Clinical Oncology (2009) 21: 408e416doi:10.1016/j.clon.2009.02.002

Original Article

Does Intensity-modulated Stereotactic Radiotherapy AchieveSuperior Target Conformity than Conventional Stereotactic

Radiotherapy in Different Intracranial Tumours?

S. D. Sharma*, R. Jalaliy, R. D. Phurailatpamz, T. Guptaz*Department of Medical Physics, Tata Memorial Hospital, Dr. Ernest Borges Marg, Parel, Mumbai, India; yDepartment of

Radiation Oncology, Tata Memorial Hospital, Dr. Ernest Borges Marg, Parel, Mumbai, India; zDepartment of Radiation Oncology,Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, India

ABSTRACT:Aims: To compare the dosimetric outcome of various conventional stereotactic radiotherapy (SRT) techniques withintensity-modulated stereotactic radiotherapy (IMSRT) in brain tumours of varying shape, size, location and proximity toorgans at risk (OARs).Materials and methods: Fused computed tomography and magnetic resonance imaging datasets of four patients withdifferent brain tumours previously treated with non-coplanar static conformal fields (SCF) were re-planned on theBrainScan treatment planning system using non-coplanar conformal arcs (CA), dynamic conformal arcs (DCA) and IMSRTwith coplanar (IMSRT_CP) or non-coplanar (IMSRT_NCP) beam arrangement. Beam shaping and intensity modulationwere carried out using a BrainLab micromultileaf collimator. The primary objective for each plan was to encompassR99% of the planning target volume (PTV) by O95% of the prescribed dose while minimising the dose to OARs.Results: The mean PTV coverage in SCF, CA, DCA, IMSRT_NCP and IMSRT_CP was 99.2, 99.5, 99.4, 99.2 and 99.2%,respectively. The highest dose within the target was !107% of the prescribed dose in all plans. Conformity was found tovary depending on the shape and location of the target. The best mean conformity index, ranging from 0.74 (CA) to 0.84(IMSRT_NCP) was observed in spherical tumours. Among the three conventional SRT techniques, DCA and SCF appearedcomparable (mean conformity index 0.72 and 0.71, respectively) and more conformal than CA (mean conformity index0.67). In all cases, IMSRT showed better target conformity than conventional SRT techniques with a mean conformityindex of 0.83 for non-coplanar and 0.81 for coplanar beam arrangement. The maximum improvement in conformityindex was observed for IMSRT_NCP in complex, concave and irregularly shaped targets. The volume of normal brain andother OARs irradiated to high ( R80%) and low ( R30%) dose varied depending on the tumour shape, size, and location,but was essentially comparable in all three conventional SRT techniques. IMSRT (both coplanar as well as non-coplanar)reduced the volume of normal brain being irradiated to moderate to high doses compared with conventional SRTtechniques, more so for large and irregular targets.Conclusions: DCA and SCF are preferred conventional SRT techniques in terms of target conformity and reduction ofdoses to OARs. The use of IMSRT_NCP further improves conformity and reduces doses to OARs in a range of brain tumourscommonly considered for stereotactic irradiation. Sharma, S. D. et al. (2009). Clinical Oncology 21, 408—416

ª 2009 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Key words: Brain tumour, conformity index, IMSRT, SRT

Introduction

Stereotactic radiosurgery (SRS) techniques using a linearaccelerator have evolved from the initial arc-basedapproach with standard circular cones to miniature multi-leaf collimator (MLC)-shaped dynamic conformal arcs (DCA)[1e4]. The radiobiological advantages of fractionationcombined with localisation precision and repositioningaccuracy of stereotactic systems has made fractionatedstereotactic radiotherapy (SRT) a widely accepted standardtreatment for several benign to low-grade intracranial

0936-6555/09/210408þ09 $36.00/0 ª 2009 The Royal Col

tumours. In the recent past, the potential of beam intensitymodulation using miniature MLC combined with the pre-cision of stereotactic positioning has been explored forsuperior dose conformation in intensity-modulated stereo-tactic radiotherapy (IMSRT) [5,6]. Although the data fora formal qualitative dosimetric comparison of conventionalSRT techniques with IMSRT are available for geometricaltargets and meningiomas [5,6], most commonly in the skullbase, similar data are lacking for other histologies, as wellas brain tumours having complex, concave, or irregularshapes and at differing locations. Moreover, it is not

lege of Radiologists. Published by Elsevier Ltd. All rights reserved.

