assembled at the Memorial Sloan-
Kettering Cancer Center. The system was used for treat-
ment of paraspinal lesions and prostate cancer (17,18).
The first commercial CT-linac system in the United
States was installed in 2000 in Morristown Memorial
Hospital, New Jersey (19). The system consists of a Siemens
medical linac and a moveable Siemens CT scanner that
slides along a pair of rails (“CT-on-Rails”). A picture of
the system is shown in Figure 14.3A. The CT scan is per-
formed with the patient rotated 180 degrees from the
treatment position. The initial clinical experience with this
system has been reported by Wong et al. and Fung et al.
(19,20). A similar “CT-on-Rails” commercial system is
installed at the University of Texas M. D. Anderson Cancer
Center (EXaCT™, Varian Oncology Systems, Palo Alto,
CA). The mechanical accuracy of the system is found to be
within 0.5 mm (21). The system, as shown in Figure 14.3B,
has been recently upgraded with a 6-degree-of-freedom
couch (HexaPOD™, Medical Intelligence, Germany),
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 232 n  Treatment Planning in Radiation Oncology

A B
Figure 14.3.  A: A Siemens Primatom™ CT-on-rails contains a Primus™ linear accelerator and a Somatom™ sliding-gantry CT scanner. The
first Primatom™ was installed at the Morristown Memorial Hospital, New Jersey (Photograph courtesy of Lisa Grimm, PhD). B: A CT-on-rails
system combining a General Electric Smart Gantry™ CT scanner and a Varian 2100EX linear accelerator. A 6-degree-of-freedom couch
(HexaPOD™, Medical Intelligence, Germany) is installed on top of the standard Varian ExaCT™ couch. CT scan of the patient in immobilized
treatment position is acquired after rotating the couch 180 degrees.

which allows for more precise couch translations and
small rotations. The system has been routinely used for
fractionated SBRT, treatment of spinal metastases (22),
and lung cancers. The biggest advantage of an in-room CT
scanner for IGRT is the similarity of the image quality and
fields of view with planning CT images.
kV Cone-Beam CT
Gantry-mounted kV imaging systems are capable of radiog-
raphy, fluoroscopy, and cone-beam CT (CBCT), providing a
versatile solution for IGRT applications (23–25). CBCT
imaging involves acquisition of projection images of the
patient as the gantry rotates through an arc of at least
180 degrees plus the “cone-beam angle” subtended by the
imaging panel (∼200 degrees total). A filtered back-projection
algorithm is used to reconstruct the volumetric images
(26). Geometric calibration of the CBCT system is needed
periodically to maintain image quality and geometric accu-
racy (27). Corrections on the order of 0.2 cm are required
to compensate for the gravity-induced flex in the support
arms of the source, detector, and gantry. Sub-millimeter
spatial resolution has been demonstrated in phantom. It is
possible to reconstruct volumetric images with nearly iso-
tropic spatial resolution, which is useful in cases requiring
high resolution, such as stereotactic radiosurgery. Kilovoltage
CBCT images demonstrate acceptable soft-tissue contrast for
target and organ-at-risk localization.
Since October 2005, all three major manufacturers have
offered CBCT capabilities (Elekta Synergy™, Elekta Inc.,
Sweden; Varian On-board Imager (OBI), Palo Alto, CA;
and Siemens Artiste™, Germany). A picture of the com-
mercial implementation of the kV-CBCT system by Elekta
(Synergy™) and by Varian (TrueBeam™) is shown in
Figure 14.4A and B, respectively. Elekta’s system uses a

A B
Figure 14.4.  A: An Elekta Synergy™ unit (Elekta Inc., Sweden). B: A Varian TrueBeam™ unit (Varian Oncology Systems, Palo Alto, CA). Both
linear accelerators have a kV imaging system orthogonal to the therapy beam direction. Both systems provide 2D radiographic, fluoroscopic,
and CBCT modes.

LWBK933_Ch14_p229-258.indd 232 6/1/11 6:43 PM


slightly larger flat panel detector (41 by 41 cm), compared
to Varian’s detector (40 cm wide by 30 cm long), which limits
the scan length to 15 cm when using the full-fan scanning
mode. A “shifted detector” (or half-fan) technique can extend
the axial field of view (FOV) to at least 40 cm (28). To further
increase the FOV with the existing imager size, Li et al. has
recently proposed an “off-axis” ellipse cone-beam scanning
method, which shifts the center of rotation during CBCT to
increase the sampling outside regular FOV, while sacrificing
the sampling in the center (29).
Limitations of CBCT image quality include elevated
x-ray scatter, which reduces image contrast and introduces
cupping artifacts. Scatter can be reduced by using post-
processing methods (Elekta’s solution) (30) or anti-scatter
grids (Varian’s solution). Because of regulations on gantry
rotation speed (maximum 1 rpm), CBCT image quality is
adversely affected by the breathing motion. The IGRT
setup process may add 5 minutes (1–2 min scan time and
1–3 min for image registration and approval) to the regu-
lar treatment schedule.
MV Helical CT (Tomotherapy)
Tomotherapy (TomoTherapy Inc., Madison, WI) is an inte-
grated technology that combines a helical megavoltage CT
(MVCT) with a linear accelerator, which is specially
designed for delivering intensity-modulated radiation in a
slit geometry. The concept was originally proposed by
Mackie et al. (31,32) and substantially developed by the
University of Wisconsin group (33–37). Helical tomother-
apy refers to the continuous gantry and couch motion,
which, as shown in Figure 14.5A, resembles the motion
from a conventional helical CT scanner. Low-dose, typically
1 to 2 cGy, pretreatment MVCT images are obtained from
the same treatment beam line but with a nominal energy of
A B
Figure 14.5.  A: A picture of tomotherapy unit (TomoTherapy Inc., Madison, WI) (Photograph courtesy of H. Ning, PhD). Tomotherapy is an
integrated IGRT system, which combines a linear accelerator with an MVCT image guidance system. B: A Siemens MV CBCT imaging system
using a conventional linac and a flat-panel EPID. Source: Reprinted from Morin O, Gillis A, Chen J, et al. Megavoltage cone-beam CT: system
description and clinical applications. Med Dosim 2006;31:9.
LWBK933_Ch14_p229-258.indd 233
Image-Guided Radiation Therapy  n 233
4 MV. The CT detector uses an array of 738 channel xenon
ion chambers and an FOV of 40 cm can be reconstructed.
There is no limitation in the superior–inferior direction.
Owing to the use of MV beam for imaging, MVCT
image quality is not as high as that from a diagnostic CT
image: the noise level is higher and low-contrast resolution
is less. Nevertheless, the MVCT images provide sufficient
contrast to verify patient position (37) and to delineate
many anatomic structures (38,39). It is interesting to note
that the MVCT numbers are linear with respect to the elec-
tron density of material imaged, which yields reliable and
accurate dose calculations (40). This capability, together
with the strong research effort in treatment plan optimiza-
tion and image registration by the TomoTherapy group
(41–43), makes tomotherapy appealing as an integrated
solution for image-guided adaptive radiotherapy.
MV Cone-Beam CT
Megavoltage cone-beam CT (MV CBCT) uses the elec-
tronic portal imaging device (EPID) mounted on a linac
gantry and the therapy MV x-ray as a basic configuration
for CT imaging. The initial attempt was performed by
Swindell et al. (44) and subsequently implemented by
Mosleh-Shirazi et al. (45). With recent advance in highly
sensitive EPIDs, particularly a-Si flat panel detectors (46–48),
it has become possible to rapidly acquire multiple, low-
dose 2D projection images with current treatment
machines. Similar to kV CBCT described in previous sec-
tions, a CBCT imaging system uses a large image detector
and a single rotation of the x-ray source to complete the
image acquisition. In addition to the MV x-ray source, the
use of a large-area receptor (EPID) with no effective MV
scatter-reduction mechanism limits image quality. The
amount of scatter reaching the detector depends on the
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 234 n  Treatment Planning in Radiation Oncology
photon energy, field size, and the thickness of the imaged
object; however, the imaging system can be optimized by
calibrating the system using standard site-specific calibra-
tion phantoms (49,50).
Figure 14.5B shows a prototype MV CBCT system from
Siemens. The system consists of a standard treatment unit
(Primus™, Siemens Medical Solutions, Concord, CA) and
an a-Si flat-panel adapted for MV photons on a retractable
support. The 41 × 41 cm flat-panel x-ray detector (AG9-ES,
PerkinElmer, Optoelectronics) consists of a 1 mm copper
plate and a Kodak Lanex fast scintillation plate (Gd2O2
S:Tb) overlaid on a light-sensitive and charge-integrating
thin-film transistor (TFT) array. Due to a more stringent
requirement for geometric integrity, a calibration proce-
dure is required to correct for mechanical support sag
(49,50). The image acquisition lasts ∼45 seconds with gan-
try rotation over a 200-degrees arc, at a rate of one image
per degree. Image reconstruction time is less than 2 min-
utes for a 256 × 256 × 270 image volume (0.7 mm3 voxel
size). Imaging dose ranges from 2 to 8 cGy (51).
The MV CBCT system has good image quality for bony
structures and acceptable quality for soft-tissue targets,
due to the higher imaging dose. An advantage of both MV
CBCT and MVCT systems is the reduced influence of
implanted metal objects on image quality, in contrast to
kV CT, which exhibits strong artifacts when high-Z mate-
rial is present. MVCT images thus provide complementary
information, which cannot be discerned in conventional
CT images (Fig. 14.6). An additional advantage of MV
Figure 14.6.  Images showing the artifacts due to the presence of metal
objects in the conventional kV CT images (left panels). Artifact-free
images were obtained with a MV CBCT (right panels). Source:
Reprinted from Morin O, Gillis A, Chen J, et al. Megavoltage cone-beam
CT: system description and clinical applications. Med Dosim 2006;
31:11.
LWBK933_Ch14_p229-258.indd 234
CBCT is that the physics of absorbed dose from a thera-
peutic MV beam is well understood, thus enabling accu-
rate calculation of dose from an MV CBCT scan that could
be included in the treatment plan (51). Soft-tissue contrast
is the principal limiting factor of MV CBCT systems.
Investigators at the University of California San Francisco
have used a lower-Z target material, which generates more
low-energy photons and enhances image contrast (49).
One study showed that removal of the flattening filter
improved contrast by 200% (52).
Digital Tomosynthesis
Digital tomosynthesis (DTS) is a special situation of
tomographic reconstruction, which uses limited arc (20 to
40 degrees) of projection images (53–55). The reconstruc-
tion planes are approximately perpendicular to the direc-
tion of the x-ray beam at the arc center. They do not have
to go through the isocenter, but can be at different depths
in the patient. In some methods, reconstruction is fol-
lowed by a procedure to suppress out-of-plane objects
(56,57). The principal advantage of DTS over CBCT is the
shorter scan time, which is typically less than 10 seconds.
DTS provides soft-tissue image visualization, which can be
improved in respiratory disease sites by combining with
breath-hold or respiration correlation of the projection
images (58).
Depending on the acquisition arc length, spatial resolu-
tion is less in the direction perpendicular to the recon-
structed planes, which can be addressed by acquisition of
a second DTS from a quasi-orthogonal direction to the
first. Reference DTS images can be calculated from the
planning CT, similar to the calculation of DRRs (59). A
comparison of the conventional CT, CBCT, and DTS
images of the same patient is shown in Figure 14.7.
Hybrid Cone-Beam CT
Combining kV and MV projection images for CBCT recon-
struction has been reported (60). A hybrid CBCT can be
achieved by combining orthogonal kV and MV x-ray pro-
jection images with a partial arc gantry rotation as little as
90 degrees (61). The resultant projection images span an arc
length of 180 degrees. Acquisition requires only 15 seconds,
making it optimal for breath-hold imaging.
4D Computed Tomography Imaging
Respiratory motion is one of the important factors in the
management of radiation therapy for moving tumors,
which can have displacements up to 3 to 4 cm (62). CT
scans acquired synchronously with the respiratory signal
can be used to reconstruct a set of (3D) CT scans, repre-
senting the 3D anatomy at different times (or respiratory
phases). This collection of 3D CT data sets is called respi-
ration-correlated CT (RCCT), or 4D CT, which describes
the snapshots of patient’s 3D anatomy over a periodic
respiratory signal. Typically, the breathing cycle is divided
6/1/11 6:43 PM

