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Cancer/Radiothérapie 14 (2010) 446–454

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ating and tracking, 4D in thoracic tumours

ating et tracking 4D dans les tumeurs thoraciques

. Verellen ∗, T. Depuydt , T. Gevaert , N. Linthout , K. Tournel , M. Duchateau ,. Reynders , G. Storme , M. De Ridderepartment of Radiotherapy, UZ Brussel, Oncologisch Centrum, Laarbeeklaan 101, 1090 Brussels, Belgium

r t i c l e i n f o

rticle history:vailable online 31 July 2010

eywords:mage-guided radiotherapyatingrackingBRT

a b s t r a c t

The limited ability to control for a tumour’s location compromises the accuracy with which radiationcan be delivered to tumour-bearing tissue. The resultant requirement for larger treatment volumes toaccommodate target uncertainty restricts the radiation dose because more surrounding normal tissue isexposed. With image-guided radiation therapy (IGRT), these volumes can be optimized and tumourici-dal 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 such as hypofractionated radio-therapy (or stereotactic body radiotherapy), deliberate inhomogeneous dose distributions coping withtumour heterogeneity (dose painting by numbers and biologically conformal radiation therapy), andadaptive radiotherapy. In short: “individualized radiotherapy”. Tumour motion management, especiallyfor thoracic tumours, is a particular problem in this context both for the delineation of tumours andorgans at risk as well as during the actual treatment delivery. The latter will be covered in this paperwith some examples based on the experience of the UZ Brussel. With the introduction of the NOVALISsystem (BrainLAB, Feldkirchen, Germany) in 2000 and consecutive prototypes of the ExacTrac IGRT sys-tem, gradually a hypofractionation treatment protocol was introduced for the treatment of lung tumoursand liver metastases evolving from motion-encompassing techniques towards respiratory-gated radi-ation therapy with audio-visual feedback and most recently dynamic tracking using the VERO system(BrainLAB, Feldkirchen, Germany). This evolution will be used to illustrate the recent developments inthis particular field of research.

© 2010 Published by Elsevier Masson SAS on behalf of the Société française de radiothérapieoncologique (SFRO).

ots clés :adiothérapie guidée par l’imageatingrackingBRT

r é s u m é

La capacité limitée de contrôler la position de la tumeur compromet la précision avec laquelle l’irradiationest délivrée aux tissus tumoraux. Il en résulte une augmentation du volume irradié pour inclure le volumecible et une diminution de la dose du fait de l’augmentation du volume de tissus sains irradiés. Avecla technique de la radiothérapie guidée par l’image (IGRT), ces volumes cibles peuvent être optimiséset une dose plus forte délivrée, pour un taux de contrôle tumoral maximal et des effets secondairesminimaux. En outre, avec la capacité de délivrer la dose avec une haute précision et la connaissance entemps réel de la position du volume cible, la radiothérapie guidée par l’image a permis l’exploration de

nouvelles indications, comme la radiothérapie hypofractionnée, la radiothérapie délibérément adaptéeà l’hétérogénéité de la tumeur (dose painting), et la radiothérapie adaptive. Ces approches correspondent

vidualisée ». La gestion des tumeurs mobiles, spécialement celles du thorax, est

à « une radiothérapie indi un problème particulier dans ce contexte, aussi bien pour la délinéation du volume cible et des organesà risque que pour la réalisation du traitement. Ces aspects seront présentés dans cette publication avecquelques exemples de l’UZ Brussel. Avec l’introduction du système Novalis® (BrainLABTM, Feldkirchren,Allemagne) en 2000 et consécutivement à l’introduction du prototype ExacTrac IGRT, un protocole detraitement a été élaboré peu à peu pour les tumeurs pulmonaires et les métastases hépatiques, depuis

∗ Corresponding author.E-mail address: dirk.verellen@uzbrussel.be (D. Verellen).