Table 1 e Patient characteristics and target volumes

Case Diagnosis SiteGTV(cm3)

PTV(cm3)

1 Craniopharyngioma Sellar/suprasellar 20.62 51.922 Optic chiasmatic glioma Sellar/suprasellar 6.43 29.533 Cerebellar astrocytoma Posterior fossa 14.13 49.654 Schwannoma Right parasellar 34.09 88.28

GTV, gross tumour volume; PTV, planning target volume.

409DOSIMETRIC COMPARISON OF IMSRT AND CONVENTIONAL SRT IN INTRACRANIAL TUMOURS

entirely clear how IMSRT would compare with other existingand well-established SRT techniques for spherical targets.This study was undertaken to compare the dosimetricoutcome of various SRT techniques and to evaluate thepotential role of IMSRT in the treatment of brain tumours ofdifferent shape, size, location and proximity to organs atrisk (OARs) using the same device for beam shaping andintensity modulation. The dosimetric outcome of IMSRTusing coplanar fields (IMSRT_CP) was compared withdifferent conventional stereotactic irradiation techniques,including multiple non-coplanar static conformal fields(SCF), conformal arcs (CA) and DCA. Moreover, the role ofnon-coplanar beam arrangement in IMSRT planning(IMSRT_NCP) was also evaluated for improvement inconformity and reduction of OAR doses.

Materials and Methods

Patient Selection

Four paediatric patients with different benign and low-grade brain tumours were selected for this dosimetric study(Table 1). These cases were selected to represent tumoursvarying in shape, size, location and proximity to criticalorgans. The mean planning target volume (PTV) of theselected cases was 55 cm3 (range 29.5e88.3 cm3).

Dose Planning

Fused computed tomography and magnetic resonanceimaging datasets of these four patients previously treated

Table 2 e Description of various treatment techniques and typical pla

Planning technique No. fields/arc

Static conformal fields (SCF) 6e7 uniform-intensity non-c

Conformal arcs (CA) 6 uniform-intensity non-copl

Dynamic conformal arcs (DCA) 6 uniform-intensity non-coplIntensity-modulated radiotherapye

non-coplanar (IMRT_NCP)6e7 intensity-modulated non

Intensity-modulated radiotherapye

coplanar (IMRT_CP)6 intensity-modulated coplan

with 6 MV X-rays using multiple non-coplanar SCF wereselected for the present dosimetry study. All patients wereplanned on BrainScan (V5.31, BrainLAB GmbH, Heimstetten,Germany) treatment planning system (TPS) using 6 MVX-rays. The SCF plan consisted of six or seven non-coplanarstatic fields, each field individually shaped to the beams eyeview projection of the target using a miniature MLC. The 26pairs of miniature MLC (BrainLAB) with its variable pro-jected leaf width of 0.3, 0.45 and 0.55 cm at the isocentrecan define a maximum field size of 10.2� 10.2 cm2 and canoperate in the dynamic mode for the modulation of beamintensity. The details of the beam geometry used in this SCFplanning and shaping of conformal field have been describedelsewhere [7]. Each patient was re-planned on theBrainScan TPS with non-coplanar CA, non-coplanar DCAand IMSRT with coplanar (IMSRT_CP) or non-coplanar(IMSRT_NCP) beam arrangement. Typical plan parametersfor all the different planning approaches are summarised inTable 2. These parameters were customised to individualcases by optimising the couch and gantry angles by a fewdegrees from the typical geometry. The beam geometry ofevery patient was kept unchanged in CA and DCA. However,unlike CA where the shape of the field aperture remainsconstant during an arc, in DCA the shape of the miniatureMLC was automatically adjusted to the projection of thetarget in beams eye view for every 10� increment from thegantry start angle. The dynamic sliding window techniquewas used for IMSRT. The IMSRT_NCP plan was carried outusing the same beam arrangement as in SCF for therespective patient, whereas the IMSRT_CP plan was gener-ated for each patient using six equally spaced coplanarfields. In all techniques, a 0.1e0.2 cm isometric margin wasadded uniformly around the target to account for penumbraand, thereby, improve target coverage. The position ofa few miniature MLCs in each field was manually edited inthe SCF plans to improve target conformity. The BrainScanTPS uses a pencil beam algorithm for regular dosecomputation and the dynamically penalised likelihoodmethod, a variant of the maximum likelihood estimator, toobtain optimum fluence in IMSRT planning [8,9]. All planswere generated using a single isocentre. A dose of 54 Gy in

