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Image-guided radiotherapy
A u tho rs
M. De Ridder, D. Verellen, N. Linthout, K. Tournel, S. Bral, G. Storme
Key wo rds
Radiotherapy, image-guided radiotherapy, intensity-modulated radiotherapy, partial
tumor boost, respiratory gating
Summary
Progress in radiotherapy is guided by the need
to realize improved dose distributions, i.e. the
ability to reduce the treatment volume towards
the target volume and still ensuring coverage
of that target volume in all dimensions. These
advancements are usually not to be attributed
to a single event, but rather a combination of
many small improvements that together enable
a superior result. Image-guidance is an important link in the treatment chain and is as such a
major factor in this synergistic process. Imageguided radiation therapy (IGRT) aims at instant
knowledge of the tumor volume location during
irradiation or alternatively, studying the motion
and volume changes of the target volume,
allowing management of these effects in the
Introduction
The control rate after radiotherapy is proportional to the dose of radiation that is delivered to the
tumor, which is traditionally explained in a linear,
quadratic model of cell killing. The limiting factor
in escalating the radiation dose towards tumoricidal levels is the collateral damage caused to nearby
healthy tissues. In addition to tolerance dose, the
irradiated volume of surrounding healthy tissues
is a critical parameter in the development of radiation induced toxicity. Traditionally, the irradiated volume encompasses the gross tumor volume
(GTV) and the area at risk for microscopic spread.
To assure a proper coverage of this clinical target
volume (CTV), a margin is added to compensate
for daily positioning errors and internal motion of
organs, resulting in the planning target volume
(PTV), to which the radiation dose is prescribed.1,2
One way to escalate the dose to the tumor without
increasing the irradiated volume of surrounding
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treatment planning process. The limited ability
to control the tumor’s location, compromises the
accuracy with which radiation can be delivered
to tumor-bearing tissue. The resultant larger
treatment volumes required to accommodate
target uncertainty may limit the radiation dose,
owing to the larger amounts of surrounding
normal tissue exposure. With IGRT these volumes can be optimized and tumoricidal doses
may be delivered, achieving maximum tumour
control with minimal complications. Moreover,
with the ability of high precision dose delivery
and real-time knowledge of the target volume
location, IGRT has initiated the exploration of
new indications in radiotherapy, previously considered to be unfeasible.
5255-63)
tissue, is to create a conformal dose distribution
that tightly matches the shape of the target volume. This became possible due to the evolution in
computerized planning systems and sophisticated
dose delivery systems, such as intensity modulated
radiotherapy (IMRT) and conformal arc therapy
(Figure 1 on page 256).3 To further decrease the
irradiated volume of nearby organs, it is necessary
to decrease the PTV itself and thereby limit the
volume of healthy tissues that is intentionally irradiated. This can be achieved with the implementation of image guided radiotherapy (IGRT), which
enables instant knowledge of the tumor location
and even control of organ motion during treatment.4 As a result, the margins can be decreased
from centimetres to millimetres.5 For a spherical
tumor of 5 cm for instance, a reduction of 2.0 cm
to 0.5 cm safety margin results in decreasing the
irradiated volume of surrounding organs from 316
cm3 to 48 cm3.
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Figure 1. Intensity-modulated radiotherapy (helical tomotherapy) for rectal cancer. Dose distribution of a plan
without (left) and with (right) a simultaneous integrated
radiation boost. The difference dose levels (Gray) are represented by corresponding colours. Note the dose painting
around the planning target volume to spare the small bowel
(delineated in black) and the bladder (delineated in blue)
and the steep dose-fall from 55.2 to 46 Gy.
Clinical considerations for IGRT
The therapeutic success of a radiation treatment
is determined by the balance between tumor control and normal tissue complication probability
(TCP-NTCP balance). Indeed, in a high proportion of patients the biological dose necessary for
tumor eradication can not be delivered because of
a high probability of complications due to collateral damage to surrounding tissues. The principal
goal of radiation research is to improve the TCPNTCP balance. This can be achieved by combining
radiotherapy with chemotherapy, considering the
synergistic anti-tumoral effects of both modalities.