278-3218/$ – see front matter © 2010 Published by Elsevier Masson SAS on behalf of the Société française de radiothérapie oncologique (SFRO).oi:10.1016/j.canrad.2010.06.002

D. Verellen et al. / Cancer/Radiothérapie 14 (2010) 446–454 447

la prise en compte du mouvement des cibles jusqu’au gating respiratoire avec guidage « audio-visuel »et plus récemment le tracking dynamique avec le système Vero® (BrainLABTM, Feldkirchren, Allemagne).Ces évolutions seront utilisées pour illustrer les développements récents dans ce domaine particulier de

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. Introduction

The prognosis of inoperable lung cancer remains very poorespite a lot of efforts to improve treatment results, and the

nvestigation on new planning strategies such as combinedreatments in radiotherapy and chemotherapy, altered fraction-tion schemes and dose escalation is currently on-going withromising results [14,38,67,15,53]. Many solutions are being inves-igated to control both the dose delivery and tumour motionn the thoracic region, which can be classified as stereotac-ic body radiation therapy (SBRT) and image-guided radiationherapy (IGRT) [17,35,45,60,43,2]. Respiratory motion affects allumour sites in the thorax as well as in the abdominal regionnd motion control allows for reduction of irradiated healthyissues and possible escalation of dose to the target volume25].

Apart from techniques to accurately describe motion,ifferent methods are being developed for motion manage-ent during treatment, such as forced shallow breathing

y abdominal compression or breath hold motion-ncompassing techniques, and respiratory synchronizedechniques such as respiratory gating and real-time tracking35,45,60,66,26,65,12,33,8,24,4,16,46,28,57,58,41,36,37]. All theseechniques require some kind of IGRT to reach full potential.ven when using a stereotactic body frame to suppress breath-ng induced motion, Wulf et al. showed that with a margin forarget variability of 5 mm (antero-posterior and latero-lateral)nd 10 mm (cranio-caudal) about 12–16% of the targets might beissed partially [66]. Therefore, the conclusion was drawn to rec-

mmend CT-verification of the patient inside the body frame prioro each treatment session to detect these targets with increasedeproducibility. Motion-encompassing techniques, a secondption, refer to the idea of incorporating information on tumourotion into the treatment planning process, either by introducing

atient individualized margins or using this information in theptimisation procedure [7,3,13]. Internal motion can be assessedy time resolved imaging techniques such as “slow” CT scanning orET, which due to its slow acquisition time offers information onumour position propability [8,24,4]. Alternatively, multiple fastT acquisitions during the respiratory cycle can be used describ-

ng the target’s motion during the respiratory cycle. Respiratoryotion, however, is irregular and there exist no general respiratory

atterns that can be assumed by observation prior to treatment.rgan motion causes an averaging or blurring of the static doseistribution along the path of motion, and for IMRT an additionalotion artefact follows from a possible interplay between motion

f the leaves of the collimator and the component of target motionerpendicular to the beam [57,58,3,18]. As a result, respiratory-ynchronized techniques will most often offer the optimal solution.t should be noted that sometimes the object being measured for

otion could be the tumour itself, an artificial marker implantedn or near the tumour or a surrogate organ such as the diaphragm45,33,9,44,32]. However, the breathing pattern itself is usuallybtained from an external signal allowing real-time observation

e.g. infrared reflective markers placed on the patient’s surface,pirometers or a flexible bellow), and the mechanical couplingith the tumour is often weak resulting in complex relationships.oreover, the correlation between breathing pattern and tumour

asson SAS pour la Société française de radiothérapie oncologique (SFRO).

position can be disturbed or lost completely by transient changesin breathing. Breathing synchronized techniques need to establisha correlation between the real-time external breathing signaland the internal tumour motion and this correlation needs to beverified with regular intervals during the course of treatment.

Respiratory gating involves the administration of radiation dur-ing certain intervals within a particular portion of the patient’sbreathing cycle, commonly referred to as the beam-on-area or gat-ing window. The choice of the gate width is a trade-off betweenminimizing motion within the gate and beam-on time, and breath-hold techniques are being introduced to optimise the duty cycle[65,28]. Another means of accommodating respiratory motion isrepositioning the radiation beam dynamically so as to follow thetumour’s changing position, referred to as real-time tumour track-ing. The latter can be established by synchronizing the linac’scollimating system with the target motion [20,49]. With conven-tional MLCs, however, only one dimension can be compensated forefficiently and the beam-collimating device needs to be alignedsuch that the leaf motion coincides with the major axis of thetumour motion. Compensation of 2D motion might be offeredwith the pan-and-tilt-like solution currently under developmentand full 3D compensation is realized with the linac mounted to arobotic arm [37,44,19,10,34]. Compared to the gating technique thetracking approach potentially offers higher delivery efficiency andless residual target motion provided there is no system latency inthe beam adaptation [44]. It should be noted that these trackingapproaches rely on an accurate prediction model of the breath-ing motion to anticipate the future position of the tumour, whichproved to be challenging [35]. An excellent overview of the man-agement of respiratory motion in radiotherapy can be found in thereport of the AAPM Task Group 76 [21].