Figure 14.7.  A coronal planar image reconstruction based on conventional kV CT (left), CBCT (middle), and digital tomosynthesis (DTS, right)
(Photograph courtesy of Fang-Fang Yin, PhD).
into 10 respiratory phases. Four-dimensional medical
imaging techniques has been reviewed recently (63).
Respiration-Correlated CT
The approach common to RCCT methods is to acquire
sufficient data for generating CT images at all phases of
the respiratory cycle while simultaneously recording res-
piration, then retrospectively correlating the CT images
with phase. CT acquisition uses either a cine or helical
mode. In cine mode, repeat CT slices are acquired over
slightly more than one respiratory cycle with the couch
stationary while recording patient respiration; the couch
is then incremented and the process repeated. Following
acquisition, the images are sorted with respect to the respi-
ratory signal, leading to a set of volume images at different
respiration points in the cycle (64,65). Helical acquisition
uses a low pitch and adjusting the gantry rotation period
such that all voxels are viewed by the CT detectors for at
least one respiratory cycle (66,67). RCCT images have
been widely characterized and applied clinically for esti-
mating the extent of a moving tumor in lung (68–70).
The selection of the type of respiratory signal can vary,
which may change the interpretation of the RCCT images;
however, a periodic motion is always implied. Deviations
from the regular periodic motion will have an impact on
the quality of RCCT images and on the accuracy of anat-
omy discerned from these images. Commercial systems
commonly use one of the two types of respiratory moni-
tors. One such monitor (Real-time Position Management,
RPMTM, Varian Oncology Systems, Palo Alto, CA) cap-
tures the up/down motion of a box with infrared reflectors
placed on the patient’s abdomen or chest using an infrared
camera. The other is a “pneumo bellows” system (Phillips
Medical Systems, Milpitas, CA) that records the digital
voltage signal from a differential pressure sensor wrapped
around the patient’s abdomen. RCCT scans can be used in
so-called 4D treatment planning to explicitly account for
tumor motion (63,68,70,72,73).
LWBK933_Ch14_p229-258.indd 235
Image-Guided Radiation Therapy  n 235
CT images are sorted based on a respiration phase
angle assigned by an algorithm that determines the peri-
odic behavior of the respiratory signal. Phase-based sort-
ing assumes repeatable breathing cycles, that is, that the
anatomy is at same position for a given phase in every
cycle, which is usually not the case for normal breathing
with its varying cycle-to-cycle amplitude variations, and
has led to investigations into sorting based on the dis-
placement of the respiratory signal (71,74–76).
Respiration-Correlated CBCT
A limitation of CBCT systems is image degradation caused
by patient motion artifacts, which is a consequence of the
limited gantry speed and the resultant long (∼1  min)
acquisition times. Respiratory motion in particular
degrades images in the thorax and abdomen. Different
methods are under active investigation to reduce motion
in CBCT. One approach is respiration-correlated CBCT
(RC-CBCT) using retrospective sorting of projection
images into different breathing phases (77,78). A slower
gantry rotation is required to acquire sufficient projec-
tions in each phase bin, resulting in scan times of 3 to
6 minutes. The limited number of projections per phase
reduces the contrast resolution and introduces image view
artifacts; thus, the method is more suited to detecting
high-contrast objects such as tumor in parenchymal lung
(77–79).
An alternative approach is to process the CBCT images
to correct for motion, using a motion model of the patient
(80–84). Most of the methods make use of deformable
image registration (DIR) to deform the images to a com-
mon motion state.
Non-radiographic Imaging
Ultrasound Imaging
Ultrasound is a noninvasive, non-radiographic, and real-time
imaging technique for soft-tissue targeting in radiotherapy,
6/1/11 6:44 PM
 236 n  Treatment Planning in Radiation Oncology
particularly for prostate cancer, but also for upper abdom-
inal malignancies (85–89). Fung et al. have recently
reviewed ultrasound guidance for IMRT (90).
The ultrasound transducer, which is made of the piezo-
electric crystal, is both a sound source and a sound detec-
tor. An ultrasound transducer transmits brief pulses of
ultrasound that propagate into the tissues. Whenever there
is a change in acoustic impedance, for example, owing to
the tissue density or elasticity changes at the interface of
two organs, some of the ultrasound will be reflected back
to the transducer as echoes. The round-trip time from the
pulse transmission to reception of an echo is used to deter-
mine the transducer-to-object distances. A scan line con-
verter will construct a 2D image of the patient, in which the
amplitude of echoes varies along depth direction. When
sweeping the ultrasound through a volume, a 3D ultra-
sound image can be constructed. The basic principles of
this imaging technique limit its use to soft-tissue structures
and tumors in pelvic, abdominal, and breast locations.
Although ultrasound has been widely used in patient
setup, inherently poor image quality and the unfamiliar
appearance of ultrasound images for radiation therapists
have limited its potential for more precise image guidance.
Figure 14.8 shows a pair of ultrasound images (top row)
Figure 14.8.  A pair of ultrasound images is shown in the top row. The images were acquired from an ultrasound-guided alignment system
(BAT™, NOMOS, Chatsworth, CA). A pair of CT images of the same patient is shown in the bottom row. The CT images were acquired using
an in-room CT-on-rails scanner within 5 minutes of the ultrasound image acquisition. The alignment relative to the planning CT by these two
independent systems was within 2 mm.
LWBK933_Ch14_p229-258.indd 236
and corresponding CT images (bottom row) for a prostate
cancer patient undergoing ultrasound-guided setup (91).
In this example, the agreement between ultrasound and CT
alignments is within 2  mm. It has been shown that the
inter- and intra-user variability is large for ultrasound-
guided setup, mainly because of the poor image quality,
anatomic distortion due to pressure variation and inade-
quate user training (86,92). When compared with
implanted fiducial markers for prostate localization, the
ultrasound alignment displayed even more variations (93)
and a larger planning margin is recommended (94). Dobler
et al. studied the displacement of prostate when acquiring
transabdominal ultrasound images (95). X-ray simulations
were performed before and during ultrasound image
acquisition for 10 patients who had undergone iodine-125
seed implantation. The seeds, which were visible in x-ray
images, were used to represent prostate position. A maxi-
mum displacement of the prostate of 2.3 mm in anteropos-
terior and 1.9  mm in craniocaudal direction and a
rotational change of up to 2.5 degrees were observed. If the
system was not handled correctly and too much pressure
was applied, a shift of the prostate of up to 10 mm could be
induced. Tome et al. has reported on ultrasound commis-
sioning and QA procedure for radiation therapy (96).
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Stereoscopic Optical Surface Imaging
Stereoscopic optical surface imaging (OSI) provides real-
time imaging capability, primarily used in patient setup
for superficial tumors, such as the breasts, or immobile
tumors such as in the head. One currently available OSI
device (AlignRTTM, VisionRT, Ltd., London, UK) is com-
posed of two to three ceiling-mounted stereo-camera
pods, each contains two cameras and a speckle pattern
projector. The triangulation between the fixed stereo cam-
eras and a skin point identified by the speckle pattern
serves to calculate their distances and the location of the
point in space. A patient skin surface image is recon-
structed from the visible surface points. The accuracy of
the surface imaging is within 1.0 mm.
Because OSI does not visualize the tumor, it requires
substantial validation against another established image
modality, such as radiographic imaging. Early studies of
surface imaging in radiotherapy have been reported by
Massachusetts General Hospital (97) and Johns Hopkins
University (98) in 2005. Validated with x-ray imaging, OSI
provides a quick and non-radiologic means for image-
guided setup. It has been applied in breast, lung, brain, and
head and neck. The common procedure for patient setup
is to register the surface image to a reference region of
interest (ROI) defined on the delineated patient surface in
a simulation CT.
Magnetic Resonance Imaging
MRI is based on the radiofrequency signal from the relax-
