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RandomisedcontrolledtrialofProstateRadiotherapyInhighriskandnodepositivediseasecomparingModerateandExtremehypofractionation[PRIMETrial]

PRIMEtrial_PI:DrVedangMurthy,Protocolversion1.2Dated:18.12.2017 Page1


PrincipalInvestigator:VedangMurthy

Co Investigators:GaneshBakshi,RahulKrishnatry,GaganPrakash,MahendraPal,Santosh

Menon,PalakPopat,VenkateshRangarajan,ArchiAgrawal,SheetalKulkarni

Statistician:SadhanaKannan

Location:TataMemorialHospitalandACTREC,TataMemorialCentre,Mumbai,India



TRIALSUMMARY

PROTOCOLTITLE

Randomised controlled trial of ProstateRadiotherapy Inhigh riskand node positive disease comparing Moderate and Extremehypofractionation(PRIMEtrial).

RATIONALE

Extreme hypofractionated radiotherapy is a shorter durationtreatment with probable similar clinical efficacy as moderatelyhypofractionation Radiotherapy. Given the potential positiveeconomic impact with shorter duration treatment with similarclinical outcomes and probable similar toxicity profile, SBRT(extremehypo-fractionation) inprostatecancercanbeofferedasatreatmentoption,especiallyinalimited-resourcesetting.

AIM

The aim of the study is to compare the efficacy with SBRT andmoderate hypo-fractionation in high risk and node positiveprostatecancer

PRIMARYSTUDYOBJECTIVES

To assesswhether extreme hypo-fractionationwith SBRT in highrisk prostate cancer is non inferior to moderately hypo-fractionatedstandardradiotherapy

STUDYDESIGN

Two arm, Prospective Randomized Trial with a non-inferioritydesign

TRIALPOPULATION

Inclusioncriteria:1.Age:above18years.2.Participantsmustbehistologicallyproven,adenocarcinomaprostate3.Localisedtotheprostateorpelviclymphnodes4.HighriskprostatecancerasperNCCNdefinition

clinicalstageT3aorGleasonscore8/Gleasongradegroup4orGleasonscore9-10/gleasongradegroup5,PSA>20ng/mL.orVeryhighriskprostatecancerasperNCCNdefinitioni.eT3b-T4orPrimaryGleasonpattern5/Gleasongradegroup5or>4coresGleasonscore8-10/Gleasongradegroup4or55.Abilitytoreceivelongtermhormonetherapy/orchidectomy6.KPS>70(seeappendix7.Nopriorhistoryoftherapeuticirradiationtopelvis8.Patientwillingandreliableforfollow-upandQOL.9.SignedstudyspecificconsentformExclusioncriteria:1.Evidenceofdistantmetastasisatanytimesincepresentation2.Lifeexpectancy<2year3.PreviousRTtoprostateorprostatectomy.4. Severe urinary symptoms or with severe IPSS score inspite ofbeingonhormonaltherapyfor6mnthswhichintheopinionofthephysicianprecludesRT5.Patientswithknownobstructivesymptomswithstricture.6. Any contraindication to radiotherapy like inflammatory boweldisease.7. Uncontrolled comorbidities including, but not limited todiabetesorhypertension8.Unabletofollowuporpoorlogisticorsocialsupport

Arm1-[standardarm]



TREATMENTREGIMEN ModeratehypofractionatedRT,Will receive a total dose of 68Gy in 25# to the primary over 5weeks, with treatment being delivered daily. Patients with nodepositive diseasewill receive a dose of 50Gy in 25# to the pelvicnodes.Boost to gross nodal disease will be considered based ontheresponsetohormonaltherapytoadoseof60-66Gy/25#asasimultaneous integrated boost (SIB). An option of equivalentbiologicaldoseusing60-62.5Gyin20#maybeallowedformulti-centricaccrualinthefuture.Arm2–[ExperimentalArm]Extremehypofractionationwith SBRT,will receive a course of 5fractionsofradiation;eachfractionsizewillbe7.25Gy.Thetotaldose will be 36.25 Gy. Patients with node positive disease willreceiveadoseof25Gyin5#tothepelvicnodes.The5treatmentswillbescheduledtobedeliveredalternatedayoverapproximately7-10days.Anoptionofequivalentbiologicaldoseusing35-36.25Gyin5weeklyfractionsmaybeallowedformulticentricaccrualinthefuture.DoseCoverageThe95%isodoselineusedfortheprescriptiondoseshouldcoveraminimumof95%ofthePTV