n parameters

s Typical table (T) and gantry (G) angles (()

oplanar fields T ¼ 10, G ¼ 260;T ¼ 350, G ¼ 100;T ¼ 60, G ¼ 60 & 120;T ¼ 300, G ¼ 300 & 240T ¼ 90, G ¼ 340

anar arcs T ¼ 0, G ¼ �(60e120)T ¼ �30, G ¼ �(30e130)T ¼ �60, G ¼ �(30e130)

anar arcs Same as CA-coplanar fields Same as SCF

ar fields T ¼ 0, G ¼ 0, 52, 104,156, 208, 260 and 312

Fig. 1 e Resultant dose distribution from all five different techniques: (a) non-coplanar static conformal fields (SCF), (b) non-coplanarconformal arcs (CA), (c) dynamic conformal arcs (DCA), (d) intensity-modulated stereotactic radiotherapy with non-coplanar beamarrangement (IMSRT_NCP) and (e) intensity-modulated stereotactic radiotherapy with coplanar beam arrangement (IMSRT_CP) for a complexand irregularly shaped target in the case of a right parasellar schwannoma.

410 CLINICAL ONCOLOGY

30 fractions was prescribed and normalised to the isocentre,with 100% as the prescription isodose. To facilitate directcomparison between different techniques, the primaryplanning objective was to encompass R99% of PTV byO95% of the prescribed dose at the isocentre, whilemaintaining the maximum dose limit at 107%, as recom-mended by International Commission on Radiation Units andMeasurements Report 50 (ICRU 50) [10]. Moreover, maxi-mum effort was made to keep the dose to the OARs asminimum as possible.

Plan Evaluation

The dosimetric outcome of different techniques wascompared qualitatively and quantitatively in terms oftarget volume coverage, conformity and irradiation ofnormal brain and OARs, such as temporal lobe andbrainstem, to varying dose levels. Target coverage wasestimated as the percentage of the target volume (VT)covered by the prescription dose (VT,Pi), i.e. target cover-age¼ (VT,Pi/VT)� 100%. The conformity of the target was

411DOSIMETRIC COMPARISON OF IMSRT AND CONVENTIONAL SRT IN INTRACRANIAL TUMOURS

estimated using a conformity index defined by Paddick [11]as conformity index¼ {VT,Pi� VT,Pi}/{VT� VPi}, where VPi isthe volume enclosed by the prescription isodose. Thisconformity index also takes into account the location of theprescription isodose volume (VPi) relative to the targetvolume (VT). The volumes of normal brain, temporal lobesand brainstem receiving high (R80%) and low (R30%) doseswere also compared. Results are reported as mean valueswith respective standard deviations.

Results

Dose Coverage and Conformity to Target

The resultant dose distribution from all five techniques ina complex and irregularly shaped target (case 4: parasellarscwhannoma) is shown in Fig. 1aee. Qualitative evaluationof the dose distribution resulting from different conven-tional SRT techniques showed better dose conformation tothe target volume with DCA and SCF plans as compared withCA. The IMSRT_NCP plan was most favourable with regardsto target conformity and avoidance of critical organs ascompared with other techniques. Dose homogeneity waswithin the ICRU 50 recommendations in all plans. Table 3shows quantitative evaluation of dose-volume indices ofinterest. All treatment planning techniques covered O99%of the PTV in every patient. The mean target coverage(standard deviation) was 99.2% (0.18), 99.5% (0.10) and99.4% (0.27) in SCF, CA, and DCA plans, respectively.The corresponding values from IMSRT_NCP and IMSRT_CPplans were 99.2% (0.17) and 99.2% (0.18). The highest dosewithin the PTV was !107% of the prescribed dose in all plansfor all cases. The conformity was found to vary depending onthe shape and location of the target. The best meanconformity index, ranging from 0.74 (CA) to 0.84(IMSRT_NCP) was seen in optic chiasmatic glioma (case 2),which represents the most spherically shaped tumour amongthe selected cases. Target conformity was seen to decreasewith increasing target complexity (large, concave andirregularly shaped targets). Among the three conventionalSRT techniques, SCF and DCA were comparable with regardto target conformity, with a mean conformity index of 0.71(standard deviation 0.05) and 0.72 (standard deviation0.04), respectively. CA plans were the least conformal