ation process of the dipole moment of an atom with
unpaired proton, such as 1H in tissue, after it is excited
with a radiofrequency pulse sequence in the presence of an
external magnetic field. The field strength is ∼0.2 Tesla (T)
for open-field MRI and 1.5 T or 3 T for a regular MRI
scanner. The geometric location of the signal is deter-
mined using the field gradient, phase and frequency
encoding. The soft-tissue heterogeneity provides an envi-
ronment that alters the relaxation process, thus providing
high soft-tissue contrast.
MRI imaging is more versatile than radiologic imaging,
as it provides different image appearances when different
pulse sequences are applied, such as T1-weighted,
T2-weighted, and fast fluid-attenuation inversion recovery
(FLAIR) (99). These MRI images are often used in delin-
eating a tumor or postoperation cavity and evaluating
local edema, especially for brain cancer. MRI can also pro-
duce non-axial scans in any spatial orientation. Like radio-
logic imaging, MRI can produce 2D planar, 3D volumetric,
and 4D volumetric set images (63). Four-dimensional
prospective volumetric MRI imaging has been utilized in
radiotherapy (100).
MRI may suffer from geometric distortion due to non-
uniformity of the external magnetic field strength. This
scanner-specific factor can be corrected by measuring the
field gradient with a large grid phantom (101). MRI does
not produce a visible image in bone due to little relaxation
LWBK933_Ch14_p229-258.indd 237
Image-Guided Radiation Therapy  n 237
in the solid phase. A limitation for radiotherapy applica-
tions is that an MR image cannot be easily converted to
electron density, which is essential for dosimetry calcula-
tion in a treatment planning system. Recently, MRI-based
treatment planning has been reported (102–104).
Several MRI-guided radiotherapy systems are currently
under development. Such systems offer not only in-room
soft-tissue-based target alignment, but also near real-time
MRI volumetric imaging for tumor motion monitoring.
The section “MRI Real-Time Volumetric Imaging” discusses
these systems in more detail.
Intra-Fractional Real-Time Imaging
and Motion Compensation
The main goal of real-time tracking is to minimize the
effect of target motion not only between treatments, but
also during a treatment fraction. Real-time tracking usu-
ally requires real-time motion monitoring (detection) and
the execution of correction with the shortest time delay. In
almost all cases, implanted markers are used as surrogates
for target position. Therefore, the proximity of the mark-
ers to the target and their motion relative to the target are
important factors in their reliability for a real-time track-
ing system. In the following sections, we review different
approaches for real-time monitoring and tracking.
Fluoroscopic Imaging with Implant Fiducials
Commercial fluoroscopy-based tracking systems can be
categorized into (1) room-mounted and (2) linac gantry-
mounted systems. The primary reason for using fluoro-
scopic imaging is to detect metal fiducials, which are
implanted in or near the tumor. The fluoroscopic images
can be matched to a reference DRR.
A very interesting, room-mounted system for real-time
tracking has been developed by Shirato et al. in collabora-
tion with Mitsubishi at the University of Hokkaido
(105,106). It uses a pair of x-ray tubes that rotate on a
circular track embedded in the floor, as shown in Figure
14.9A. Each tube has a corresponding x-ray detector that
rotates synchronously on a ceiling-mounted track, so as to
avoid obstruction of the patient by the treatment gantry.
The x-ray tubes allow pulsed imaging interlaced with linac
pulses to treat the patient. The radio-opaque marker
images are tracked with pulsed fluoroscopy prior to the
beginning of the treatment and patient is repositioned so
that the end of one of the tracks corresponding to the least
mobile portion of the motion is within a predefined gating
window. During irradiation, fluoroscopy continues and the
beam is automatically switched on when the detected
image of the fiducial is within the window; otherwise, it is
turned off.
A commercially available room-mounted system, as
shown in Figure 14.9B, is developed by BrainLab (ExacTrac™,
BrainLAB AG, Feldkirchen, Germany). The ExacTrac is an
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 238 n  Treatment Planning in Radiation Oncology
A B
Figure 14.9.  Two room-mounted kV image-guided IGRT real-time tracking systems. A: A real-time tracking radiation therapy (RTRT) system
(Photograph courtesy of Hiroki Shirato, MD, PhD). B: ExacTrac system, BrainLAB AG, Feldkirchen, Germany (ExacTrac® is a trademark of
BrainLAB AG in Germany and the United States.)
integrated IGRT system for target localization, setup
correction, and the delivery of high-precision stereotactic
radiotherapy and stereotactic radiosurgery. The image
guidance utilizes two distinct imaging subsystems: a real-
time infrared (IR) tracking and a kV stereoscopic x-ray
imaging subsystem. Two ceiling-mounted IR cameras are
used to monitor the movement of infrared-reflecting mark-
ers placed on patient’s skin or on the reference frame
mounted on the treatment couch. The marker images are
automatically compared to stored reference, generating ini-
tial couch shift instruction to set up the patient. The x-ray
imaging system performs further internal target alignment
based on either bony landmarks or implanted fiducial
markers. The reference DRRs are provided by the BrainLab
treatment planning system. During treatment delivery, the
IR tracking system and the fluoroscopic x-ray imaging sys-
tem work together to monitor target position and to per-
form treatment interventions. The external fiducial markers
can be “tuned” to the internal fiducial markers during a pre-
treatment verification procedure. Two types of treatment
interventions can be performed: adaptive gating of the
treatment beam or real-time correction of target offset by
using a 6D robotic couch (ExacTrac™, BrainLAB AG, Feld-
kirchen, Germany). CyberKnifeTM system (Accuray Inc.,
Sunnyvale, CA) has also its own room-mounted stereo-
scopic x-ray imaging system and 6D robotic couch. Research
and clinical experience of using these systems have been
reported by various groups (107–110).
Gantry-mounted kV imaging systems usually have only
one kV x-ray imager and achieve the orthogonal pair by
rotating the gantry. These systems include Varian’s On-
board Imager (OBI) and Elekta’s Synergy. These kV imag-
ing beam lines are orthogonal to the MV treatment beam
line (EPID), sharing the same isocenter of gantry rotation,
as shown in Figure 14.4. The gantry-mounted kV imaging
system is not blocked by the treatment unit, but it may
have limited clearance or the potential for collision with
LWBK933_Ch14_p229-258.indd 238
the immobilization device or the couch. The kV-MV con-
figuration provides a possibility to acquire images during
treatment (111). To avoid scatter interference between the
two x-ray beams, alternating the beam-on time may be
used (113).
A prototype kV-MV dual in-line imaging system is
commercially available (ArtisteTM, Siemens Medical Sys-
tems, Germany) (113,114). This is achieved by placing the
kV x-ray tube in a retractable lower shelf. The kV image
detector is mounted just below the MV collimator. The
MV therapy beam must penetrate the kV image detector
to treat the patient. This design allows for simultaneous
imaging of the beam shaping device (MLC-collimated
beams) and patient’s anatomy for beam-by-beam verifica-
tion of treatment delivery or motion compensation.
Optical Fiducial Motion Surrogates
Optical tracking determines an object’s position by mea-
suring light either emitted or reflected from the object.
The hallmark of optical tracking systems is their high spa-
tial and temporal resolutions (0.1 mm and <0.1 s, respec-
tively) in tracking infrared markers attached to the
patient’s external surface. The positions of the optical
markers relative to the target volume, together with the
desired marker positions relative to the treatment isocen-
ter, are determined during CT simulation. In the treat-
ment room, the real marker positions are measured
relative to isocenter; a rigid-body transformation deter-
mines marker displacements from their desired positions
and hence target displacement from the isocenter. Real-
time feedback allows one to correct the patient’s position
continuously during treatment. Meeks et al. have reviewed
the technology in several implementations for intracranial
and extracranial stereotaxis radiotherapy (115). The first
systems used rigid arrays of optical markers that were
attached to the patient via a biteplate linkage. Subsequent
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 Image-Guided Radiation Therapy  n 239