RECRUITMENTTARGET 434 total number of patients with 217 patients in experimentalarmand217patientsinstandardarm.65patientstobeaccruedperyearintheprojectwithatotalstudyduration of about 8 years, with a 4-year follow up period and auniformaccrualrate.

PRIMARYENDPOINT

1. To assess the 4 year Biochemical Failure free Survival (BFFS)betweenthetwoarms.

KEYSECONDARYENDPOINTS

1. Toevaluateacuteandlatetoxicitywithbothtreatments.2. TofindtheProstatecancerspecificsurvivalandoverallsurvival

ofpatientsreceivingmoderatelyhypofractionatedRTandSBRT.3. To estimate the out of pocket expenditureinvolved in

patientsreceivingthetwotreatmentschedules.4. Toassessqualityoflife

FOLLOWUP

• Allpatientswill followup3-6weeks fromendof radiotherapy,followedby3-6monthlyforthefirsttwoyearsdependingontheclinical need and 6 monthly thereafter. At baseline and everyfollow-updatawillbecollectedandrecordedinCRF

• Physicianassessmentof toxicitywithRTOG toxicity criteriaandCTCAE ver4.03 criteria for proctitis, rectal pain, rectal bleedingandurinarycomplaintsatbaselineandfollowup.

• Physician assessment during and end of RT with scoring oftoxicityandIPSSscoring

• PhysicianassessmentwithclinicalexaminationandserumPSA.• QOL will be assessed at baseline and 6 monthly using theQLQC30andPR25EORTCQuestionnaire.



Background

Prostatecancerisoneofthemostcommoncancersseeninthewesternpopulationandisalso seen on a rising trend in India. It is the fourthmost common cancer in both sexescombined and the secondmost common cancer inmenworldwide[1] [GLOBOCON 2012]andisthesecondleadingsiteofcanceramongmalesinlargeIndiancitieslikeDelhi,Kolkata,Pune and Thiruvananthapuram, third leading site of cancer in cities like Bangalore andMumbai and it is among the top ten leading sites of cancers in the rest of the PBRCs ofIndia.[2]

Highriskprostatecancerisanaggressiveformofprostatecancer,definedbyNCCNascaseswith at least one of thefollowing features: Gleason score of 8–10, clinical stage T3a orhigher,or PSA > 20 ng/mL[3][NCCN]. The standard of care for locally advanced high riskcancer is external beam radiotherapy alongwithlong term hormonal therapy. [4-6].Longtermclinicalandbiochemicalcontrol isachievablewithdoseescalation in radiotherapy inprostatecancer.Withadvancesinhighprecisiontechnologyinradiotherapy,itispossibletotargetanddeliverhigherdosestothetumourwithsparingofthenormaltissue.

Theradiobiologicalstudieshaveshownthatprostatecancerhasalowalpha/betaratiointhe range of (0.9-2.2) [7,8].Thismeans increased fraction size may improvebiochemicalcontrol without significantly increased toxicity tonearby tissues (bladder,rectum).Thusalowα:βratioofprostatecancerhashighsensitivitytodoseperfraction.Thismakes hypo-fractionated radiotherapy radio-biologically superior than conventionalfractionated schedules as it leads to a considerably higher biologically equivalent dosedelivery.

