ARTICLE
Auteur(s) : Guy
Soete, Dirk Verellen, Guy Storme
Department of Radiotherapy, UZ Brussel, av. Laarbeek 101, B-1090
Bruxelles, Belgique
Article reçu le 18 Juin 2007, accepté le 28 Août 2007
Prostate cancer (PC) is currently the most common cancer
diagnosed in men in most western countries and the incidence
continues to rise [1]. When PSA was introduced in the late ’80s, it
became apparent that the majority of PC patients treated with the
low radiation doses (≤ 70 Gy) used at that time experienced a
rising post-treatment PSA, indicating subsequent clinical failure
[2, 3]. This prompted radiotherapists to stepwise escalate the
dose. Ultimately several randomized trials showed a significant
benefit in biochemical control with doses ~ 78 Gy compared to
≤ 70 Gy [4-8]. Thanks to recent technical developments, these
high radiation doses can be administered nowadays without
substantial risk for severe complications.
The goal of external beam radiotherapy (RT) is to induce
clonogenic cell death to the tumour cells with minimal collateral
damage to the surrounding healthy tissues. Because of patient
positioning errors and organ motion/deformation, a volume larger
than the clinical target volume (CTV: prostate ± seminal vesicles ±
pelvic lymph nodes) has to be treated. This volume, the CTV +
margin, is called the planning target volume (PTV) [9]. The margins
permitting adequate PTV coverage can be calculated by the combined
standard deviations of positioning errors and organ motion using
so-called margin recipes [10, 11].
Two recent technical developments allowed for a dramatic
reduction of the volume of irradiated normal tissue: conformal RT
techniques (CRT) and image guided RT (IGRT).
Conformal RT provides dose distributions accurately shaped to
the PTV. Conformal beams are created in the beam’s eye view
projection of the PTV in the treatment planning system [12].
Intensity modulated RT can be considered a sophisticated type of
CRT and refers to the use of beams in which the intensity is more
complex than flat or linearly skewed (conventionally wedged beam).
Intensity modulated RT allows for “dose painting” (the on purpose
delivery of different doses to different regions in the PTV) and
creating steep dose gradients and concave dose distributions.
At least equally important as conformality is the accurate
spatial delivery of the conformal dose distribution to the PTV. In
conventional RT a simulation is performed in order to search the
radiation isocenter with regard to anatomical structures under
fluoroscopy. The lasers in the simulator room are drawn to the
patient’s skin and prior to each treatment, the skin drawings are
aligned with the lasers in the treatment room that point at the
linac isocenter. Conventional patient positioning by skin drawings
and lasers is a fairly inaccurate method to target the patient’s
bony pelvis and does not offer the possibility to deal with organ
motion.
In prostate RT various methods to reduce uncertainties in organ
and patient position are currently used. The effectiveness of
immobilization devices to improve positioning accuracy is debatable
[13, 14]. Some improvement in setup accuracy by alternative
positioning methods such as using a fixed couch height, 3D-surface
matching or IR skin markers has been reported [15-17]. Internal
prostate immobilization can be achieved using a rectal balloon [18,
19]. The latter method is inconvenient to the patient and might
occasionally introduce large errors [20, 21]. An innovative target
localization method based on detection of implanted electromagnetic
transponders has recently become commercially available (Calypso
Medical Technologies, Inc.) [22]. It represents a non-ionizing
approach for accurate and continuous target localization for
treatment setup and monitoring during radiation therapy
delivery.
Since its origin, RT has been dependent on imaging for
simulation, treatment planning and verification of patient
position. Image guided RT refers to the use of imaging (e.g.
X-rays, CT or ultrasound) instead of skin drawings and lasers for
more accurate patient positioning. Ultimately IGRT should allow for
narrowing the safety margins around the CTV, less normal tissue
irradiation and hence a reduction of side-effects. An overview of
the different IGRT solutions is given in table
1.
The use of imaging, more specifically co-registration of the
planning CT with other imaging modalities, is referred to as image
guided RT planning (IGRTP).
IGRT and IGRT planning
X-ray systems
Electronic portal imaging (EPI) is the oldest and most widely used
IGRT modality. Other systems use daily kV X-ray imaging for
positioning. More recently, ultrasound and CT for daily prostate
positioning have been introduced in clinical practice. Implanted
markers have been used in combination with EPI and X-ray
positioning systems for daily prostate targeting [23, 24]. Possible
migration of these markers seems to be of minor concern [25, 26].