systems for extracranial radiotherapy tracked external

markers to determine the patient position and/or gate the
radiation beam based on patient motion.

Video-Based 3D Optical Surface Imaging

Real-time 3D-surface matching has been characterized for
clinical use (97,98,116). The reference surface image is
either a 3D optical surface image acquired at simulation or
a CT/MRI-surface rendering from the treatment plan. The
real-time 3D surface images are captured by stereoscopic
video cameras mounted on the ceiling of the treatment
vault. A fast automatic alignment between the real-time
surface and the reference surface using a modified iterative-
closest-point method leads to an efficient and robust sur-
face-guided target refixation. Experimental and clinical
results demonstrate the excellent efficacy of <2 minutes
set-up time and high accuracy and precision of <1 mm in
isocenter shifts and <1 degree in rotation (116).
The AlignRT system has been described in a previous
section for patient alignment. In addition, it offers capa-
bilities for real-time motion monitoring. Due to pro-
cessing time required for image reconstruction, it only
provides prospective imaging at one to five frames per
second (fps), far below its maximum capture rate
Figure 14.10.  A diagram showing the prototype AC electromagnetic
(∼15 fps), (117) depending upon the size and resolution field tracking system with the detector array and the infrared cameras
of ROI. Several investigators have shown that this real- (Calypso Medical Technologies, Inc., Seattle, WA) The Beacon™ tran-
time surface imaging capability can be applied to head sponder is shown in the inset.
motion monitoring during frameless stereotactic radio-
therapy or radiosurgery (118,119). Using a 3D optical
surface image acquired at treatment as reference, sys- MRI Real-Time Volumetric Imaging
tematic errors of the imaging system can be cancelled
out and achieve a sub-millimeter accuracy for motion Another innovative technology being developed for radia-
detection. tion therapy applications is an integrated MRI-guided
gamma ray IMRT system (Renaissance System™, ViewRay,
Real-Time Electromagnetic Inc., Gainesville, FL). A schematic diagram of the IG-
Localization and Tracking IMRT system is shown in Figure 14.11. The system con-
sists of a low-field open MRI system and three Cobalt
Continuous tracking of target position without ionizing irradiation sources; the latter was chosen for its compati-
radiation is possible with a novel technology utilizing AC bility with the MRI system. The computerized multileaf
electromagnetic fields to induce and detect signals from collimator system provides gamma-ray intensity modula-
implanted “wireless” transponder (Calypso Medical Tech- tion equivalent to linac-based IMRT systems. The thrust
nologies, Inc., Seattle, WA). The system consists of a console, of the technology is the MRI-guided, real-time volumetric
optical tracking system, and a tracking station. The console imaging system, which can track patient’s 3D anatomy
instrument is situated in the treatment room and includes a every 0.5 to 2.0 seconds without interrupting the treat-
display screen and the AC magnetic array (Fig. 14.10). The ment delivery. As stated earlier, MRI has superior soft-
magnetic array is lightweight and contains source coils tissue contrast, which can be used for better definition and
that generate signals to excite the transponders, and sensor tracking of target volumes. As an integrated imaging,
coils that detect the unique response signals returned by adaptive treatment planning and dynamic delivery system,
each transponder. Unlike passive fiducial markers, the this promising technology is perhaps the only “near” real-
Calypso system can actively detect the position of tran- time, volumetric soft-tissue targeting system. Because of
sponders without using the radiographic method. The the known limits of the Cobalt source, such as low energy
Calypso 4D Localization System can update target posi- and large penumbra, the plan quality is compromised.
tion 10 times per second, which is sufficiently fast to track Recently, there has been development of integrated MRI-
breathing motion of the tumor. Sub-millimeter tracking linac systems, thus combining the advantages of high soft-
accuracy and clinical experience in prostate target local- tissue discrimination for tracking and linac quality radiation
ization has been reported (120–124). treatment (125–127). There are two designs, with the

LWBK933_Ch14_p229-258.indd 239 6/1/11 6:44 PM

 240 n  Treatment Planning in Radiation Oncology
Figure 14.11.  A schematic of a prototype MRI-guided real-time volumetric tracking system for IGRT (Renaissance System™, ViewRay, Inc.,
Gainesville, FL). The system is designed to have a low-field open MRI for real-time imaging and three-headed Cobalt source for intensity-
modulated gamma ray irradiation (Photograph courtesy of James Dempsey, PhD).
radiation beam either parallel or perpendicular to the mag-
netic field. A nontrivial technical task is to shield the mag-
netic field from the linac in transporting electrons to the
target. In addition, the presence of magnetic field affects the
motion of the scattered secondary electron scatters, thereby
distorting the dose distribution. Nevertheless, integrated
MRI-linac systems promise high-precision radiation dose
delivery guided by high-quality soft-tissue visualization.
Real-Time Tumor Motion Compensation
Real-time tracking refers to continuous adjustment of the
radiation beam or patient position during treatment so as to
follow the changing position of the tumor or its surrogate. A
means of localizing the target in real time is coupled to the
repositioning control system. In principle, real-time tracking
provides more efficient treatment than gating, in that the
beam duty cycle is at or near 100%, while reducing the mar-
gin needed for target motion. In the following sections, we
summarize three strategies in various stages of development
involving motion tracking of a linac system.
Dynamic Multi-leaf Collimator Approach
Keall et al. have demonstrated motion tracking using
dynamic MLC (DMLC) (128). The Calypso electromag-
netic system can provide a near real-time signal of prostate
motion with <2 mm accuracy and 220 ms system latency
(123). One concern of this motion compensation
approach is the anisotropic spatial resolution. Depending
on whether the motion is along or perpendicular to the
leaf motion, the spatial resolution is either <1 mm (the
leaf motion accuracy) or 5 mm (the leaf width), respec-
tively. The mechanical motion limitations of MLC pose
constraints when DMLC is used simultaneously for
motion tracking and IMRT delivery. Investigators have
examined different strategies to optimize leaf trajectories
for this purpose (129,130).
LWBK933_Ch14_p229-258.indd 240
Mobile Treatment Couch Approach
D’Souza et al. have proposed compensation of the tumor
motion using a mobile couch (131). Unlike the DMLC
approach, this method compensates for 3D tumor motion
with isotropic spatial resolution; however, there may be
patient-related physical and medical concerns. For
instance, couch motion could induce a counterreaction
from the patient, body shift, or tissue deformation when
changing motion directions, especially for obese patients.
Clinically, a patient may feel dizziness or nausea. Recently,
a dynamically adjustable head support was developed for
repositioning and for potentially tracking head motion in
6D (translations and rotations) with sub-millimeter accu-
racy in frameless stereotactic radiotherapy (132,133). As
the head is fairly well immobilized with a thermoplastic
mask and/or head mold, the motion is slow and the
motion range is on the order of 1 to 3 mm. Therefore, the
compensating motion for repositioning would be small
and slow, posing little or no clinical concerns.
Movable Gantry Approach
The CyberKnifeTM (Accuray Inc., Sunnyvale, CA) is an
intelligent robotic IGRT system consisting of a small
X-band linear accelerator mounted on a 6D robotic arm
and a 6D robotic couch for patient alignment. The robotic
arm can move at a speed of several centimeters per second,
which allows it to keep up with breathing-induced tumor
motion. The room-mounted x-ray stereoscopic guidance
system provides IGRT setup as well as real-time tracking
for image-guided radiosurgery applications, as depicted in
Figure 14.12A. An optical tracking system of IR reflectors
on a vast worn by the patient provides a real-time target
motion signal that is confirmed by periodic x-ray imaging.
The CyberKnife is the first clinical radiotherapy system to
use real-time motion compensation and has accumulated
a wealth of data on the experience of tracking moving tar-
gets in a wide variety of treatment scenarios (134–136).
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 Image-Guided Radiation Therapy  n 241

A B
Figure 14.12.  A CyberKnife system (Accuray Inc., Sunnyvale, CA) is shown in (A). A VERO system (BrainLAB AG Feldkirchen, Germany and
Mitsubishi Heavy Industries, Tokyo, Japan) is shown in (B) (Photograph courtesy of Dirk Verellen, PhD). Both systems offer quick gantry movement
aiming to a moving tumor, guided by room-mounted or gantry-mounted stereoscopic x-ray imaging systems.