Randomized trials in a variety of solid tumors have
demonstrated that combined modality treatment
improves local control and overall survival. However, this also significantly increases toxicity, which
can be explained by a lack of specificity of both radiation and chemotherapy for cancer cells as opposed
to rapidly dividing normal cells.6,7 Ongoing trials
are evaluating whether the use of CRT-IGRT may
decrease the NTCP of combined chemoradiotherapy. Modern radiosensitizing strategies try to exploit
the biological specificity of tumors by targeting
growth-factors and pro-angiogenic pathways such
as EGF and VEGF, or by targeting specific features
of the tumor microenvironment, such as hypoxia or
the pro-inflammatory tumor infiltrate.8,9
Recent evolutions in CRT-IGRT offer an alternative strategy to improve the TCP-NTCP balance.
New delivery techniques such as IMRT enable complex dose distributions with sharp dose gradients,
allowing an increase of the radiation dose to the
target volumes, without increasing the irradiation
of nearby tissues.10 However, it is widely recognized
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that there are unavoidable uncertainties in the process of planning and delivering radiotherapy. Some
of these relate to the identification of the extent of
microscopic disease spread, while others are associated with the delivery of radiation itself. It is important that the magnitudes of these uncertainties are
well understood and minimized whenever feasible
and that the possible influence on the outcome of
treatment is estimated correctly. In “conventional”
radiotherapy, information about the extent and frequency of these uncertainties is crucial in determining the extent of safety margin around the tumor
that is necessary to ensure “adequate” tumor coverage and in assessing whether the goal of sparing
a critical organ is likely to be achieved. With the
introduction of IMRT, exact knowledge and adjustment of appropriate margins become of primary
importance, since the resulting sharp dose gradients
are unforgiving with respect to misalignment and
motion. This misalignment or motion may result in
unacceptable high irradiation doses to healthy tissue or important under-dosage of the target volume.
Nowadays, IGRT serves multiple purposes: (1) optimal reduction of treatment margins, (2) the concept
of “dose-painting-by-numbers” and hypofractionated radiotherapy require almost exact knowledge of
the anatomy during dose delivery in real-time, and
(3) interactive adaptation of the treatment based on
daily assessment of changes in tumor volume and
response.
CRT-IGRT was initially implemented in dose escalation protocols in prostate cancer, which resulted in
improved biochemical control rates, while preventing an increase in rectal and bladder complications.
A retrospective analysis of 2,991 patients that were
consecutively treated, was reported by Kupelian and
colleagues and showed equal biochemical failure
rates for prostatectomy, permanent seed implantation and high dose radiotherapy (> 72 Gy), while
the outcome was significantly worse for standard
dose radiotherapy (< 72 Gy).11 This study nicely illustrated that due to the ability of CRT-IGRT in
delivering higher doses, radiotherapy may become
an alternative for surgery. However, prospective
randomized trials comparing radiotherapy directly
to surgery are difficult to realize, considering that
most physicians and patients have a preference for
either treatment modality, based on local expertise
and the (un)availability of CRT-IGRT. Alternatively, CRT-IGRT can be used to spare normal tissues,
while maintaining the dose to the target volume.
This approach was successfully implemented in the
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Figure 2. Dose painting by numbers. Do It Yourself Flowers, by Andy Warhol (1962). The concept of painting by numbers
translates to radiotherapy in that the colour coding obtained from, for instance, PET information (metabolic information) can
be quantified and translated into biological effective dose to be delivered with IMRT.
treatment of head-and-neck cancer, where sparing
of parotid glands has decreased the incidence of
xerostomia (or dry mouth) improving the quality of
life. This approach was also used in the preoperative treatment of rectal cancer, where helical tomotherapy allowed a decrease in acute gastrointestinal
and urinary toxicity.12,13 Because intra-abdominal
organs, such as the small bowel, the stomach, the
liver and the kidneys, are more radiosensitive than
most solid tumors, radiotherapy is not commonly
used for intra-abdominal malignancies. CRT-IGRT
offers the possibility to prescribe tumoricidal radiation doses, while limiting the irradiated volume of
these organs and opens a new therapeutic avenue for
a variety of GI cancers, such as hepatic malignancies
and pancreatic cancer.
