1. This study aims to evaluate survival outcomes, quality of life, and activities of daily living in patients with high-grade gliomas treated with conformal radiation therapy followed by a boost with Cyberknife radiosurgery. 2. Patients with confirmed high-grade gliomas and good performance status will receive maximal safe resection followed by intensity-modulated radiation therapy and a Cyberknife boost to the tumor area. 3. The primary objectives are to assess progression-free survival, overall survival, quality of life scores, and activities of daily living after higher radiation doses.

1. Principal Investigator: Dr Siddhartha Ghosh*
Co-Principal Investigator: Dr Debnarayan Dutta*
*Apollo Speciality Hospital, ChennaiTitle: Prospective assessment of activities of daily living, quality of life and survival function in good performance status high grade gliomastreated by conformal radiation therapy followed by boost with Cyberknife

2. Why this study
-All dose escalation studies were done in pre-TMZ era
-Role of dose escalation with better imaging, lesser margin and TMZ needs to be evaluated.
-CyberKnife will provide lesser margin & higher dose to contrast enhancing mass after conformal radiation therapy
-Higher dose may improve survival without additional toxicity

3. •PoorprognosisHGGptswillbeaccruedafterscreening.
•Ptswillbeaccruedin12monthsanddurationofthestudyismaximum3years.
•PtswillingforthestudywillundergoModifiedBarthel’stest,qualityoflifequestionnaireandclinicalevaluationpriortoradiationtherapytreatmentandatsubsequentfollowups.
•Allptswillbetreatedwithmaximalsaferesectionfollowedbyadjuvantradiationtherapywithintensitymodulatedradiationtherapy(3DCRT;50Gy/25fr/5wk)followedbyboosttothecontrastenhancingareaswithCyberknife(20Gy/5fr/1week).
•Treatmentwillbestartedafterrecoveryfromthesurgery.GTViscontrastenhancingregiononMRIscan.CTVis1.5-2cmmargin.PTVmarginwillbe5mm.Appropriatesupportivecare(steroids,anticonvulsants).
•CyberknifeboostwillbestartedwithinoneweekofcompletionofIMRT.TargetwillbecontrastenhancingregiononMRIscan.Perfusionscan,MRspectroscopywillguideinthetargetcontouring.PatientwillcontinueTMZtillcompletionofradiation(includingCyberknife).
•Concomitantchemotherapy(Temozolomide;75mg/m2D1-42)willbegivenalongwithradiation.
•AdjuvantTMZwillbestarted4weekaftercompletionofRT(200mg/m2;D1-5,4weeklyfor6cycles).
•Analysiswillbedonewithrespecttosurvivalfunction,ADLandQOLscores.Costeffectiveanalysiswillbedone.
Methodology

4. Title: Prospective assessment of ADL, QOL & survival function in good performance status HGGs treated by 3DCRT followed by boost with CK Eligibility Criteria-Histopathologicallyconfirmed high grade gliomas(GBM). -Karnoskyperformance status >70. -Willing for IMRT and Cyberknife treatment. Ineligibility criteria-Age > 65 yrs. -Previous radiation or surgery treatment for brain disease. -Patient not expected to complete planned treatment.

5. Inclusion criteria for screening in the trialTitle: Prospective assessment of ADL, QOL & survival function in good performance status HGGs treated by 3DCRT followed by boost with CK Answer must be [yes]
•High graded glioma: [Yes] / [No]
•Willing for 3DCRT and Cyberknife treatment: [Yes] / [No]
•Suitable to complete planned treatment with surgery and radiation: [Yes] / [No] Answer must be [No]
•Age >65 yrs: [Yes] / [No]
•Prior radiation or surgery treatment for brain disease: [Yes] / [No]

6. Primaryaim:
1.Toevaluatesurvivalfunctions(progressionfreeandoverallsurvival)afterhigherradiationdosewithconformalRTandCyberknifeboost. Secondaryaim:
1.Toevaluatequalityoflife(QOL)andactivitiesofdailyliving(ADL) afterhigherdosageofradiationtherapyandatsubsequentfollowup. Title: Prospective assessment of ADL, QOL & survival function in good performance status HGGs treated by 3DCRT followed by boost with CK

7. Radiationschedule
ConformalRT:CTV:Pre-operativevolume(T1contrastandincludingT2hyperintense)
PTV:0.5cmmargin
Doseschedule:50Gy/25fr/5wk,5days/wk
PTVcoveragewith95%isodose.
93%isodosecoverage>99%PTVvolume.
CyberknifeBoost:CTV:Post-IMRTcontrastenhancingresidualdisease
NoCTVorPTVmargin
Additionalinformationfromperfussionscanmaybetaken.
Inthatsituation,apartfromcontrastenhancingregionhyperperfused
regionwillalsobeincludedinGTV.
Doseschedule:20Gy/5fr/1wk
ConcTMZ 75 mg/m2 & AdjTMZ 200 mg/m2
Title: Prospective assessment of ADL, QOL & survival function in good performance status HGGs treated by 3DCRT followed by boost with CK

8. Assessments
•ToxicityassessmentCTCAEV3toxicityassessmentcriteria
•Activitiesofdailyliving:ModifiedBarthel’sIndex(BI)
•Qualityoflife:EORTCQLQC30&BN20(HindiandEnglish)
•SurvivalfunctionsTitle: Prospective assessment of ADL, QOL & survival function in good performance status HGGs treated by 3DCRT followed by boost with CK