Clinical experience in frameless image-guided cranial
(137,138), spinal (139–141), pancreatic (142), and lung
radiosurgery (143,144) has been reported.
The VEROTM system is a joint development by BrainLAB
AG (Feldkirchen, Germany) and Mitsubishi Heavy Indus-
[AQ4] tries (Tokyo, Japan). It is based on a gimbal design, as shown
in Figure 14.12B, such that the radiation gantry can rotate
quickly to track a moving tumor (145–147). For both pan-
ning and tilting rotations, the maximum motion range at
treatment isocenter is 4.4 cm (or 2.5 degrees). The response
lag time is <50 ms for both panning and tilting rotations.
With system lag compensated by using a predicting model,
sub-millimeter accuracy of motion tracking has been
achieved in initial tests (147). One prototype, installed in
UZ Brussels Hospital, the Netherlands, is equipped with an
EPID for portal imaging and two orthogonal kV imaging
systems that are 45 degrees from the MV beam. CBCT capa-
bility is available and patient position corrections are pro-
vided by a BrainLAB 5DOF robotic couch that is integrated
in the system. Although more characterization studies of
the system are needed, initial tests have shown its potential
for tumor motion tracking.
Igrt Requirements and Considerations
IGRT Commissioning and Quality Assurance
Commissioning and QA of all IGRT-enabled technologies
are essential. In the past few years, the American Associa-
tion of Physicists in Medicine (AAPM) has issued several
task group (TG) reports, covering in-room kV x-ray imag-
ing for patient setup and target localization (TG #104)
(148), medical accelerator QA (TG #142) (149), stereotac-
tic body radiation therapy (TG #101) (150), and manage-
ment of respiratory motion (TG #76) (62). These reports
provide guidelines for clinical use and QA of the IGRT
imaging systems and procedures. In the following, we
summarize three important aspects: geometric accuracy,
image quality, and motion detection.
Clinical “Gold Standard” for IGRT
One of most important tasks in commissioning an in-room
imaging modality is to compare the imaging isocenter with
the treatment isocenter. Traditionally, it is paramount to
check the alignment of radiation isocenter, mechanical iso-
center, and laser isocenter. When using IGRT imaging
modalities, their isocenter coincidence with the treatment
radiation isocenter must be initially and periodically
checked to assure a clinically acceptable tolerance on their
discrepancy. The MV EPID is used as the gold standard as it
provides direct reference to the treatment beam line. For
stereotactic procedures, the discrepancy should be within
1.0 mm; otherwise, it should be within 2.0 mm (149). Due
to the stringent geometric accuracy requirement for the
alignment of the OBI and EPID detectors, a calibration pro-
cedure is required to correct the mechanical sagging
(27,49,50,151). Customized QA phantoms have been devel-
oped for different IGRT systems, including kV and MV
imaging systems of a linac (149,152) and MVCT imaging
system of a helical tomotherapy (153,154).

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 242 n  Treatment Planning in Radiation Oncology
Imaging Quality QA
Bissonnette and coworkers have established QA program for
CBCT imaging quality with the Elekta Synergy and Varian
OBI systems. The description includes flat-panel detector
stability, performance and image quality of 10 volumetric
imaging systems over a period of 3 years (155). Details on
correcting background (dark current) and pixel-by-pixel
gain uniformity (flood image) of the plat-panel detector are
discussed. Similar to diagnostic imaging QA, the CatPhan
500 phantom (The Phantom Laboratory, Salem, NY) is used
to quantify image quality (156,157). A comprehensive QA
program by Yoo et al. covers safety and functionality, geo-
metric accuracy, and image quality for the Varian OBI sys-
tem (158). Image quality characterization and QA procedures
for EPID (159), MV CBCT (160), and MVCT in helical
tomotherapy (154) have also been reported.
Non-gantry mounted x-ray imaging and non-radiolog-
ical imaging have been reviewed by Bissonnette (155),
including the commissioning of image-guided technolo-
gies and procedures, QA of geometric accuracy and imple-
mentation of a clinical IGRT QA program. A stereotactic
head phantom (Model 605 Radiosurgery Head Phantom;
CIRS, Norfolk, VA) or equivalent is used for imaging QA
of the CyberKnife system (155,161).
Motion-Related QA Processes
In AAPM TG #142 (149), x-ray (MV and kV) 2D radio-
graphic imaging, 3D tomographic (fan-beam and cone-
beam) imaging, and 4D imaging are included as part of
the QA process for medical accelerators. For 2D fluoro-
scopic imaging, the temporal resolution should be 100 ms
or less, which will produce a uncertainty <2  mm for a
moving object at a speed no greater than 2 cm/s. Jiang et al.
have laid out major clinical QA challenges in respiratory-
related procedures, including respiratory gating, breath
holding, and 4D CT imaging (162). As external surrogates
are used in most respiratory gating and breath holding,
the authors conclude that the biggest challenge is how to
ensure treatment accuracy in these cases. Indeed, many
reports have discussed the unreliability of the internal–
external correlation using external fiducials, such as IR
reflectors for motion monitoring. When external respira-
tory fiducial markers are used, a pretreatment calibration
and during-treatment verification against x-ray radio-
graphic imaging is needed. Clinical motion management
guideline has been published in AAPM TG #76 (62),
covering respiration-induced motions of the target and
normal tissue.
Image Registration
Image registration quantitatively aligns the daily 3D or 2D
setup images with the planning CT volume or DRR images,
respectively. Such image registrations can be suboptimal as
the underlying anatomy changes, including daily motion,
deformation, or physical changes. Clinically, the focus on
LWBK933_Ch14_p229-258.indd 242
registration of the tumor position is commonly accepted.
Visual verification, together with manual adjustment, is
necessary for automatic registration. Most visual verifica-
tion is performed in three orthogonal planar views using
color blending, checkerboard, split windows, and differ-
ence images. A 3D volumetric visualization to seek most
homogeneous color distribution of mono-color images on
a volumetric anatomical landmark has been reported with
greater spatial accuracy for rigid anatomy (163,164). Image
registration method QA should be performed using an
appropriate phantom. A QA procedure for image registra-
tion and segmentation has been reported (165).
Rigid Image Registration
Most registration tools, which are used for image-guided
patient setup, belong to rigid image registration with up to
six degrees of freedom (6DOF or 6D). Owing to limitation
of the standard treatment couch, three or four DOF are
usually employed, unless a 6D robotic couch is available.
As patient motion and deformation is inevitable, rigid
image registration has limited accuracy. In addition, inter-
observer variation for manual image registration is well
known. The registration accuracy, couch adjustment accu-
racy, kV-MV isocenter discrepancy, and couch walk for
non-coplanar beams determine the overall setup accuracy
for tumor localization.
Locally focused rigid image registrations are more clin-
ically relevant in the presence of tissue deformation.
Zhang et al. (166), Van Kranen et al. (167), and Giske et al.
(168) have reported using multiple ROIs for rigid registra-
tion and evaluated the local deformation among the three
to nine different ROIs in the head and the neck region.
Park and coworkers have developed a spatially weighted
image registration method to allow users to define the
structure of interest, such that a better registration result
is achieved with respect to the structure of interest (169).
Manual intervention of the semiautomatic registration
using visual guidance is always required.
Deformable Image Registration
DIR is not suitable for setup correction with simple couch
shifts, as rigid transformation cannot compensate for tis-
sue deformation. Nevertheless, DIR is essential for evalu-
ating cumulative delivered dose distribution, and therefore
necessary for adaptive actions to compensate for potential
dosimetric deviation from what was planned in the
remaining treatment fractions. DIR has been intensively
studied (42,170–173) and is an important tool in present-
ing developments of high-precision radiotherapy. Indeed,
many clinical studies using DIR have been reported since
2007, including automatic segmentation and dose distri-
bution mapping for adaptive radiotherapy (174–179).
In the IGRT context, DIR plays a significant role in the
following three areas. First, it can track a deformed anat-
omy voxel by voxel from deformed images to a reference
image, producing a deformation transformation matrix,
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Figure 14.13.  Automated image segmentation of multiple repeat CT data sets. In this head-and-neck example, contours drawn manually on the
planning CT were deformed to obtain contours for repeat CT scans obtained during the course of radiotherapy. Deformations were carried out
using transformation matrices based on deforming planning CT image to match each of the repeat CT images. Such automatic segmentation
tools, once validated by clinical studies, would make adaptive replanning practical.
which is useful in studying tumor and organ motion.
Zhang et al. have illustrated that the combination of DIR
with principal component analysis (PCA) provides a
patient-specific motion model (180). Such a DIR-PCA
approach has been further developed to predict lung tumor
location based on single x-ray projection image (181).
Second, the deformation transformation matrix can be
used for mapping segmented anatomic ROIs, such as
delineated tumor and organs at risk, from a reference
image to other deformed images. Such an auto-contour-
ing technique is essential for 4D and adaptive radiother-
apy, as illustrated in Figure 14.13. Wijesooriya et al. have
studied the accuracy of the automated segmentation
among different phase CT images in 4D CT by comparing
692 pairs of automated and physician-drawn contours.
The surface congruence of the gross tumor volume (GTV)
and all organs was within 5 mm in >90% of all cases (178).
Wang et al. have studied the use of deformable registration
to propagate contours in daily CBCT for both lung and
head-and-neck cancer patients, and found the volume
overlap index to be 83% between the deformed and the
physician-drawn contours (175). Physician evaluation of
these automated contours is highly recommended, espe-
cially in the presence of motion and metal artifacts.
Third, the deformation transformation matrix can be
applied to map a dose distribution that is calculated based
on static volumetric CT images to a reference volumetric
image (128,182). At the end, a cumulative dose distribu-
tion can be determined for evaluating delivered radiation
dose using daily setup images and for 4D planning based
on all phase CTs within a 4D CT image set (183). In IGRT,
the principal advantage of DIR is to track radiation doses
deposited in a deformed organ over the course of fraction-
LWBK933_Ch14_p229-258.indd 243
Image-Guided Radiation Therapy  n 243
ated treatment, which is a basis for image-guided adaptive
radiotherapy (184–186).
Information Technology Infrastructure for IGRT
With the increasing use of highly conformal treatment
techniques, such as IMRT, VMAT, and SBRT, the need for
image guidance is mounting at every stage of the radio-
therapy process. Implementation of IGRT into routine
clinical workflow requires tighter integration of imaging
and treatment systems and more efficient information
flow. IGRT represents a shift from a traditionally static
treatment planning process to a more dynamic, close-loop
practice with multiple feedback check/control points. To
meet the technical and logistical needs for this dynamic
treatment process, the following infrastructure and soft-
ware tools are considered important to IGRT applications:
■ IGRT Data Management
■ Radiotherapy Picture Archival and Communication
System (RT-PACS): Further development is needed
to meet the evolving needs of new IGRT workflows
and extra data requirements using efficient central-
ized communication among different imaging and
treatment procedures.
■ Digital Imaging and Communications in Medicine
(DICOM) and its radiotherapy (RT) extension are
industrial standards for facilitating connectivity and
interoperability of medical image data. Advance-
ments in IGRT have revealed shortcomings in the
DICOM-RT standard and the need to address them.
The development of new-generation objects is being
addressed by a DICOM working group for radiation
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 244 n  Treatment Planning in Radiation Oncology
therapy objects (187). Compatibility of DICOM and
DICOM-RT files among different vendors may need
further attention.
■ Record and Verify (R&V) server: With the more fre-
quent use of volumetric image acquisition and pos-
sible adaptive replanning during the course of
treatment, data storage requirements can increase 1
to 2 orders of magnitude. It is also essential to have
mirrored servers, robust data backup mechanism,
and a disaster recovery strategy for routine, continu-
ous clinical operations (188).
■ IGRT Facilitating Tools:
■ DIR: Both rigid and DIR tools are necessary for
implementing various IGRT approaches at different
levels to correct for geometric and dosimetric varia-
tions (171,176,189,190).
■ Fast treatment planning and optimization algo-
rithms: With the increasing need for treatment plan
adaptation to the changed anatomy or altered target
volumes, it becomes necessary to develop fast treat-
ment planning and optimization strategies (191).
■ Cross-platform planning comparison tools: The
computational environment for radiotherapy
research (CERR), developed by Deasy and cowork-
ers, provides a common platform for creating multi-
institutional IMRT treatment plan database,
including adaptive plans. This also provides a plat-
form for data mining in the planning database for
clinical outcome research and analysis (192–194).
Selection of IGRT Technology
The selection of an appropriate image-guidance solution
is a complex process that is a compromise of clinical
objective, product availability, existing infrastructure, and
manpower (195,196). The deployment of a new technol-
ogy requires a thorough understanding of the complete
clinical process and the necessary infrastructure to sup-
port data collection, analysis, and intervention. The AAPM
TG #104 report (148) suggests four aspects of consider-
ations, clinical, technical, resource, and administration,
when choosing an IGRT solution. We believe that these
considerations will evolve, depending on industry trend
and economics. Ten key points are as follows:
i. Clinical objectives (dose escalation/normal tissue
sparing)
ii. Structures of interest (target and normal structures)
iii. Strength of surrogates (skin markers, bony land-
marks, implanted fiducials, etc.)
iv. Desired level of geometric precision (radiosurgery/
hypofractionation)
v. Uncertainties to be managed through the use of
margins
vi. Method of intervention/correction (degrees of
freedom)
vii. Techniques of managing tumor motion
LWBK933_Ch14_p229-258.indd 244
v iii. Magnitude of dose gradients
ix. Available treatment capacity and patient load (treat-
ments/hour)
x. Identification of individuals responsible for mainte-
nance and development
Igrt Correction Strategies
and Applications
Online Versus Off-line Corrections
The development of various mechanisms for measuring
patient position has created a wealth of valuable data for
correction of patient position. The use of these data to
stratify treatment decision and to modify the treatment
process is referred to as a correction strategy. Strategies are
broadly divided into online and off-line approaches. The
online approach makes adjustment to the treatment
parameters or patient position based upon data acquired
during the current treatment session. This may be as sim-
ple as adjusting the couch position or as complex as full
reoptimization of the treatment parameters based on
changes in the shape and relative position of target and
normal structures. The off-line approach is one in which
the intervention is determined from an accumulation of
information that may be drawn from previous treatment
sessions or other times of measurement. The online
approach is generally categorized as having a greater
capacity to increase precision with an associated increase
in effort for the same level of accuracy as can be achieved
with off-line strategies, but at the cost of a higher work-
load. In general, clinical implementations typically oper-
ate with a hybrid of online and off-line approaches that
are invoked under different error thresholds. A familiar
example is seen in conventional portal film practice in
which the first treatment session is adjusted “online” (at
the time of therapy), while subsequent corrections are
applied off-line (physician review of portal images). For a
detailed review of the numerous strategies in clinical use,
the reader is referred to recent reviews in the literature
(6,7,146,191,197).
More complex IGRT procedures, which employ increased
frequency of imaging, alignment tools, and decision rules,
offer potentially increased accuracy compared to conven-
tional practice. The overhead associated with the align-
ment tools and decision rules can be prohibitive unless
properly integrated. The adaptive radiotherapy program
at William Beaumont Hospital (184–186,198,199) was
made possible only through in-house software integration
efforts. Similarly, effort was also required from the proce-
dure and policy perspective to coordinate the actions of
the off-line efforts with the radiation therapists operating
the machine. Online approaches require elevated levels of
software and hardware integration for operation as the
analysis and interpretation are performed at the time of
therapy.
6/1/11 6:44 PM