Various prospective randomised trials have studied the safety and efficacy of moderatehypo-fractionationinprostatecancerandhasbeennowconsideredasthestandardofcare[9-11].Withthebenefitshownwithmoderatehypofractionation,therehasbeenagrowinginterestintheroleofextremehypofractionationinprostatecancer.

Extremehypofractionationwithstereotacticbodyradiationtherapy(SBRT)hasanemergingroleasanalternativetechniquetodeliverhighdoseradiotherapytotheprostatethroughanon-invasiveapproach,comparabletoHDRbrachytherapy,butwithanon-invasiveapproach[12-15].SBRT isdefinedbytheAmericanSociety forRadiationOncologyandtheAmericanCollegeofRadiologyasatreatmentmethodtodeliverahighdoseofradiationtothetarget,utilizingeitherasingledoseorasmallnumberoffractionswithahighdegreeofprecisionwithinthebody.

Multiplesingle-institutionstudiesontheuseofSBRTastheprimarytreatmentforprostatecancer have suggested the treatment to be safe and quicker alternative toprolongedfractionation schedules [17-26].However the number of patientswith high riskprostatecancer included in thesestudieswas low.This ispredominantlybecauseof largenumbersoflowandintermediateriskcancerinthewestasopposedtothehighriskgroupprostatecancerpatientscommonlyseeninIndianscenario.



Table 1 gives a brief summary of various moderate and extreme hypofractionationschedules used in prostate cancer radiotherapy. The safety and toxicity evaluated inextreme hypofractionationin these studies have been comparable to moderatehypofractionation.

Thereforewithadvancetechniquesinradiotherapyplanninganddelivery,itisimperativetouseSBRTinthetreatmentofprostatecancer.

The standard duration of treatment with radiotherapy is 8weeks in conventionalfractionation;5-6weekswithmoderatehypo-fractionation,while it isonly1-2weekswithextremehypo-fractionation(SBRT).Thehealthcostsandoutofpocketexpenditureinvolvedintheconventionalhypo-fractionatedradiotherapytreatmentlargelydependsontheoveralltreatment duration. This involves expenditure not only for the patient but also thecaretaker.Moreover most of these patients presenting to a tertiary care centre fromdifferentpartsofthecountry,havelogisticissuesofaccommodation,food,travelalongwiththetreatmentcosts.Alsoforpatientsstayingawayfromfamily,5weekstreatmentwithoutconsiderable family support has a psychological impact, especially on elderly group ofpatientscommonlyseenwithprostatecancer.Thisfurtherleadstoamajorcauseofdistressamongthesepatients,especiallyinaresourcelimitedsettingasours.[27]

Extreme hypo-fractionation with a total duration of 2weeks, would offer an opportunitytooptimizethetherapeuticratiotakingadvantageofthepotentialtherapeuticgainduetolow alpha/beta for prostate to higher dose/fraction(compared to surrounding organs atrisk).Moreover, shortenedoverall treatment time,would lead to lessdistressingandearlyrecommencement of their daily activities for the patients,with an obvious impact inimprovingthequalityoflifeandhealthcosts.

Giventhepotentialpositiveeconomicimpactwithshorterdurationtreatmentwithsimilarclinicaloutcomesandprobablesimilartoxicityprofile,SBRT(extremehypo-fractionation)inprostate cancer is an attractive treatment option, especially in a limited-resource settingandcanhavealargeandpositiveimpactonthepatientcare.



Tableno1:Reportedstudiesusingmoderateandextremehypofractionationdoseschedulesinprostatecancer.