Important to note at this stage is the influence of imaging proce-dures in the diagnosis and treatment-planning set-up of the patient.Assessment of motion is only one aspect of tumour motion manage-ment; imaging artefacts introduced in the image reconstruction arealso to be considered. Basically there are three options possible forCT imaging that can include the entire range of tumour motion forrespiration. Listed in order of increased workload they can be clas-sified as: slow CT, inhalation and exhalation breathhold CT, and 4Dor Respiration Correlated CT (RC-CT). It is important to understandthat the breathing patterns and, hence, tumour motion will changeover time (between simulation or imaging sessions and treat-ment sessions) and are inherently irreproducible. When measuringtumour motion, the motion should be observed over several breath-ing cycles. With the previous generation of “slow” CT scanners, theimage of the tumour is smeared out due to breathing motion. Inthis case tumour volume and organ delineation will be extremelydifficult and subject to intra- and inter-observer variability [51,48].This technique yields a tumour-encompassing volume, with thelimitation that the respiratory motion will change between imag-ing and treatment. Moreover, motion may cause localization errorsand in some cases disappearance of small tumours that shouldbe detectable. The fast helical multi-slice CT scanners actuallyfreeze the image of the tumour at one location at one particular

moment in the breathing cycle. Thus, offering a more anatomicallyrelevant representation of the tumour. As this is not necessar-ily the average tumour position, however, this fast acquisitionmight introduce large systematic errors with respect to beam-

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48 D. Verellen et al. / Cancer/R

umour alignment when used inappropriately. Several strategiesave been investigated to solve this problem, such as inhalationnd exhalation breathhold techniques, respiratory gating and res-iration correlated or 4D CT (RC-CT) [4,21,40,31,11,54]. Inhalationnd exhalation breathhold CT scans can also be applied to obtaintumour-encompassing volume. The advantage of this approach

ver the slow scanning technique mentioned above is that thelurring caused by motion is significantly reduced. Dose calcu-

ation, however, should be performed on the CT data set that isost appropriate for that particular treatment and patient. One

ption could be to use a free breathing CT for dose calculationnd using the inhalation and exhalation scans to determine theange of motion and more accurate tumour delineation. RC-CT isrelatively new technology, made possible by the introduction

f faster CT scanners with multiple detector rows. Basically, it isn oversampled or low-pitch CT scan during which the respira-ion signal is recorded. The latter can be obtained with different

ethods, of which abdominal straps with a pressure sensor infraredarkers placed on the patient’s chest, and measuring airflow with

hermocouples or spirometers in a mouth mask are most com-on [4,11,27,29,62,30,63]. Afterwards, the CT images can be binned

sorted) according to the phase or amplitude of the external respira-ory signal (phase-angle or amplitude sorting) [30,1]. Incorporatinghe 4D information into the treatment planning is possible in dif-erent ways, again based on the treatment technique. One options to use only one phase of the respiration, e.g. the mid-ventilationhase, as being the phase where the tumour is at its average posi-ion, in combination with a “margin recipe” (based on the extentf motion observed from the other data sets) to account for theotion [64]. Some investigators use Maximum Intensity Projec-

ions (MIPs), which reflect the highest pixel value encountered fromll CTs along the viewing ray for each pixel, giving rise to an arti-cial intensity display of the brightest object along each ray onhe projection image [50]. Another option is to contour each phaseeparately, or alternatively, contour one phase and use deformableegistration to obtain the contours in the other phases, and use thenion of the contours obtained from these data sets to obtain aargin recipe. In the case of respiratory-gated radiotherapy, oneight decide to delineate the tumour volume in the treatment

hase-angle or amplitude sorted data set only (provided a similarechnique is used to obtain the external breathing signal). Again,t is important to recall the fact in that the patient’s breathinguring CT-scanning might not be representative of the breathinguring treatment and the correlation between the external signalnd internal tumour motion is prone to changes (irregular breath-ng, tumour response, base line shifts, etc.). Respiratory correlatedrradiation techniques thus require IGRT during treatment to vali-ate and/or update the correlation between the external breathingignal and the internal tumour motion. Many of these argumentslso apply to PET-imaging: RC-PET SUV determination and quan-ification of tracer uptake (e.g. for use in biologically gated radiationherapy) is more reliable and thus better suited for use in tumourharacterization and automated delineation [40,63,39,5].