Table 3 e Target coverage (TC) and conformity index (CI) with differe

Case

SCF CA DCA

TC% CI TC% CI TC% CI

1 99.5 0.72 99.5 0.67 99.5 0.712 99.1 0.78 99.6 0.74 99.2 0.793 99.2 0.66 99.3 0.62 99.7 0.684 99.1 0.70 99.4 0.63 99.1 0.72Mean (plan) 99.2 0.71 99.5 0.67 99.4 0.72

SCF, static conformal fields; CA, conformal arcs; DCA, dynamic conformradiotherapy; IMSRT_CP, coplanar intensity-modulated stereotactic radio

(mean conformity index¼ 0.67, standard deviation¼ 0.05).The worst mean conformity index was seen in cerebellarastrocytoma in the posterior fossa (case 3). In all cases,IMSRT showed better target conformity with a mean con-formity index (standard deviation) of 0.83 (0.02) for non-coplanar and 0.81 (0.02) for coplanar beam arrangements.The maximum improvement in conformity with IMSRT planswas observed in complex, concave and irregular targets,such as cerebellar astrocytoma (case 3) and parasellarschwannoma (case 4). IMSRT_CP and IMSRT_NCP plans wereessentially similar in conformity for spherical targets, butIMSRT_NCP achieved better conformity for complex targets(parasellar schwannoma).

Dose to Normal Brain and Other Organsat Risk

The volume of normal brain and other OARs irradiated tohigh ( R80%) and low ( R30%) doses varied largely depend-ing on the tumour shape, size, location and irradiationtechnique. Figure 2 shows the percentage volume of normalbrain receiving at least 80% (Fig. 2a) and 30% (Fig. 2b) of theprescribed dose at the isocentre from the differenttreatment planning techniques in all four patients. In allcases, both IMSRT plans showed better sparing of normalbrain irradiated to moderate to high doses, the maximumreduction being observed for the largest and mostirregularly shaped tumour (case 4: parasellar schwannoma).IMSRT_NCP reduced the high-dose volume of normal brainin all cases as compared with SCF, CA and DCA by anaverage of 110% (range 34e285%), 143% (69e340%) and108% (43e289%), respectively. The low-dose volume ofnormal brain was least with DCA. High-dose volumeirradiating the temporal lobes was largest in parasellarschannoma (right) and craniopharyngioma (left). As ex-pected, temporal lobes were not exposed to high-dosevolumes in cerebellar astrocytoma. IMSRT_NCP achievedbest sparing of temporal lobes (a reduction in high-dosevolumes) as compared with other techniques (Fig. 3a, b).IMSRT_NCP also showed better sparing of brainstem volumeirradiated to high (Fig. 4a) and low doses (Fig. 4b) ascompared with other techniques. The highest reduction(mean 378%) of brainstem volume irradiated to high doseswas seen in the most spherical tumour (case 2). The overall

nt techniques

IMSRT_NCP IMSRT_CP Mean (case)

TC% CI TC% CI TC% CI

99.1 0.81 99.1 0.80 99.3 0.7499.5 0.84 99.4 0.84 99.4 0.8099.2 0.81 99.1 0.81 99.3 0.7299.2 0.84 99.4 0.79 99.2 0.7399.2 0.83 99.2 0.81 99.3 0.75

al arcs; IMSRT_NCP, non-coplanar intensity-modulated stereotactictherapy.

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412 CLINICAL ONCOLOGY

reduction of high-dose volume of brainstem withIMSRT_NCP as compared with SCF, CA and DCA was 152,136 and 127%, respectively. Low-dose volume of brainstemwas maximum in SCF plans.