In conventional radiotherapy, a homogenous or uniform dose is generally delivered to the target volume, without violating the tolerance of the nearby
tissues. From a biological point of view it looks
more attractive to prescribe non-uniform target
dose distributions. Models suggest that a significant increase in TCP may be gained from partial
tumor boost doses delivered to 60% or more of
the tumor volume.14,15 Theoretically, this approach
can decrease the local recurrence rate by enabling a
large volume of the tumor to receive a lethal dose,
and preventing re-population of tumor cells located in the boost volume. The concept of partial
tumor boosts was developed many years ago, but is
regaining interest since the combination of IMRT
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and IGRT allows its clinical implementation. In
addition, recent progress in biological and physical
imaging modalities such as positron emission tomography (PET), single photon emission computed
tomography (SPECT), dynamic contrast enhanced
magnetic resonance imaging (MRI) and magnetic
resonance spectroscopy (MRS) can provide spatial
information on the biological and physical characteristics of the tumor, which may identify different
levels of radioresistance.16 This can be integrated
into the treatment planning procedure, allowing biologically relevant dose optimization taking into account estimations of hypoxia, cell proliferation rate
and cell density.17 The technique of applying nonuniform dose prescriptions is called voxel-intensity
based IMRT or “dose-painting-by-numbers”. The
intensity of the radiation varies from voxel to voxel
according to the estimated level of radioresistance,
as assessed by biological imaging (Figure 2). This
strategy is currently being explored in experimental
models and early clinical trials.18
Finally, the ability of high precision dose delivery is
initiating a revision of generally accepted fractionation schemes and concepts of radiobiology. Conventional radiation schedules with curative intention
consist of 25-35 daily fractions of 1.8-2.0 Gy. Dividing the radiation dose into such a large number of
relatively small fractions decreases NTCP, because
of sublethal damage repair between dose fractions
and cellular repopulation. At the same time, fractionation increases TCP because of reoxygenation of
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tumors and reassortment of cancer cells into radiosensitive phases of the cell cycle. However, these conventional fractionation schedules are often a burden
for patients, requiring daily visits to the hospital for
5-7 weeks and require considerable machine time,
which is an important factor in the economics of radiation therapy. These considerations led to the development of hypofractionated radiotherapy, which
by definition uses fraction doses of more than 2 Gy.
Hypofractionation was introduced in clinics in the
early sixties for the treatment of breast cancer, where
3- and a 5-day-treatment-a-week were compared.19
This and other studies showed that fraction sizes of
more than 2 Gy produce significantly more unfavourable sequelae compared to conventional fractionation. Hence higher fraction doses were abandoned for the next 30-40 years to biologically limit
NTCP.20 As the introduction of CRT-IGRT offers
a physical way to spare nearby tissues the concept
of hypofractionation is currently being revisited. If
larger radiation fractions are given daily, it results
in an acceleration of the treatment (shorter overall
treatment time) reducing repopulation of rapidly
proliferating tumors and increasing TCP.21 The recent (r)evolution in IGRT has driven the development of stereotactic body radiation therapy (SBRT),
an extreme form of hypofractionation that delivers
an ablative dose of radiation in few fractions, capable
of disrupting tumor mitosis and other cellular functions. Several phase I/II studies reported high levels
of local control in lung cancer and liver metastasis,
with acceptable toxicity.22-24 Randomized trials that
compare SBRT to surgery have been initiated.
Image-guidance techniques
As this is a review on IGRT, immobilization techniques and margin recipes will not be covered. Yet, it
is important to realize that in order to obtain its full
potential, IGRT will need to be combined optimally with immobilization devices to help the patient
maintain a certain position and margins counteracing inter-observer variability in volume delineation,
compensating for uncertainties in the involvement
of disease and representing the remaining geometric uncertainty. The clinical application of IGRT for
patient set-up verification/correction can generally
be classified in the off-line or on-line approach. The
former monitors the position of the patient during
a limited number of fractions and adapts the safety
margins and/or treatment plan accordingly. The online approach offers the possibility of reducing most
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geometric errors (both systematic and random), yet
requires automation of quantification and correction of target localization errors to make it efficient
in clinical routine. An extremely important feature
of IGRT is the ability to register the images-of-theday to a reference image-set, that usually has been
generated at the time of treatment planning, representing the ideal situation (i.e. perfect alignment
of treatment beam and target volume). The purpose
of image registration is to find the transformation
(translation, rotation and preferably deformation)
that maps one set into the other to obtain the corresponding adjustments required to align target volume and treatment beam as accurate as possible.