. Gating

The clinical introduction of dynamic field shaping arc treat-ent in combination with an image-guided technology allowing

eduction of treatment margins initiated a clinical evaluation ofypofractionation schemes at the UZ Brussel [9,47,55,59,56,52].

he aim was reduction of complications and improvement of qual-ty of life in patients treated for primary lung lesions as wells pulmonary or hepatic metastatic disease. In a first approach,he internal margin (IM) was handled separately from the set-p margin (SM) by establishing a procedure for optimal control

érapie 14 (2010) 446–454

of the SM using stereoscopic kV-imaging (NOVALIS BODY / Exac-Trac 4.0, BrainLAB, Feldkirchen, Germany), and determination ofthe actual extent of target motion to obtain an individualized andtumour specific IM in the PTV [58,42]. The latter was establishedby incorporating PET as a “slow” imaging technique to assess theindividualized internal organ movements during the treatmentplanning process as suggested by Caldwell et al. [8]. Results havebeen published on 36 cases of stage I/II non-small cell lung can-cer in inoperable patients [6]. Treatments were planned to a totalisocentre dose of 60 Gy (8 × 7.5 Gy) based on a dynamic field shap-ing arc, employing one arc to span as much area as possible and ifneeded additional weighted segments. The 2-year infield progres-sion free probability was 65%. Disease-specific survival was 75% attwo years. No patients experienced grade 3-4 toxicity.

In a second approach, adaptations to the commercially avail-able image-guidance technique had been implemented allowingbreathing synchronized irradiation with the NOVALIS system[57,58] (Fig. 1). Prior to treatment the patient was positioned usingthe infrared positioning system to align the treatment isocen-tre approximately with the machine’s isocentre. The patient wasallowed free breathing and during several seconds the breathingsignal was monitored in 3D. The operator then defined a cen-tral level or gating reference level for target localization at about30% of the breathing amplitude. Two additional imaging levelswere placed above and beneath the reference level, to quantifythe tumour movement around the gating reference level. Conse-quently, three pairs of stereoscopic X-ray images were acquiredat the corresponding imaging levels and registered with digitallyreconstructed radiographs (DRR) using an implanted radio-opaquemarker. The treatment couch was adjusted automatically to cor-rect the patient’s position based on the shift calculated from theregistration of the images acquired at the gating reference level.The beam-on-area or gating window was defined based on thecalculated tumour displacement between the gating referencelevel and the two additional levels. The size of the gating win-dow was restricted to a tumour motion of about 2.0 mm aroundthe gating reference level. The treatment beam of the linac wastriggered automatically by the IR-system to irradiate only insidethe predefined treatment window, limiting the target motion toamplitudes of about 4.0 mm during irradiation while the patientperformed free breathing. The former approach assumed a sta-ble correlation between internal and external markers, which ofcourse need not be true. Therefore, the operator could predefinean allowed tolerance around the implanted markers in the initialimages and during treatment multiple pairs of stereoscopic kV-images could be acquired at the predefined imaging levels. Eachtime the implanted markers would be automatically detected and ifthe marker position was within the allowed region, treatment pro-ceeded as planned. If, on the contrary, the implanted markers werenot in the allowed region of tolerance, the treatment was abortedand the correlation between internal en external markers neededto be re-established.

A simple phantom simulating a breathing pattern of 16 cyclesper minute and covering a distance of 4.0 cm had been introducedto assess the system’s performance to:

• trigger the linac at the right moment (using a hidden target in theform of 3 mm metal bead mounted to the phantom);

• assess the delivered dose in non-gated and gated mode (using anionization chamber mounted to the phantom);

• evaluate the interplay between organ motion and leaf motion

when applying dynamic MLC (DMLC) IMRT techniques (usingradiographic film mounted to the phantom) [57,58].