Discussion

Linear accelerator-based SRS/SRT techniques have evolvedfrom the initial arc-based approach with standard circularcones to miniature MLC-shaped DCA [1e4]. During theprogress of stereotactic planning and delivery, each newmethod was compared with the previously established bestmethod before being implemented clinically. Numerousreports on the dosimetric comparison of various SRS/SRTtechniques are available in peer-reviewed indexed medicalliterature for various intracranial tumours [5,6,12e14]. Forirregularly shaped small targets, the SCF technique hasshown superior conformity and homogeneity compared with

circular arcs [12e14]. Solberg et al. [15] dosimetricallycompared DCA with SCF and non-coplanar circular arcs andproposed DCA as an efficient and effective method foraccurately delivering a homogeneous target dose whilesimultaneously minimising peripheral doses in radiosurgeryapplications. More recently, the potential of beam intensitymodulation has been evaluated for SRS/SRT [5,6,16,17].Cardinale et al. [5] showed that IMSRT resulted in superiordose conformation in geometrical targets and betternormal brain sparing from high and low doses as comparedwith circular collimator-based arcs and custom blockednon-coplanar static fields. In a similar study on small(1.2e3.5 cm3) irregularly shaped targets, the same groupreported significant dosimetric improvements with inten-sity-modulated plans in terms of target coverage, normaltissue irradiation, and critical OAR sparing to significantdose levels [16]. However, for spherical and slightly largertumours, no or very modest advantage has previously beenreported for IMSRT [5,18,19]. In a more elaborate study,

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Fig. 3 e Percentage volume of (a) right and (b) left temporal lobes receiving at least 80% of the prescribed dose with different treatmentplanning techniques for each patient.

413DOSIMETRIC COMPARISON OF IMSRT AND CONVENTIONAL SRT IN INTRACRANIAL TUMOURS

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Fig. 4 e Percentage of brainstem volume receiving at least (a) 80% and (b) 30% of the prescribed dose with different treatment planningtechniques for each patient.

414 CLINICAL ONCOLOGY

involving meningiomas of the skull base, Baumert et al. [6]reported a higher conformity index with IMSRT (largestimprovement seen in multifocal and irregular targets) ascompared with the SCF technique. They also reportedlower moderate to high doses (50e80%) to OARs, but thevolume of normal tissues receiving low doses (!30%) couldbe larger than for uniform-intensity SCF techniques.

In an attempt to optimise the SRT delivery technique,Clark and colleagues [20] compared SCF and DCA withIMSRT in 21 patients with meningiomas of the skull base.The mean Radiation Therapy Oncology Group (RTOG)conformity index was 1.75 each in SCF and DCA, whichwas significantly inferior to IMSRT (conformity index 1.66,P ! 0.05). The conformity index in IMSRT was inverselyproportional to the PTV, with larger tumours (O25 cm3)consistently benefiting with IMSRT. The total volume ofnormal tissues getting irradiated to various dose levels wasalso significantly less with IMSRT (P ! 0.05).

More recently, the process, precision and clinicalimplementation of image-guided IMSRT using helical tomo-therapy has been described in detail [21], which shouldprovide further impetus to the adoption of such technologyin clinical practice.

None of the reported studies compared the miniatureMLC-based SRT techniques with IMSRT plans utilising bothcoplanar and non-coplanar beam arrangements. Moreover,the dosimetric effect of using different beam shaping andintensity modulation devices was not addressed in many ofthe reported studies. The current study draws strength fromthe fact that it compares all established conventional SRTtechniques (SCF, CA, DCA), and IMSRTwith coplanar and non-coplanar beam arrangements (IMSRT_CP and IMRT_NCP),with beam shaping and intensity modulation being carriedout using the same hardware and software (miniature MLCand TPS). A drawback was the limited number of patientsprecluding any formal statistical comparisons.