Peripheral solutions for IGRT
The concept “peripheral” refers to in-room imaging
devices that are not mounted on the treatment device. Being independent of the beam delivery device,
peripheral solutions for IGRT offer the advantage
that they can be used to cope with organ motion
and/or patient motion during irradiation (so called
intra-fraction motion). A disadvantage of this concept is that the system needs to be carefully calibrated with respect to the machine’s isocentre setting,
which results in an additional source of uncertainty.
The combination of multiple X-ray source / detector
systems has been introduced to solve the inherent 2D
limitation in target localization of using megavolt
(MV) images generated with the high energy treatment beam such as portal films or Electronic Portal
Imaging Devices (EPIDs). The approach of using
diagnostic X-rays for treatment set-up verification
offers a threefold advantage: (1) Image quality (a
well-documented problem in MV-based imaging) is
no longer an issue, (2) patient dose becomes less important compared to daily MV imaging and (3) the
modality can be used in fluoroscopic mode during
treatment. The Mitsubishi Electronics Co. in collaboration with the Hokkaido University developed
a room mounted kV-imaging device, soon followed
by similar reports from the University Hospital
Brussels in collaboration with BrainLAB AG on the
ExacTrac/NovalisBody system using a combination
of infrared reflective markers and a robotic couch
to accurately correct for both translational and rotational set-up errors (Figure 3).25,26,27 Alternatively
the Cyberknife approach (Accuray Inc.) leaves the
patient undisturbed applying a linear accelerator
on a robotic arm featuring 6 degrees-of-freedom to
adapt the beam delivery device according the image
information. Room mounted X-ray imaging systems
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Figure 3. The image guidance of the Novalis® System is used for target localization and consists of 2 X-ray tubes placed in
holes in the floor (central bottom of upper image) and two Amorphous Silicon detectors mounted at the treatment room ceiling (central top of upper image). The configuration is as such that the beam axes of both tubes cross the treatment beams
axis isocentrically. The lower images show the 2 digitally reconstructed radiographs (left images) and the 2 X-ray images (right
images) that are registered with each other in order to define the possible correction of the patient’s setup with respect to the
treatment machine to correspond with the treatment planning. This registration can be based on bony structures or implanted
gold markers. The latter is visible in these images.
are particularly suitable for real-time internal fiducial marker (e.g. implanted radio-opaque objects)
tracking during treatment. The X-ray sources and
imagers are fixed on the floor or ceiling to provide
high mechanical precision, assuming a proper calibration has been established. A major disadvantage
of this solution is the inability to visualize soft tissue requiring surrogate structures (bony landmarks
or implanted radio-opaque markers) to acquire positional information of the target volume. Another
drawback is the lack of information concerning the
spatial relationship between target and adjacent
organs at risk during the course of treatment. Diagnostic CT scanners have been introduced in the
treatment room because soft tissue can be visualised
offering the advantage that no surrogate is required
to visualize the target. The scanner may be positioned over the treatment couch using rails, and/or
the treatment couch may be used to transport the
patient into the bore of the CT gantry.
On-board solutions
On-board solutions refer to imaging devices that are
physically attached to the treatment delivery system.
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Major advantage of this approach is the utilisation
of the actual treatment beam to ensure alignment
of beam and target (i.e. replacing the conventional
radiographic films or portals). In addition to this the
EPID can be used for dose measurements, which
is extremely useful in detecting differences between
actual patient data as encountered during treatment
and those applied during treatment planning.28 Being a planar (as opposed to volumetric) imaging device mounted to the treatment delivery system distal
to the patient, it requires multiple gantry positions
to obtain 3D information. The latter has been solved
by introducing an additional X-ray source / detector system perpendicular to the treatment beam
axis, or 2 additional gantry mounted X-ray systems
with central axes intersecting with each other at the
linac’s isocentre. Moreover, both the EPID imager
as well as an orthogonally mounted X-ray imaging
device, can be used to acquire cone beam volumetric
CT data (CB-CT).29 These CB-based solutions offer
sufficient soft tissue visualization, avoiding the need
for surrogates in localizing most target volumes or
critical structures. On the other hand, volumetric
imaging during beam-on is not possible and limited
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Figure 4. Combined computed tomography and daily MVCT
image data. Example of an overlay (axial and sagittal crosssections are shown) of planning computes tomography data
(grey) and daily Megavolt computed tomography data (yellow), prior to (upper images) and after adjustment (lower
images).
to positioning the patient prior to treatment. The
major weakness of the gantry-mounted systems is
the sub-optimal mechanical precision (e.g. gantry
sagging) and the scatter radiation from the patient
to the imagers.