The effect of interplay had been evaluated by importing themeasured fluence maps generated by the linac into the treatment

D. Verellen et al. / Cancer/Radiothérapie 14 (2010) 446–454 449

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ig. 1. Panel A: the Novalis system with flat panel detectors mounted to the ceilinR-reflective markers to obtain the respiration signal (panel C) and video gogglesdditional imaging levels and the beam-on area. Panel D: Projection of implanted morrelation between marker potion and IR respiratory signal.

lanning system and re-calculating the resulting dose distributionrom DMCL IMRT fluence patterns acquired in non-gated and gated

ode. No measurable delay in the triggering of the linac had beenbserved based on the hidden target test. The ionization chambereasurements showed that the system was able to improve the

ose absorption from 44% (in non-gated mode) to 98% (in gatedode) for a small field irradiation (30 × 30 mm2) of a moving target.

mporting measured fluence maps, generated for a realistic patient

reatment and actually delivered by the linac, into the treatmentlanning system yielded highly disturbed dose distributions in casef the non-gated delivery, whereas the gated delivery showed goodgreement with the original theoretical dose distribution, which

ig. 2. Representation of respectively the theoretical fluence pattern as calculated by thlm moving orthogonal to leaf motion (panel C), moving parallel to leaf motion (panel Dreatment (Dynamic MLC on the Novalis). The resulting cumulative dose–volume histogr

X-ray tubes embedded in the floor. Panel B: Patient on the treatment couch withdio-visual coaching. Panel C: Respiration signal with central reference level, twowithin 3 mm tolerance level with respectively a non-acceptable and an acceptable

was confirmed by the dose-volume histograms (Fig. 2) [57,58].Using single-point dose measurements Jiang et al. have investi-gated the effects of intra-fractional organ motion in sliding windowand step-and-shoot MLC IMRT delivery modes concluding that thedose variation was found to be insensitive to the MLC delivery modewhen the tumour motion was perpendicular to the leaf motion[18]. Although these investigators only evaluated the dose varia-tion at the centre of the target volume (neglecting possible effects

of motion on other points inside the target), an interesting con-clusion was the reduction in dose variation when accounting forthe treatment fractionation, as well as their recommendation toreduce the dose rate in these particular cases. Nevertheless, these

e treatment planning system (panel A), measured on film (panel B), measured on) and measured on film for a gated treatment (panel E) for one beam of an IMRT

ams of the clinical target volume (CTV) for the entire treatment (panel F).

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onclusions might not be generalized to situations where targetnd leaves move parallel, nor when reduction of treatment mar-ins is considered. Especially the sweeping window technique wille prone to dose degradation and should not be applied clini-ally without an appropriate IGRT technique allowing some kindf breathing synchronized radiation. These examples showed thathe most prominent effect of interplay of IMRT dose delivery andrgan motion could be observed in the reduction of tumour con-rol probability (TCP) and an increase in dose heterogeneity [57,58].he normal tissue control probability (NTCP) values seemed to beffected to a lesser degree. This evaluation also illustrated that theose blurring (yielding a high dose in the centre of the CTV and

ower dose but spread in the direction of motion) is probably theost important effect and that possible hot spots inside organs at

isk due to interplay are not likely to occur. This agrees very wellith previous findings of Bortfeld et al. who performed software

imulations to evaluate motion effects in IMRT. These investiga-ors concluded that the main effect of organ motion is a weightedverage of the dose distribution over the path of motion, and thatdditional effects specific for IMRT delivery appear to be relativelymall [3,18]. In other words, the situation is not so different as foronventional beams with tight treatment margins.