Figure 14.14.  An in-room volumetric CT-
guided radiotherapy process. CT images of
patient’s setup and anatomy information are
acquired and sent to an alignment workstation
where the images are compared and aligned to
match with the planning CT. An interventional
decision is made based on the magnitude of ana-
tomic variations to assess the need for an online
or off-line correction. If necessary, dose tracking
may be enabled and used for replanning.
Correction for Inter-fractional Setup Error
Inter-fractional variations are usually larger than intra-
fractional ones; therefore, various techniques have been
developed for pretreatment setup corrections. Without
loss of generality, we consider an in-room CT-guided
IGRT system (Fig. 14.14). In the diagram, 3D volumetric
CT (CT-on-rails or CBCT) images are acquired after the
patient is immobilized and the skin marks aligned with
room lasers, then sent to an alignment workstation where
the images are registered with the planning CT. The first
level of intervention is always the correction of transla-
tional shifts. Usually, rotation has smaller effect than the
translational shifts of the target, and can be corrected
using a 6D couch with isocentric rotation. Depending on
the magnitude of the differences observed, an off-line cor-
rection protocol may be used to reduce systematic uncer-
tainties while improving operation efficiency (200–202).
The second level of intervention may be dose based. In
theory, the ultimate treatment goal should be based on the
final delivered dose distributions, instead of what was
originally planned using the initial planning CT. In-room
CT images of the patient’s treatment anatomy allows
reconstruction of the delivered dose distributions and
therefore dose tracking. Cumulative dose distributions
can be corrected infrequently using an off-line adaptive
correction scheme (191,199,203,204).
Management of Intra-fractional Tumor Motion
In the presence of significant intra-fractional motion,
additional geometric and dosimetric variations should
also be included. This will set the complexity to another
level. There are many different approaches in the manage-
ment of intra-fractional tumor motion. Not surprisingly,
most of these applications are related to the treatment of
LWBK933_Ch14_p229-258.indd 245
Image-Guided Radiation Therapy  n 245
lung and liver cancers (63,146,198). To setup a patient
with a moving tumor, marker imaging may be used by
aligning the track of the implanted marker, or a portion
thereof, with the track discerned from the reference pre-
treatment 4D CT. Alternatively, bony landmarks may be
used for setup alignment. However, the tumor motion tra-
jectory relative to the bony landmark may change, and
recent studies have shown that the inter-fractional tumor
location has significant variation (205,206).
Real-time monitoring of implanted markers, or of the
tumor directly, is needed for accurate “gating” of radiation
treatments. Respiratory monitoring and control devices
used for imaging may also be used to trigger the beam and
the MLC motion on and off during the delivery of gated
radiation treatments. The radiation beam is automatically
switched on only during a small, generally most reproduc-
ible portion of the breathing cycle. In gated IMRT, leaf
motion is also correspondingly stopped and resumed,
thereby avoiding an interplay effect (207). Similar to imag-
ing, video feedback may be used to improve breathing or
breath-hold regularity and reproducibility (208). The
same methodology may also be used for “gated breath-
hold” treatments in which the patient voluntarily or invol-
untarily holds his or her breath at the same point in the
breathing cycle. In voluntary breath-hold, the beam is
turned on only if the breath is held at the same point.
Reproducible involuntary breath-hold may be achieved
using technology such as active breathing control (ABC)
developed by Wong et al. (209,210).
There are considerations regarding implantation of fidu-
cial markers for lung cancers. Implantation is invasive and
may cause clinical complications. Marker images do not pro-
vide 3D anatomic information on tumor shape changes.
Variations of the normal anatomy are ignored altogether. In
addition, experience to date shows that markers may get lost
and drift appreciably over the course of radiotherapy. Ideally,
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 246 n  Treatment Planning in Radiation Oncology