The use of an intra-urethral radio-opaque catheter has not gained
much interest for reasons of patient inconvenience [27].
In EPI, the treatment beam itself is used to generate a 2D MV
image, usually at 0° and 90°. Some commercial systems provide
software for comparison with a reference image − a digitally
reconstructed radiograph (DRR) from the planning CT − and shifts
between the image sets are calculated automatically [28]. In order
to eliminate both systematic and random errors, daily imaging is
required. The latter is not recommended in routine. First, EPI is
not designed as an integrated positioning tool but rather as a
verification tool added to the treatment procedure. For setup
corrections, in most departments the technicians need to enter the
treatment room and manually adjust the table. This translates into
substantial extra time requirements. Second, there is the need to
deliver part of the field dose for image acquisition [29, 30].
Electronic portal imaging has been used to reduce systematic setup
errors by off-line correction but in most RT departments it simply
replaced the megavolt verification films [31-33]. Other
disadvantages of EPI are low image quality and the need for
implanted markers for prostate visualization. An advantages of EPI
is that the actual treatment beam is visualized, allowing for
verification of field edges and leaf positions. Electronic portal
imaging has also been used for dosimetric purposes [34].
The main difference between EPI and X-ray positioning is that
the former verifies a positioning procedure whereas the latter is a
positioning procedure. Examples of commercially available X-ray
solutions are the NovalisBody/ExacTrac system (BrainLAB,
Feldkirchen, Germany) and the CyberKnife (Accuray Inc.).
The IGRT technique developed by BrainLAB [35-37] uses infrared
(IR) reflecting skin marks as a first step in patient setup. The
markers are attached to the skin with self-adhesive film, their
position is marked and the patient is scanned with the markers in
place. The location of the planning isocenter with regard to the
markers is calculated by the planning software. Prior to each
treatment session, the markers are placed back on the patient.
Their location is detected by IR cameras and matched to the
planning information. The operator can then enable the couch to
automatically align the planning isocenter with the linac
isocenter. The next step is the actual image guided procedure.
Prior to each treatment session a pair of X-rays is taken
immediately following the IR positioning. Two options are
available. First an automatic co-registration of the X-ray images
with the reference DRR from the planning CT. The second option is a
fusion of radio-opaque implanted markers on the X-ray images with
expected marker positions projected on the X-rays based on the
information from the planning CT. A correction is then calculated
in order to move the patient to his correct position. The linac
time including X-ray positioning and irradiation is short (around
10’) which is a prerequisite for a system designed for daily
positioning. Because it is used on a daily basis, both systematic
and random setup errors are corrected. The images are kV and
therefore of better quality compared to EPI. The radiation exposure
to the patient for a 78 Gy treatment is estimated 40 mSv which is
at least 10 x less compared to EPI or IGRT using daily CT images
[36].
The CyberKnife system is currently the only IGRT capable of
dealing with intrafraction organ motion. In lung or liver tumours
organ motion can be related to some external breathing signal
allowing for “gated RT” [38, 39]. However, prostate motion cannot
be related to external motion and is unpredictable, the most
important displacements being caused by sudden rectal air passage
[40]. Intrafraction prostate motion remains one of the limiting
factors for reducing the PTV to CTV safety margins. Tools to deal
with intrafraction prostate motion should combine tumour tracking
(e.g. with implanted markers detected by fluoroscopy or EPI),
provide motion feedback to the multileaf collimator or linac and
finally target tracking by dynamic multileaf collimating or dynamic
movement of the linac itself. The CyberKnife system uses X-ray
information as the NovalisBody system but instead of aligning the
target with the beam, the beam (generated by a linac mounted to a
robotic arm) is aligned with the target. The position of the target
can be monitored in fluoroscopy mode and this information can be
fed back to the robot [41]. Drawbacks of this system are the need
for implanted markers and fluoroscopy and the long (30-40′)
treatment time.
A disadvantage of the X-ray solutions which they bear in common
with EPI, is that prostate visualization requires implantation of
radio-opaque markers. Positioning systems based on CT imaging allow
for volumetric prostate imaging without the need for markers.
Because of time requirements and radiation exposure to the patient
they are generally used in off-line setup correction but daily use
is feasible.