Based on the previous experimental validation a clinicalrogram was established applying conformal beam irradiationechniques in combination with the gated technology [28]. Thetudy comprises 25 patients treated with respiratory-gated radi-tion therapy between August 2005 and April 2008. The selectionriteria were defined in the treatment protocol accepted for theWO G.0412.08 study and the prominent selection criterion to treatatients with gated radiation therapy was the internal movementf the tumour. All patients evaluated for gated radiation therapyad a radio-opaque marker placed percutaneously in the lesionrior to simulation [9]. With this marker the movement of the tar-et could be visualized and evaluated by means of fluoroscopy.henever the marker movement exceeded 6.0 mm in the axial

lane or 8.0 mm in the cranial-caudal direction, the patient waseferred to gated radiation therapy. In all other cases the patientas treated with conformal radiation therapy with appropriateargins. The first nine patients of the 25-gated treatments were

rradiated during free breathing without any feedback. Patients 10o 16 had only visual feedback and the last nine patients had bothisual feedback and audio assistance. The first group of patientsncluded treatments with hypofractionation schedules of 10 × 4 Gyor palliative treatments (3 patients), 3 × 12 Gy for liver treatments4 patients) and 8 × 7.5 Gy for primary lung treatments (2 patients).he fractionation schedules in the second group were: 10 × 4 Gy foralliative treatments (2 patients); 8 × 7.5 Gy (1 patient), 4 × 15 Gy1 patient) and 3 × 20 Gy (3 patients) for primary lung treatments.n the third group, all but one patient were treated for a periph-ral primary lung tumour with a hypofractionation schedule of× 20 Gy. The last patient received 4 × 15 Gy for a centrally locatedrimary lung tumour. The average patient age was 67y (53y–77y),0y (42y–80y) and 75y (63y–85y) for the three groups respectively.

In the initial phase no feedback was provided and in the sec-nd phase only visual feedback was introduced by means of videolasses (Eye-Track FMD-200, Olympus, Hamburg, Germany). Theideo glasses displayed both the patient’s breathing signal as well ashe gating window, allowing the patient to perform a breath-hold inhe beam-on-area or limit the breathing amplitude whenever pos-ible. If the patient was not able to perform either, treatment waserformed in free breathing. In a third step an in-house developed

udio assistance was added to the treatment procedure to assisthe patient in performing breath-hold in the beam-on-area and tonform the patient to perform free breathing during target local-zation verification and during linac setup between consecutiveeams.

érapie 14 (2010) 446–454

The treatment time was analyzed to define the influence ofthe introduction of the visual feedback and later on the audioassistance. The delivery time of gated treatment during free breath-ing had an average value of 1.7 min/100 MU (SD 0.6 min/100 MU).The introduction of visual feedback reduced the average deliv-ery time to 1.4 min/100 MU (SD 0.4 min/100 MU). The treatmentswith additional audio-assistance indicate a significant reduction(p = 0.004) of the average delivery time to 0.9 min/100 MU (SD0.2 min/100 MU). The verifications of the first group of patientswere used for the evaluation of the target localization accuracy. Thisresulted in a total of 516 acquired images of which 378 were eligi-ble for analysis. An average of 11 verification images was acquiredper treatment fraction. The analysis showed an average deviationof 0.8 mm (SD 0.4 mm; max 2.6 mm) between the expected and theactual position of the internal marker at the gating reference level.

The results of the previous study confirmed the significant timereduction that is obtained by the application of guided volun-tary breath-hold at a pre-defined position in the breathing cycle.Audio assistance could be used for regularization of the breath-ing as described by Korreman et al. and Kini et al., but in the UZBrussel study the audio assistance was used to inform the patientwhat was actually happening at the console of the linac and tohelp the patient in maintaining a breathhold within the beam-on-arrest [23,22]. This practice avoided the need for someone toenter the treatment room and inform the patient to change thebreathing pattern. The technique being independent of the breath-ing consistency has also an advantage over the techniques thatare using RC-CT to define the PTV using an internal target vol-ume based on a few phases of the RC-CT scan. As mentionedbefore, the breathing pattern of the patient during the acquisi-tion of the RC-CT scan is not necessarily representative for thebreathing pattern during the treatment where the patient oftenis more agitated. The use of an internal marker close to or in thetumour as surrogate and continuous on-line verification duringthe treatment, can account for base line shifts and other devia-tions between the actual and the expected position of the tumour[21]. During this study, one more parameter, the dose rate, wasevaluated in order to decrease the treatment delivery time [28].The default dose rate used for the treatments in the previous eval-uation was 480 MU/min. Willoughby et al. reported a radiationoutput accuracy within 0.5% when the dose rate was increasedfrom 480 MU/min to 800 MU/min [61]. Comparable measurementsin our department showed equally an output consistency withinthe uncertainties of the measurements. Additionally, the internalmarker movement within the beam-on-area was compared forseveral gating windows with both 480 MU/min and 800 MU/min.The measured movements were comparable within 0.5 mm forthe different dose rates. Currently, the patients treated at the UZBrussel have a gated radiation delivery with visual feedback, audioassistance and an increased dose rate of 800 MU/min. Preliminaryresults of the first patients treated with these new settings showan average treatment time of 0.4 min/100 MU (SD 0.1 min/100 MU)what corresponds with a reduction of 76.5% of the average deliverytime of the first patient group of this study.