Integrated solutions
“Integrated solution” refers to a concept that grew
out of previous developments, but was designed
from the start for a certain purpose. The helical tomotherapy (TomoTherapy Inc.) approach is such an
example, where the concept of an add-on sequential
tomotherapy device has been combined with helical CT-scanning obtaining a 2-in-1 concept. It is a
treatment modality in which IMRT is delivered in
a rotational fashion using a 6 MV linac mounted
to a ring-based gantry. Simultaneously, the patient
is slowly translated through the bore allowing high
modulation and conformity of the dose distribution.
From the patient’s point of view the source describes
a helical trajectory.30 The continuously rotating gantry combined with a CT-detector array system allows MVCT imaging and can be used for in vivo
dose transmission measurements for dose verification. Basically it is a CT-scanner where the diagnostic X-ray tube has been replaced with a 6 MV linac
and the collimating jaws (or shutters) are replaced
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with a binary collimator consisting of small high
density metal leaves, creating 64 small beams that
can be switched on/off rapidly for IMRT by varying
the fraction of opening time during rotation. In a
way similar to diagnostic CT, the patient is treated
in slices by a narrow photon beam. CT-image acquisition is accomplished with all leaves open prior to
treatment (Figure 4). A logical “next-step” is to introduce MRI in IGRT as it offers superior soft tissue
contrast compared to radiographic imaging. At the
university of Utrecht a prototype is being designed,
combining a linac mounted on a ring-based gantry
and a 1.5T MRI device. Inherent to its design, the
approach is limited by interaction of the radio-frequency (RF) signal used for MR imaging with the
RF-pulses required for electron acceleration in the
linac and the influence of the strong magnetic field
from MRI on the dose absorption process. To cope
with these limitations, Dempsey et al (James Dempsey, personal communication, 2006) designed a 0.3T
MRI combined with 3 60Co-sources equipped with
multileaf collimators (MLC) for IMRT mounted on
a ring-based gantry. Both MRI concepts are promising, but are still in the development phase.
Image-guidance and motion management
Respiratory motion affects all tumor sites in the thorax and some in the abdominal region, and again,
motion control will allow reduction of irradiated
healthy tissues and possible escalation of dose to the
target volume.31 Apart from techniques to accurately describe motion, different methods are being developed for motion management during treatment,
such as forced shallow breathing by abdominal compression or breath-holding, motion-encompassing
techniques and breathing synchronized techniques
(e.g. respiratory gating and real-time tracking). Using a stereotactic body frame to suppress breathing
induced motion, Wulf et al showed that with a margin for target variability of 5 mm (antero-posterior
and latero-lateral) and 10 mm (cranio-caudal) about
12-16% of the targets might be missed partially.32
Therefore, they concluded that CT-verification prior
to each treatment session is recommended to detect
these targets with increased reproducibility. Motion
encompassing techniques refer to the idea of incorporating information on tumor motion into the treatment planning process, either by introducing patient
individualized margins or using this information in
the optimization procedure. Internal motion can be
assessed by time resolved imaging techniques such
as “slow” CT scanning or PET, which offers infor-
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mation on tumor position probability due to its slow
acquisition time. Alternatively, multiple fast CT acquisitions during the respiratory cycle can be used
describing the target’s motion during the respiratory
cycle. However, respiratory motion is irregular and
no general respiratory patterns exist that can be assumed by observation prior to treatment. Mostly,
respiratory-synchronized techniques offer the optimal
solution. It should be noted that sometimes the object being measured for motion is the tumor itself,
an artificial marker implanted in or near the tumor
or a surrogate organ such as the diaphragm. Moreover, the breathing pattern itself is usually obtained
from an external signal allowing real-time observation (e.g. infrared reflective markers placed on the
patient’s surface, spirometers or a flexible bellow)
and the mechanical coupling with the tumor is often weak, resulting in complex relationships. Respiratory-synchronized techniques need to establish a
correlation between the real-time external breathing
signal and the internal tumor motion and this correlation needs to be verified with regular intervals
during the course of treatment. Based on 4D CT
measurements, Lu et al have shown that the internal
motion is strongly related to the amplitude of the external signal (the signal for respiratory motion can be
characterized by amplitude or phase).26 Respiratory
gating involves the administration of radiation during certain intervals within a particular portion of
the patient’s breathing cycle, commonly referred to
as the “gate”. The choice of the gate width is a tradeoff between minimizing motion within the gate and
beam-on time. Breath-holding techniques are being
introduced to optimise the duty cycle. Some studies have shown the anatomic position of the tumor
to be more reproducible at end respiration. On the
other hand, when breath-holding techniques are
introduced at (moderate) deep inspiration, the relative damage to healthy lung tissue can be reduced
and it seems to be more comfortable for the patient.