prospective volumetric imaging would be desirable for both
geometric guidance and dosimetric assessment, such as 4D
volumetric MRI integrated with a linac (125–127). Never-
theless, implanted markers may be ideal for tracking targets
during treatments, and often serve as a gold standard for
verification of the target location.
Real-time tumor motion tracking has been implemented
with the CyberKnife unit with guidance of both x-ray imag-
ing of implanted fiducial markers and an optical external
motion surrogate (211–213). For other types of linacs, such
capability is still at the development stage. Zimmerman
et al. have demonstrated motion tracking with intensity-
modulated arc therapy (214). Depuydt et al. have demon-
strated sub-millimeter beam tracking accuracy in a
phantom study using a gimbals-based linac unit (147).
Population-Based and Individualized Margins
The relative importance of systematic and random errors
in the determination of PTV margins should be considered
in the design of the clinical strategy. Geometric errors in
radiation field placement are typically characterized by dis-
tributions of nonzero mean and variance. The mean
describes the systematic discrepancy for an individual
patient and the variance of the random component. Several
authors have highlighted the relative importance of these
two categories of errors in determining appropriate PTV
margins (215,216). These conclusions are not completely
general, as the number of fractions is an important factor in
determining the relative importance of these two categories
of error, especially for SBRT cases with less than five fractions.
A treatment margin depends not only on the imaging
modality chosen and tumor surrogate used, but also on
the patient immobilization dedicated for a treatment
(217). A proper patient immobilization improves setup
reproducibility and reduces voluntary patient motion,
therefore decreases systematic and random errors. Margin
is also dependent on the motion-management technique
employed. For involuntary respiratory motion, breath-
hold, motion compression, motion gating, or tracking will
compensate for tumor motion at different levels. As a con-
sequence, the margin will be reduced, such that it is
smaller than a motion-encompassing internal tumor vol-
ume (ITV) (184,218–220). The ability to reduce margin by
using image guidance will therefore decrease the normal
tissue toxicity and increase dose acceleration, particularly
important for SBRT.
In prostate cases, image-guided margin reduction is
one of most dramatic examples in all anatomic sites. With
in-room CT guidance, a 3-mm margin was reported ade-
quate for prostate dose coverage, but may lose some of the
seminal vesicles coverage due to daily variation in rectal
filling that causes local deformation (221). A comparative
study using four different IGRT setup methods, skin
marks, 3D bony landmarks, 3D fiducial markers, and
Calypso transponders, has shown that the last two meth-
ods can achieve 4  mm and 3  mm margin requirement,
respectively (222). Another study has compared four setup
techniques using skin marks, 2D bony registration, ultra-
sound guidance, and in-room 3D CT (223). It has pro-
posed a correction for patient-specific systematic shifts
after the bony landmark alignment, and provides equiva-
lent dose coverage to ultrasound guidance. A recent
Calypso study has shown that a margin of 2 mm would
produce sufficient CTV dose coverage based on 1,267
tracking sessions of 35 patients (224). Figure 14.15A
demonstrates that the alignment accuracy increases along
with the complexity of the alignment technology: from

A B
Figure 14.15.  A: Patient setup accuracy of prostate cancer using different in-room imaging modalities. Generally, the accuracy increases with imaging
frequency, dimension, and use of fiducial. The skin mark and ultrasound setup have largest variation, as indicated by the error bars. The margin could
[AQ8] be reduced from 8 to 2 mm based on this finding. Source: Reprinted with permission from Semin Radiat Oncol 2007;17:268–77. B: Target coverage
based on various types of image-guided setups for treatment. In this example, 24 treatment-time CT scans of a prostate cancer patient were used to
compare the effectiveness of four alignment techniques for patient setup using a fixed-margin IMRT plan. The minimum target dose is lowest
(59.3 Gy) for skin marks-based setup and highest (76.0 Gy) for the CT-guided setup. The day-to-day variations in the minimum dose (represented
by the error bars) are smallest for CT-guided technique and largest for skin-mark and ultrasound-guided techniques.

LWBK933_Ch14_p229-258.indd 246 6/1/11 6:44 PM

 Image-Guided Radiation Therapy  n 247

skin to bone to ultrasound and to CT (6). The dosimetric
result (prostate underdose) for one patient exhibiting rel-
atively large organ motion is shown in Figure 14.15B.
In head and neck cases, an IGRT assessment of setup
error for 225 patients suggests that 3 mm margin is appro-
priate (225). The major variation for this anatomical site
comes from deformation. Depending on tumor location,
locally focused image registration is needed to minimize
the setup uncertainty due to deformation (166–168).
In lung cases, both inter- and intra-fractional motion
affect setup accuracy, and the overall margin would be
the sum of the two terms: regular setup margin plus the
ITV. Yan and coworkers proposed a margin formula that
contains both components of population-based and
individualized systematic and random errors for lung
cancer (217,226). Such a margin formula was applied in
clinical cases and 3D CT-guided setup resulted in a 65%
to 75% margin reduction. To compensate for the base-
line drift, Pepin et al. have reported using a dynamic gat-
ing window (228). As the tumor motion is location and
patient specific and 4D CT imaging provides the means
to measure the patient-specific ITV, individualized
tumor motion margin is often applied in lung cancer
treatment (217).
Anatomic Variations and
Dosimetric Consequences
Inter- and Intra-fractional Variations in Anatomy
Typical inter- and intra-fractional organ variations and
setup uncertainties of gynecological tumors, liver, dia-
phragm, lung tumors, prostate, seminal vesicles, bladder,
and rectum have been reviewed by Langen et al. (228) and
Booth et al. (229). Both publications have reported sig-
nificant variations for all organs studied. Even with careful
immobilization and alignment of the patient, significant
changes occur because of the nonrigidity of anatomy,
bowel gas movement, and the variable filling of the blad-
der (230–233). Li et al. have reported inter-factional ana-
tomic variations for all major sites based on daily CT
assessment (234). Target and normal structure variations
can also follow certain trends, including volume shrinkage
up to 12 months after the initial hormone treatment (235),
and soft-tissue changes such as tumor shrinkage and
weight loss. Figure 14.16A shows a side-by-side compari-
son of a head and neck target volume that has shrunk sig-
nificantly during the course of treatment. The skin
contour no longer matches well with the immobilization
mask. Changes in target volume and position of normal

Figure 14.16.  A: An example of setup error

for a patient immobilized with a thermo-
plastic facemask due to tumor shrinkage as
treatment progresses. Approximately half
way through the treatment course (right
panel), the lower neck was not centered on
the headrest, presumably due to the rela-
tively “roomier” mask. B: Dosimetric
impact of inter-fractional variations in
head and neck anatomy. The solid lines
show the volumes of the parotid glands (left
and right) decreased as the treatment pro-
gressed. At the same time, the centers of
both parotid glands also moved medially
due to tumor shrinkage and weight loss. As
a result, the percent of parotid volume
exceeding 26 Gy increased by least 10% over
the course of radiotherapy. B

LWBK933_Ch14_p229-258.indd 247 6/1/11 6:44 PM

 248 n  Treatment Planning in Radiation Oncology
critical organs (such as the spinal cord) could have sig-
nificant clinical consequences (166,167). In a prostate
IMRT treatment, changes in bladder filling can cause
prostate and surrounding organs to move away from the
planning position, as demonstrated in Figure 14.17. Dur-
ing a 20- to 30-minute IMRT treatment delivery, intra-
fractional motion may cause significant dose deviation for
a session.
Dosimetric Effects due to Inter-fractional Motion
The common approach to evaluating the dosimetric effect
of a delivered dose is by applying the treatment plan to the
daily setup 3D CT images with the corresponding setup
isocenter shift. The actual dynamic leaf sequence can also
be retrieved from a treatment log file for synchronized
dose reconstruction (236). To generate a cumulative dose
distribution over multiple fractions, DIR is applied to map
the daily dose distribution to a reference image for final
dose evaluation (178).
In prostate cases, it is reported that 25% (8/33) of
patients would have geometric or dosimetric miss without
daily MVCT improve tumor localization (237). Obese
patients and patients with large daily rectal motion would
be most subject to such marginal miss. van Herk has
pointed out that the systematic uncertainty is more
important and should be minimized as much as possible
(215). Langen et al. (238) have investigated the dosimetry
consequences of prostate motion during helical tomother-
apy for 16 patients with 515 daily MVCT scans. The study
LWBK933_Ch14_p229-258.indd 248
Figure 14.17.  Intra-fractional varia-
tions of anatomy observed in a pros-
tate patient in the span of 20 minutes.
CT images were acquired just prior
and immediately after an IMRT
treatment fraction. The contours of
pelvic anatomy before treatment
(left) are overlaid on the CT image of
the patient acquired immediately
after the treatment (right). Prostate
target (red) was displaced anteriorly
for >5 mm.
finds that the mean change in target D95% is 1 ± 4% and
the average cumulative effect is smeared out after five frac-
tions. In individual fractions, the D95% may be off by as
high as 20%. For normal tissues, such as the rectum, Chen
et al. have reported that dose variation is significant due to
daily variation of the rectal volume and 27% of actual
treatment would benefit from adaptive replanning. The
authors recommend an empty rectum for both planning
and treatment to avoid such adverse effects (239). Any
effort to make patient conditions reproducible is worth-
while so as to treat as planned.
In breast cases, Goddu et al. have demonstrated the
potential benefit of daily MVCT setup by simulating the
integrated dose distribution without image-guided setup
correction. Significant dose reduction in the PTV is
observed mostly at the lung interface where steep dose
falloff is expected (240). The possible adverse dosimetric
effect is anisotropic with regard to the steep dose falloff.
For highly conformal head and neck IMRT treatments,
it is desirable to reduce the dose to the parotid glands in
order to minimize the incidence of late xerostomia (241).
Unfortunately, the parotid glands can decrease in volume
and move medially during the course of treatment (242).
As a result, parotid dose can increase by 10% and exceed
26 Gy, as illustrated in Figure 14.16B, in which one patient
received repeat CT imaging during his course of IMRT
treatment. A single mid-course correction to adapt the
treatment plan to the anatomical change could help reduce
the dose for both parotid glands (243).
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 Image-Guided Radiation Therapy  n 249

B
Figure 14.18.  A: Potential consequence of respiratory motion on target coverage. An IMRT plan, developed using conventional
CT, was applied to the patient’s 4D CT. Dose distributions were calculated in each of the 10 phases of the breathing cycle. A
portion of the CTV, shown in thick yellow line, was not covered by the 70 Gy prescription dose line (red) in phases 1 through
4. B: Comparison of a treatment plan as perceived on a free-breathing CT (top row) and as realized after accounting for breath-
ing motion in all 10 phases (bottom row). The latter was obtained by summing dose distributions computed on individual
phases of the 4D CT image (A), and mapped to a reference CT image using deformable image registration (DIR).