Table 1 Overview of prostate IGRT methods with their
advantages (+) and disadvantages (-)
|
Feature
|
X-ray
|
EPI
|
kV CT
|
MV CT
|
US
|
MRIa
|
|
No radiation exposure for image acquisition
|
-
|
---
|
---
|
---
|
+
|
+
|
|
Good image quality
|
+
|
-
|
+
|
-
|
+
|
+
|
|
No need for implanted markers
|
-
|
-
|
+
|
+
|
+
|
+
|
|
Integrated and fast; suitable for daily use
|
+
|
-
|
-
|
-
|
+
|
?
|
|
No organ displacement due to image acquisition
|
+
|
+
|
+
|
+
|
-
|
+
|
|
Deals with intrafraction organ motion
|
±b
|
-
|
-
|
-
|
-
|
?
|
aOnly prototypes available.
bOne commercially available system combines tumour
tracking with dynamic feed-back to robot mounted linac.
Kilovolt (kV) CT systems
A first option is to place a conventional (kV fan beam) CT scan in
the treatment room [42]. The scanner may be positioned over the
treatment coach (CT on rails) or the the coach can be used to move
the patient into the bore. Advantages are high speed and excellent
volumetric image quality. A relative disadvantage is that
resolution in the craniocaudal axis is dependent on the slice
thickness. This first option is rarely used in practice because of
its low cost-effectiveness due to the large amount of idle time. A
second more convenient option is to to install a kV X-ray tube with
detectors on-board on the linac [43]. The slow gantry rotation
inherent to linacs led to the introduction of cone-beam or volume
CT-imaging using an X-ray source with a flat panel detector (e.g.
Synergy from Elekta or On-board Imager from Varian). These systems
allow for a full volumetric reconstruction by one rotation of the
gantry. The images are kV based and therefore of excellent quality.
The spatial resolution is excellent in the three dimensions in
contrast to fan beam CT.
Megavolt (MV) CT systems
As with EPI compared to X-rays, the application of MV for CT has
the inherent disadvantage of low image contrast compared to kV
solutions. On the other hand, scatter artefacts e.g. due to the
presence of a hip prosthesis or implanted markers are less
important in MV CT. As with kV CT, two options are available. The
first option, helical tomotherapy (Hi-Art, Tomotherapy Inc.)
represents the fusion of a linac with a helical MV fan beam CT,
allowing for daily CT assisted positioning followed by a rotational
IMRT treatment [44]. Immediately after the acquisition of the MV
CT, the scan is fused with the planning CT to determine whether
patient setup is correct. Both automatic and manual image fusion
are supported and the translations/rotations obtained from the
fusion. can be used to correct the setup. Theoretically such
correction could be performed by modifying the IMRT delivery but in
practice the patient is moved to the correct position. Operating
the CT detectors during treatment can be used to reconstruct the
actual dose delivered to the patient, which can be compared to the
planned situation as ultimate treatment verification. In this way,
future treatment sessions could be tailored to previous suboptimal
dose distributions, a procedure referred to as “adaptive RT”. The
second option is to use the EPI system available on most
conventional linacs to produce a MV cone beam CT image [45]. A
major concern with MV cone beam imaging is the poor detection
efficacy of X-ray detectors in the MV energy range, resulting in an
important extra-doses required for image acquisition.
Other IGRT solutions
Daily ultrasound positioning is an attractive method because no
radiation is involved and the prostate itself is positioned without
the need for implanted markers. However with ultrasound positioning
there are concerns about interobserver variability and the possible
introduction of errors during image acquisition by pressure to the
patient’s lower abdomen [46, 47].
Prototypes of integrated MRI-radiation devices are being
investigated in the Netherlands and the US [48, 49]. In the future,
they will allow for IGRT without the need for implanted markers or
radiation exposure for image acquisition.
There exists an ongoing interest in heavy particle therapy
because of the physical and radiobiological advantages compared to
photons [50]. Heavy particles are highly susceptible to tissue
inhomogeneities and inter-/intrafraction changes in patient
position and anatomy can have a profound impact on the delivered
dose distribution. In case of carbon irradiation, online spatial
verification of absorbed dose with in-beam positron emission
tomography is currently being investigated [51].