Another way of accommodating respiratory motion
is repositioning the radiation beam dynamically to
follow the tumor’s changing position, referred to as
real-time tumor tracking.
Conclusion
This review paper demonstrates that the recent
progress in radiotherapy, resulting from the synergistic combination of improved dose distributions
(conformal radiotherapy or CRT) and frequent imaging (IGRT) during the course of radiotherapy,
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has drastically improved the quality of radiotherapy
and has broadened its possibilities and indications.
High precision radiotherapy is indicated in those
situations where the dose that has to be delivered to
a tumor exceeds the tolerance dose of the surrounding tissues. Since the progress in CRT and IGRT
were simultaneously implemented in clinical use, it
is difficult to discriminate the relative contribution
of each modality.
Glossary
• Image-guided radiotherapy (IGRT): Frequent imaging in the treatment room during a course of
radiation therapy to guide the treatment process.
• Conformal radiotherapy (CRT): Describes the
aim in radiotherapy of conforming or shaping the
high-dose volume to the planning target volume.
Alternatively, conformal avoidance refers to sparing of organs at risk. To do so, dose delivery systems such as conformal arc therapy and intensity
modulated radiotherapy (IMRT) are being used.
• Intensity-modulated radiotherapy (IMRT): Radiotherapy technique with varying intensity of
irradiation within a radiation field. This can be
obtained by using differential dose absorbers or by
varying the time of radiation at different points.
• Tomotherapy: Therapy analogue of computed
tomography. A specially designed collimator generates an intensity modulated profile and at the
same time the gantry rotates around the long axis
of the patient and as such irradiates a slice of the
patient. One approach is the slice-by-slice arc rotation approach, where the patient is translated
longitudinally between consecutively gantry rotations to treat sequential transaxial slices. In helical
tomotherapy, the patient is being translated longitudinally, slowly and continuously, during the
gantry rotation.
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Key messages for clinical practice
1. In order to assure proper coverage of the clinical target volume (CTV) by radiation, a margin
needs to be added, compensating for daily positioning errors and internal motion of organs,
resulting in the planning target volume (PTV). Therefore the PTV includes normal tissues nearby
the tumor, to which radiation is intentionally delivered.
2.The dose of radiotherapy necessary to control a tumor may often not be delivered because of
the high probability of complications in nearby normal tissues. This problem can be tackled by
the generation of conformal dose distributions that tightly match the volume of the PTV and/or
by decreasing the amount of normal tissue in the PTV.
3.IGRT is defined as frequent imaging in the treatment room allowing treatment decisions made
on the basis of these images. IGRT aims at decreasing CTV-to-PTV margins from centimetres to
millimetres.
4.The synergy between conformal radiotherapy (CRT) and IGRT has drastically improved the quality of radiotherapy and has broadened its possibilities and indications. The clinical implementations of CRT-IGRT enabled dose escalation, conformal sparing, non-uniform dose distributions
and initiated a revision of fractionation schedules.
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Correspondence address
Authors: M. De Ridder, D. Verellen, N. Linthout,
K. Tournel, S. Bral, G. Storme
Department of radiotherapy, Oncology Center,
University Hospital Brussels
Please send all correspondence to:
Prof. Dr. M. De Ridder
Department of radiotherapy
Oncology Center
University Hospital Brussels
Laarbeeklaan 101
B-1090 Brussels
Belgium
Tel: 0032 (0)2 477 6147
Fax: 0032 (0)2 477 6212
[email protected]
Conflicts of interest: the authors have nothing to
disclose and indicate no potential conflicts of interest.
Call for contributions from readers
Dear reader,
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have a clear impact on your activities in daily clinical practice such as diagnostic work-ups and
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The Editorial Board and Ariez Medical Publishing Ltd.
O N C O L O G Y vol.
2
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