9. Assessments
Assessment
Pre-RT
4 week post RT
3 mo post-RT
6 mo post RT
9 mo post RT
12 mo post-RT
@ 3 monthly
Till 3 yrs
Clinical evaluation
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CTCAE v3
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Blood examination (CBC)
√
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MRI Scan*
×
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×
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×
×
×
Modified Barthel’s
√
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EORTC QLQ C30 & BN20
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Title: Prospective assessment of ADL, QOL & survival function in good performance status HGGs treated by 3DCRT followed by boost with CK

10. Patient required: 25 patientsDuration of the study: Accrual in twelve months and follow up for 3 years. Statistical analysis: Survival function improvement if any after higher radiation dose will be evaluated one year after accrual of 25 patients or at 3 year after initiation of the study. Neurological function and QOL will also be evaluated.Totalduration of hospital visit in days with respect to overall survival will be analyzed. Discontinuation of study: Study will be discontinued if 1) poor patient accrual (<10 patients in 2 years), 2) High incidence of acute toxicity (>50% patient requiring admission related to radiation induced events), 3) high mortality rate ( first 5 patient assessment, if median survival <6 months) Title: Prospective assessment of ADL, QOL & survival function in good performance status HGGs treated by 3DCRT followed by boost with CK

11. References
1.ThilmannC,ZabelA,GrosserKH,etal.Intensity-modulatedradiotherapywithanintegratedboosttothemacroscopictumorvolumeinthetreatmentofhigh-gradeglioma.IntJCancer.2001;96(6):341- 9.
2.JonesB,SangheraP.Estimationofradiobiologicparametersandequivalentradiationdoseofcytotoxicchemotherapyinmalignantglioma.IntJRadiatOncolBiolPhys.2007;68(2):441-8.
3.TaphoornMJ,StuppR,CoensC,etal.Health-relatedqualityoflifeinpatientswithglioblastoma:arandomisedcontrolledtrial.LancetOncol.2005;6(12):937-44
4.BrownP,BallmanK,RummansT,etal.Prospectivestudyofqualityoflifeinadultswithnewlydiagnosedhigh-gradegliomas.JNeurooncol76(3);283-91:2006.
5.BudrukkarA,JalaliR,DuttaD,etal.ProspectiveQualityofLifeassessmentusingEORTCQLQ30andbraincancermodule(BN20)in257consecutiveadultpatientswithprimarybraintumoursinatypicalNeuro-OncologyclinicinIndia.JNeurooncol2009Jun23[PMID:19548070]
6.BrazilL,ThomasR,LaingRetal.VerballyadministeredBarthelIndexasfunctionalassessmentinbraintumourpatients.JNeurooncol34(2);187-92:1997.
7.MahadevanA.APhaseIIStudyofHypofractionatedRadiationWithCyberknifeStereotacticRadiosurgeryBoostforHighGradeGliomasinElderlyPatientsWithGoodPerformanceStatus(www.clinicaltrials.gov)[NCT00386919]

12. References
1.StuppR,MasonWP,vandenBentMJ,etal.Radiotherapyplusconcomitantandadjuvanttemozolomideforglioblastoma.NEnglJMed2005;352:987-996.
2.StuppR,HegiME,MasonWP,etal.EffectsofradiotherapywithconcomitantandadjuvanttemozolomideversusradiotherapyaloneonsurvivalinglioblastomainarandomisedphaseIIIstudy:5-yearanalysisoftheEORTC-NCICtrial.LancetOncol2009;10:459-466.
3.JalaliR,DattaD.ProspectiveanalysisofincidenceofcentralnervoussystemtumourspresentinginatertiarycancerhospitalfromIndia.JNeurooncol2008:87;111–114.
4.JalaliR,BasuA,GuptaT,etal.EncouragingexperienceofconcomitantTemozolomidewithradiotherapyfollowedbyadjuvantTemozolomideinnewlydiagnosedglioblastomamultiforme: singleinstitutionexperience.BrJNeurosurg2007;21:583-87
5.LaperriereNJ,LeungPM,McKenzieS,etal.Randomizedstudyofbrachytherapyintheinitialmanagementofpatientswithmalignantastrocytoma.IntJRadiatOncolBiolPhys1998;41:1005- 1011
6.SouhamiL,SeiferheldW,BrachmanD,etal.Randomizedcomparisonofstereotacticradiosurgeryfollowedbyconventionalradiotherapywithcarmustinetoconventionalradiotherapywithcarmustineforpatientswithglioblastomamultiforme:reportofRadiationTherapyOncologyGroup93-05protocol.IntJRadiatOncolBiolPhys2004;60:853-60
7.SelkerRG,ShapiroWR,BurgerP,etal.TheBrainTumorCooperativeGroupNIHTrial87-01:arandomizedcomparisonofsurgery,externalradiotherapy,andcarmustineversussurgery,interstitialradiotherapyboost,externalradiationtherapy,andcarmustine.Neurosurgery.2002;51(2):343-55

13. Study statusAccrual: Recruiting PatientsFor Screening contactDr Debnarayan DuttaMail: duttadeb07@gmail.comPh: +91 9884234290