Dosimetric Effects of Intra-fractional Motion
The dosimetric consequence of intra-fractional breathing
motion for lung tumors can be demonstrated by 4D CT
images. Figure 14.18A shows a case study that used a free-
breathing CT image to design a treatment plan with an
inadequate 8-mm margin to cover the CTV (shown in yel-
low). The actual dose distribution does not cover the
entire target volume in some of the breathing phases due
to respiratory motion, which is not detected in the free-
breathing CT. Using DIR, the cumulative dose distribution
from the 10 individual phases is calculated and mapped to
a free-breathing fast CT scan (near full exhalation, #7).
The resultant cumulative dose distribution summed from
the entire breathing cycle shows a dose deficiency in the
CTV (red arrow), as illustrated in the bottom row of
Figure 14.18B. In this case, the cumulative dose distribution
when using the internal target volume (ITV) derived from
the 10-phase 4D CT does not underdose the target but
results in treatment to a larger volume. The ITV method
is an example of using an individualized margin to account
for target motion in treatment planning. The dosimetric
impact of motion in free breathing and gated radiotherapy
of lung cancer has been studied using Monte Carlo dose
calculation (244). The doses are similar between free
breathing and all phases, except for the end-inspiration
phase in which the tumor is underdosed by ∼10%.

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 250 n  Treatment Planning in Radiation Oncology
Wu et al. have compared three delivery techniques,
3DCRT, IMAT, and IMRT, in five treatment cases in liver,
with tumor motions ranging from 0.5 to 1.75  cm. The
variation in D95% is largest (−8.3%) for IMRT and smallest
(<2%) for 3DCRT, with negligible dose–volume histo-
gram variations for normal tissues (178). Kuo et al. have
found that with an adequate margin for motion, D95%
variation is <2% in the CTV (72).
Adaptive Approaches for Correcting
Dosimetric Deviations
William Beaumont Hospital has pioneered the adaptive
radiotherapy strategy by using a purpose-built treatment
planning system to facilitate off-line dosimetric evaluation
and replanning (185,199). Without the support from a
more automated planning system, routine replanning is
not feasible under current clinical conditions. Special staff
effort may only be reserved for those patients with poten-
tially severe dosimetric consequence (245). Mageras and
Mechalakos have discussed treatment planning in the
IGRT context and the various challenges to treatment-
plan adaptation strategies in various disease sites (6). An
alternative treatment planning approach to evaluating a
PTV is to simulate motion and other uncertainties directly
in the dose calculation. A benefit of this approach is that
the resultant dose distributions of not only the CTV, but
also organs at risk can be examined.
Recent articles have reviewed clinical applications of
adaptive radiotherapy for various treatments (191). The
adaptive concept as applied to radiotherapy practice
derives from modern informatics and control theory. Off-
line adaptation has been implemented in various institu-
tions (246–248), and online replanning has been reported,
with computation time within 5 to 8 minutes (249). The
knowledge gained from geometric and dosimetric varia-
tions via clinical IGRT research will be useful for guiding
the treatment planning process to be more cautious in
certain clinical scenarios.
Future Directions
Image-guided radiotherapy is commonly considered in
the context of treatment delivery verification, but it is
more appropriate to broaden its scope to include imaging
at other stages of the radiotherapy process (8). We, there-
fore, briefly discuss future directions as they apply to this
broader definition.
In the application of IGRT to treatment delivery, we
have better understanding of various uncertainties, cor-
rection strategies, and technical limitations. Geometri-
cally, a large body of evidence has shown the improved
accuracy in patient setup and motion management. Dosi-
metrically, IGRT improves treatment delivery in certain
plans that involve sharp dose gradients or a moving
target. Clinically, increasing evidence has unveiled the
connections of local failure with marginal miss and
LWBK933_Ch14_p229-258.indd 250
high-grade toxicity with organ motion (1–3). Well-
designed clinical trials are needed to demonstrate its
advantages fully. We believe that further advance in IGRT
relies on the innovation and integration of multiple auto-
mated technologies to facilitate extra evaluations and
additional processes. Parallel computing technologies,
such as graphics processing unit (GPU) technology (181),
is a solution for increasing real-time performance, espe-
cially for intra-fractional motion management and online
dosimetric replanning. In motion monitoring, non-
radiographic alternatives may be more clinically desir-
able, such as in-room MRI imaging with near real-time
volumetric information (62). In off-line and online dosi-
metric replanning, automated and integrated systems are
necessary to make such actions clinically feasible. The
treatment efficacy and benefit of real-time tracking and
online adaptation must be evaluated with clinical evi-
dences, such as improved potency of hypo- or single-
fractioned SBRT.
In image-guided treatment planning, biological imag-
ing with different molecular probes will play an increasing
role in reducing the uncertainties in delineation of gross
and clinical tumor volumes. Different molecular probes
for detecting different biological attributes of cancer may
prove useful in accurately defining the biological tumor
volume, as shown in Figure 14.19. Various molecular trac-
ers are available for probe tumor metabolism, prolifera-
tion, hypoxia, and angiogenesis. The concept of
multiplexed imaging used in diagnosis to simultaneously
probe different molecular targets may be adopted by the
therapeutic clinic as theragnostic imaging (250) to pre-
scribe the distribution of therapeutic dose (8). Micro-
scopic cancerous cells spreading beyond the GTV requires
histopathological assessment and accurate registration
with 3D anatomic image.
In image-guided treatment evaluation, multi-modality
imaging must be applied to assess the complex radiation
response. This will remain an intense clinical research arena
to improve our fundamental understanding of the radiation
response at molecular, cellular, organ functional, and phys-
iological levels. Proper biological attributes, such as DNA
double-strand breaks, need to be identified and probed.
Ideally, response assessment within the treatment course
would be most beneficial for individualized treatments,
while the reality is lack of an effective assessment index even
after treatment. A response-driven, biologically adaptive
radiotherapy is still distant from clinical practice. The dosi-
metric feedback loop, which is within the reach to ensure
that the treatment process goes along the intended course
(6,191), can provide more reliable clinical data to tune pre-
diction models of treatment outcome.
Radiation therapy has gone through a series of techno-
logical revolutions following several breakthroughs in
imaging in the past three decades. We have witnessed the
growth of IGRT, which has provided improved geometric
and dosimetric accuracy in radiation therapy of localized
cancers. We believe that there are more technologic
6/1/11 6:45 PM
 Image-Guided Radiation Therapy  n 251

Figure 14.19.  Imaging paradigm in radiation oncology hypothetically illustrating the possibility of integrating different
functional imaging modalities (panels A–D) with CT-defined gross tumor volume (GTV) (panel E) to obtain a combined
biological target volume (BTV) (panel F). Panel A: Metabolism (i.e., FDG); panel B: proliferation (i.e., FLT); panel C: hypoxia
(i.e., Cu-ATSM); and panel D: angiogenesis (i.e., MMP). Improved tumor target coverage and/or dose escalation to these
physiological sub-regions may be achievable. A region of increased angiogenesis can be seen in panel F that lies outside other
biological regions. This may represent a potential area of recurrence that should be included into the overall BTV. Lines
(yellow) outlining the anatomical GTV (panel E) and BTV (panel F) accentuate the change in target volume delineation.

advances to come at all levels of IGRT, closing the physical,
biological, and clinical feedback loop for radiation
therapy.
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 [AQ 1]  In TOC the chapter title was “Image-Guided Radiotherapy” whereas in chapter opening page “Image-Guided
Radiation Therapy” is given. Please check and confirm the correct chapter title.
[AQ 2] In TOC only two authors were listed, but in chapter opening page two more author names are given. Please check.
[AQ 3] Please check the edit to this paragraph.
[AQ 4]  The term “gimballed-design” has been changed to “gimbal design.” Please check.
[AQ 5]  Please provide volume number and page range for reference (148), if appropriate.
[AQ 6]  Please provide volume number for reference (168).
[AQ 7]  Please provide volume number and page range for reference (225).
[AQ 8]  Please provide complete reference.

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