3. Tracking

Recently (June 2009), the VERO system, a novel radiation ther-apy accelerator platform developed for image-guided stereotacticbody radiotherapy, has been installed in the UZ Brussel (Fig. 3). This

device is a joint product of BrainLAB (BrainLAB AG, Feldkirchen,Germany) and MHI (Mitsubishi Heavy Industries, Tokyo, Japan)[19]. A newly developed small and light six MV C-band linac withattached MLC is mounted on an O-ring gantry. The ring itself canrotate ±60◦ for non-coplanar irradiation. The linac-MLC assembly is

D. Verellen et al. / Cancer/Radiothérapie 14 (2010) 446–454 451

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ig. 3. The VERO system at the UZ Brussel, consisting of an O-ring gantry allowingon-coplanar irradiation, gimballed linac, EPID, dual source X-ray imaging system,D robotic treatment couch, and infrared tracking system.

ounted to orthogonal gimbals, allowing for pan-and-tilt motion ofhe therapeutic beam. This mechanism offers the possibility to per-orm real-time tracking of moving tumours. The maximum motionmplitude of the beam axis at isocentre distance is 4.4 cm (or 2.5◦)n both pan and tilt direction. For on-board imaging, the VERO sys-em is equipped with both an EPID for MV portal imaging as wells two orthogonal kV imaging systems attached to the O-ring at5◦ from the MV beam axis. The latter allowing for cone-beam CTcquisition, simultaneous acquisition of orthogonal kV images anduoroscopy for tumour tracking. An ExacTrac (BrainLAB AG, Feld-irchen, Germany) automated infrared (IR) marker-based patientositioning device with 5-DOF robotic treatment couch is inte-rated into the VERO system. A prototype of the real-time tumourracking is currently installed on the system at UZ Brussel enablinghe VERO system to actively track an IR marker, and an assessmentas made of the tracking capabilities in terms of tracking errors,

ystem latency and the equivalence of pan and tilt gimbals motioni.e. 2D isotropy or equivalence).

In the experimental set-up, the gantry and O-ring angles werexed at 0◦, and the infrared tracking device was used to follow an

R marker movement in a horizontal plane at SAD 1000 mm [10]Fig. 4). The MLC field size was set to 30 × 30 mm2 and the lighteld of the system was projected onto a sheet of paper perpen-icular to the initial beam axis. The projection of the light fieldas used to identify the beam position at all times, whereas the

hadow of the IR marker represented the target that was to beracked by the system. The projections of light field and markerhadow were captured using a photo camera with movie functiont a frame-rate of 30 fps. The MPEG movie frames were convertedo bitmap files for further processing and analyzed using a Houghransform based feature detection. The IR marker is detected as aircular object in the image, the field outline as a rectangular object.he centroids of these objects were used to define respectivelyhe tracked marker and the tracking beam position. To determinehe tracking error, the IR marker was placed on a moving phan-om generating a 1D sinusoidal motion with different frequenciesanging from five breaths-per-minute (bpm) (0.085 Hz) to 30 bpm0.500 Hz), and a fixed amplitude of 20 mm. The 30 bpm in combina-ion with the 20 mm amplitude reaches a maximal tracking speed of

0 mm/s. The VERO tracking forward prediction, a 3rd order poly-omial prediction function, in the prototype software was set to0 ms, 35 ms and 50 ms for all frequencies. In addition a measure-ent was performed without forward prediction to quantify the

ystem lag (Fig. 5). The experiment was performed separately for

Fig. 4. Experimental set-up to verify tracking accuracy of the VERO gimballed linac.The projection of the light field and the shadow of the marker are captured by thecamera system for analysis.

the X direction (pan) and the Y direction (tilt). In addition to theartificial sinus waves, a patient signal was also investigated.