415DOSIMETRIC COMPARISON OF IMSRT AND CONVENTIONAL SRT IN INTRACRANIAL TUMOURS

The dosimetric comparison of the three conventional SRTtechniques using uniform beam intensity favoured DCA interms of conformity and OAR sparing (reduction of doses tonormal brain and brainstem), which is in agreement withpreviously published data [15,17]. However, a quantitativecomparison is neither possible nor tenable, as the reportedstudies lacked quantitative dosimetric parameters andwere conducted on small tumours treated with radio-surgery. Although DCA seems to be dosimetrically favour-able to SCF, logistical issues, such as the ease ofimplementation, quality assurance requirements andtime-resource burden, also need to be considered whileselecting the appropriate SRT technique in the clinic. Thisstudy has shown that IMSRT plans achieve superiorconformity for a range of targets as compared with arc-based techniques (CA and DCA) as well as SCF. The meanconformity index (0.83) estimated from the IMSRT_NCPplans in this study on a range of benign to low-gradeintracranial tumours with differing shapes, volume andlocation was comparable with that of Baumert et al. [6]who also reported a mean conformity index of 0.83 witha similar technique. However, the mean conformity indexof the SCF plans (0.71) used in this study was better thanthat of Baumert et al. (0.65) using an identical technique.This could primarily be due to the selection of morecomplex and irregularly shaped targets in Baumert et al.’sstudy. There was substantial improvement in conformityeven for the spherically shaped tumours (cases 1 and 2)with IMSRT. Similar to previous reports, IMSRT_NCP plansresulted in maximum improvement in the conformity indexand OAR sparing in the largest and most complex-shapedtarget (case 4: parasellar schannoma) [5,6,16]. The use ofnon-coplanar beam arrangement in IMSRT leads to onlya marginal increase in conformity index as compared withcoplanar beams, but can help in reducing OAR doses. A six-field arrangement was chosen as the benchmark IMRT_CPtechnique, as no major dosimetric advantage was seenwhen the number of fields was increased to nine.

Doses outside the target volume were also considerablyless at all dose levels in the IMRT_NCP plan as compared withother competing techniques. The volume of normal brainoutside the PTV irradiated to various dose levels is generallyconsidered important, as there is a relative lack ofanatomically specified regions in the brain correlating withlong-term toxicity of irradiation. Neurocognitive dysfunc-tion is perhaps the most important late sequelae ofradiotherapy, particularly in children and young adults. Allthe four selected cases in this study belonged to thepaediatric population, wherein a reduction in dose to thenormal brain as well as other OARs should potentiallytranslate into maximal clinical benefit. However, even ifthe comparison was attempted on adults with comparabletumours, the dosimetric outcome of all presented tech-niques would probably have been similar to the children inthe current study. Temporal lobes, particularly mesialtemporal lobes and the hippocampus, have been shown toharbour neural stem cells, believed to be responsible forcognitive functions and are therefore increasingly beingrecognised as distinct avoidance structures [22]. IMSRT plans

consistently showed a reduction in moderate- to high-dosevolumes of both temporal lobes as compared with CA or fixedfields. There is emerging evidence that a reduction in dosesto temporal lobes translates into preservation of neuro-cognitive function in children treated with conformalradiotherapy techniques [23e25]. IMSRT by minimising dosesto the temporal lobes as compared with uniform-intensityconformal techniques should potentially further improvethe therapeutic index for these patients. Nevertheless, it ispertinent to note that modest differences in dosimetry areunlikely to result in clinically different outcomes.

The potential of single-fraction intensity-modulated SRS(IMSRS) has not yet been fully realised. In a planning study[26] involving six patients with small benign tumours of theskull base, it was concluded that RTOG radiosurgeryguidelines were best met with the DCA technique ratherthan the IMSRS approach, which increased the time forplanning, delivery and integral doses to the brain. Thebrainstem is one of the most critical organs in single-fraction SRS applications. CA and fixed-field techniquesthat are commonly used for uniform-intensity radiosurgeryplans strictly need to respect the tolerance of thebrainstem, sometimes even at the cost of target coverageor conformity. The favourable dosimetric profile shown byIMSRT may provide a therapeutic window in such settings toapply single-fraction IMSRS as well.

Conclusion

Among the three conventional SRT techniques, DCA and SCFseem to be comparable in terms of target conformity andreduction in dose to normal brain, brainstem and other OARs.Both techniques are dosimetrically superior to CA, whichseems to be the least preferred technique. IMSRT_NCPachieves superior target conformity and better sparing ofOARs compared with all conventional SRT techniques ina range of benign and low-grade brain tumours varying inshape, volume and location, commonly considered forstereotactic irradiation in contemporary neuro-oncologypractice. Apart from dosimetric advantages, factors such asease of implementation, quality assurance requirements,and time-resource burden also need to be considered whenselecting the appropriate SRT technique. Clinical validationof the dosimetric comparison needs to be carried out inappropriately designed prospective clinical trials.

Author for correspondence: S. D. Sharma, Medical PhysicsDepartment, 126G, Annex Building, Tata Memorial Hospital,Dr. Ernest Borges Marg, Parel, Mumbai 400 012, India. Tel: þ91-22-24177000x4301, 4307; Fax: þ91-22-4146937; E-mail: dayananda.sharma@relianceada.com

Received 11 March 2008; received in revised form 3 January 2009;accepted 2 February 2009

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