Image guided RT planning
Dose calculation in RT treatment planning involves correction for
tissue inhomogeneities and is therefore dependent on the
information (Hounsfield units) of CT imaging. However for the case
of PC, CT scan is an inaccurate imaging tool with regard to
structure delineation. Magnetic resonance imaging and recently
available CT-MRI co-registration software allow for more precise
prostate delineation mainly in the region of the prostate apex
[52]. Other advantages of MRI are the possibility to visualize the
gross tumour volume, the ability to detect extracapsular extension
or SV invasion not detected by transrectal ultrasound and the
visualization of the penile bulb [53, 54]. Avoiding penile bulb
irradiation might be of benefit with regard to ED, as several
studies showed a correlation between ED and penile bulb dose [55,
56]. Improved imaging during RT planning with MRI, dynamic contrast
enhanced MRI or MRI-spectroscopy can enable us to identify the
gross tumoural lesion [57]. As most recurrences occur within this
lesion [58], overdosage of the lesion might improve outcome after
RT. The feasibility of such treatments using IMRT has been reported
recently [59]. The use of MRI in prostate RT planning is currently
still hampered by the limitations of CT-MRI co-registration
software, especially for non-rigid co-registration (i.e. taking
into account shape differences between CT and MRI).
Comments and conclusion
Following analysis of over 8500 men with PC from the CaPSURE
database (Cancer of the Prostate Strategic Urologic Research
Endeavor), Cooperberg et al. observed a significant downward risk
migration over time [60]. Most PC cases discovered with present
diagnostic techniques belong to the low and intermediate risk
groups (“localized PC”). A significant proportion of these are
indolent cancers, i.e. cancers that will never become symptomatic
during lifetime. The diagnosis of these indolent cases has been
called “overdiagnosis” with an associated threat of “overtreatment”
with associated morbidity [61]. In that respect the increasing
financial pressure by recent expensive treatments - permanent seed
implant brachytherapy (BT) and robot assisted laparoscopic
prostatectomy - should not be disregarded. In localized prostate
cancer, the choice between watchful waiting, radical prostatectomy
(RP), permanent seed implant BT and RT takes into consideration
disease characteristics, life expectancy (i.e. age and
comorbidity), effectiveness and potential side effects of the
different treatments and patient preference.
At present RP is the only treatment shown to offer a survival
benefit compared to watchful waiting in a contemporary randomized
trial [62]. Based on these data, for men presenting with organ
confined PC the World Health Organization considers RP the
treatment of choice for men with a long life expectancy [63]. Of
notice, oncological outcome and complications/side effects are
known to be strongly dependent on expertise in case of surgery. In
an extensive review comparing open retropubic prostatectomy,
laparoscopic radical prostatectomy and robot-assisted laparoscopic
prostatectomy, Herrmann et al. concluded that patient outcome is
determined by the surgeon’s expertise rather than the specific
technique that is being used [64]. In terms of quality of life,
patients managed by surgery experience substantially more urinary
incontinence [65, 66] and erectile dysfunction [67, 68] compared to
men treated with RT. In the process of treatment decision, the data
provided by van Tol-Geerdink et al. should not be disregarded. It
appears that a substantial proportion of prostate cancer patients,
when offered the choice between two treatments, prefer the less
toxic treatment, even at the cost of an associated survival
disadvantage [69].
Conformal RT techniques and IGRT in recent years have permitted
to safely escalate the radiation dose. Retrospective data show
comparable biochemical control for organ confined PC treated with
RT at a dose of ≥ 72 Gy, BT and RP [70]. In the context of modern
RT techniques, randomized trials directly comparing RP to RT no
longer seem unethical. In the UK, the Medical Research Council is
initiating a randomized trial comparing watchful waiting, RP and RT
(ProtecT study: Prostate testing for cancer and Treatment).
The safe administration of high radiation doses for PC has been
made possible by technical progress, first the development of CRT
techniques and − most recently and still under development − a
variety of IGRT solutions. In practice, EPI and X-ray based systems
are still the most commonly used positioning tools. Combined with
implanted markers, they allow for dealing with the problem of
interfraction prostate motion. In practice however, most patients
have no markers implanted and are positioned based on bony anatomy.
For patients that are positioned without markers or another means
of direct prostate visualization, the rectum should be emptied
before planning CT. Rectal distension on planning CT is
significantly related to worse outcome, presumably due to
geographic misses [71]. Image guided RT techniques are becoming
even more important in hypofractionated RT (fewer and larger daily
fractions) for PC. Based on recent radiobiological data, such
schedules are increasingly being used and the risk of impaired cure
due to geographical miss is statistically larger compared to
classical fractionation [72].
The ideal IGRT system would allow for daily prostate imaging
without possible introduction of errors due to image-acquisition
itself, do so within a reasonable time frame, without the necessity
for implanted markers and preferentially without exposing the
patient to radiation. It should also account for intrafraction
prostate motion. A solution that combines all these features does
not exist so far.
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