The prototype system latency was calculated from the phaseshift between the motion of the tracking beam and the motion ofthe tracked object for a prediction time set to 0 ms. An averagewas calculated over all applied sinus frequencies from 5 bpm to30 bpm. The system latency determined for the IR marker track-ing was 47.7 ms (SD 2.3 ms) and 47.6 ms (SD 2.0 ms) for the Xand Y direction respectively. The tracking error was characterizedin terms of systematic error, root mean square error (RMSE) and90% percentile of the absolute tracking error values (E90%) eachcalculated over a whole number of sinus periods. The maximal sys-tematic errors, calculated as the average of the difference betweentracked object and tracking beam position, were below 0.2 mm forall motion sequences. Without forward prediction, the trackingerror is strongly dependent on the motion frequency and valuesof up to 1.84 mm and 2.98 mm for X and 1.60 mm and 2.99 mm forY were seen for RMSE and E90% respectively. Compensating thesystem latency with a forward prediction gimbals control of 50 msreduced both maximum values of RMSE and E90% respectively to

0.29 mm and 0.59 mm for X, and 0.41 mm and 0.82 mm for Y. Thetracking behaviour in X and Y direction separately without forwardprediction showed an average breathing frequency of 19.1 bpm. TheRMSE and E90% were respectively 0.95 mm and 1.37 mm without

452 D. Verellen et al. / Cancer/Radiothérapie 14 (2010) 446–454

F t, thef

fp

tgtdfacmttc

4

oiniPiadodtsiadop

ig. 5. Graphs showing the tracked object movement and tracking beam movemenor an amplitude of 20 mm without forward prediction.

orward prediction, and 0.20 mm and 0.37 mm for 50 ms forwardrediction.

These preliminary tests of the VERO tracking prototype showedhe system’s performance regarding mechanical tracking speed andimbals system latency to follow one IR marker in space with theherapeutic beam. The performance of the tracking in both X and Yirection is similar, unlike for MLC tracking where substantial dif-erences may arise between tracking of fast moving tumours inlinend perpendicular to the MLC leaf trajectories. The future clini-al system will use a combination of stereoscopic kV imaging andultiple external IR markers on the patient to track the tumour. In

he clinical kV fluoroscopy based tracking system, additional sys-em lag from the image acquisition and processing will have to beompensated for by the forward prediction.

. Conclusions

Advances in multi-modality imaging have initiated new devel-pments in radiation therapy, and vice versa. The clinicalntroduction of advanced sophisticated treatment delivery tech-iques such as IMRT implies more stringent requirements on

maging in obtaining morphological and functional information.rogress in molecular and functional imaging provides new andndividualized treatment options in deciding not only where butlso how the dose should be delivered. The development, vali-ation, and translation of IGRT strategies to clinical practice areccurring rapidly, facilitating the reduction of healthy tissue irra-iation and introducing new treatment strategies. Radiotherapyreatment units can now be considered as state-of-the-art roboticystems capable of 3D soft tissue imaging immediately before, dur-

ng or after treatment delivery, improving the target localizationt the time of radiation delivery, and ensuring that the treatmentose is delivered as planned. Without image guidance at the timef therapy, changes in position, shape, and breathing motion mayrevent the desired dose from being delivered to the patient. The

tracking error and speed based on the projections captured by the camera system

clinical situations most likely to benefit from IGRT include those inwhich the tumour is in close proximity to sensitive healthy tissues,the doses required to control the tumour are higher than the toler-ance levels of adjacent normal tissues or biologically conformal toaddress the tumour’s heterogeneity, the consequences of position-ing errors are severe, and organ motion and set-up error are large.The latter, 4D in thoracic tumours, is where gating and trackingirradiation techniques might make a difference in both the tumourcontrol as well as the patient’s quality of life.

Conflicts of interest

The authors have not declared any conflicts of interest.

Acknowledgements

Part of this work has been financially supported by the “Fondsvoor Wetenschappelijk Onderzoek – Vlaanderen (FWO)”, grantsG.0486.06 and G.0412.08, the “Hercules Foundation” and corporatefunding from BrainLAB AG. There are no other conflicts of interest.

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