StudyNo ofpatients

MedianFollow-up(months)

Totaldose(Gy)

Dose/fraction(Gy)

Free from PSAfailure

Definition offailure

Latetoxicity

Hormone(%)

GU ≥2(%)

GI≥2(%)

ExtremehypofractionationwithSBRT

Madsen[20] 40 41 33.5 6.7 Low, 90% (4

years)Nadir+2/ASTRO# 20 8 No

Freeman[19] 41 60 36.25 7.25

Low, 92.7% (5years) Nadir+2 9.5 2.5 No

Tang[21] 30 12 35‡‡ 7 NA NA13 at 6months

13 at6mo 3

Friedland[22]

112 24 35–36 7–7.2 NA NA 0 0.9 19

Katz[23] 50,254§§ 17,30 35,

36.25 7,7.25

Low, 99%, Int,100%,High,83% (lastfollow-up)

Nadir+2 2,6.3 0,2.9 19

Bolzicco[24] 45 20 35 7

Low and Int,100% NA 2.2 2.2 38

Jabbari[27] 20 18.3 38 9.5

All risk groups,100% NA 13¶¶ 8¶¶ 47%

Boike[25] 15, 15,15##

30, 18,12

45,47.5,50

9, 9.5,10

100% Nadir+2 13, 20,7

7,7,0 22



Moderatehypofractionation

Pollack[13-14] 50 39 70.2 2.7 Int and High, 83% (5

years) Nadir+2 25(5years 6(5years) 44

Kupelian 770 45 70 2.5 Low,94;Int,83%;High,72%(5years Nadir+2/ASTRO# 7(5years) 6(5years) 60

CHHiPDearnaleyetal.[25-26]

1065/37#1074/20#1077/19#

74Gy/37#60Gy/20#57Gy/19#

233

15%low73%intermediate12%high

NA

5yearsG2+GU(RTOG,NS)9.1 % (37#)11.7 % (20#)6.6 % (19#)

Acute G2 +GI(p<0.0001)25%(37#)38%(20#)38%(19#)5yearsG2+GI(RTOG,NS)13.7%(37#x)11.9%(20#)11.3%(19#)

97

HYPROAluwinietal.[12]

397

407

60

78Gy/39#

64.6 Gy/19fx

2G

3.4Gy

27%intermediate73%high NA

3 yearsG2+GU39%3 yearsG3+GU12.9%(3 yearsG3+GUp=0.02)

3years G2+GU41.3%3 yearsG3+GU19.0%

3 yearsG2+GI17.7%3 yearsG2+GI21.9%

66%



Hypothesisforpresentstudy:

Extremehypo-fractionation with SBRT in high risk prostate cancer is non inferior tomoderately hypo-fractionated standard radiotherapy while producing acceptable toxicityandadvantageintermsofshorteningoftreatmentduration

Aim

TheaimofthestudyistocomparetheefficacywithSBRTandmoderatehypo-fractionationinhighriskandnodepositiveprostatecancer

Objectives:

PrimaryEndpoint

ü Theprimaryobjectiveof the study is toassess the4 yearbiochemical Failure freeSurvival(BFFS)betweenthetwoarms

SecondaryEndpoints

ü Toevaluateacuteandlatetoxicitywithbothtreatments.ü TofindtheProstatecancerspecificsurvivalandoverallsurvivalofpatientsreceiving

moderatelyhypofractionatedRTandSBRT.ü To estimate the out of pocket expenditure involved in patientsreceiving the two

treatmentschedules.ü Toassessqualityoflife



Methodology:

Trialdesign

Thiswillbea2arm,ProspectiveRandomizedTrialwithanon-inferioritydesignPatientswill be randomized tooneof thesebelowmentionedarmsusing stratifiedblockrandomizationmethod.

Arm1[standardarm]:ModeratelyhypofractionatedRadiotherapy(217patients)

Arm2[Experimentalarm]:Extreme hypofractionationwith Stereotactic bodyradiotherapy(217patients)

Eligibilitycriteria

Inclusioncriteria-

1. Age:above18years.2. Participantsmustbehistologicallyproven,adenocarcinomaprostate3. Localisedtotheprostateorpelviclymphnodes4. HighriskprostatecancerasperNCCNdefinition

clinical stage T3a or Gleason score 8/Gleason grade group4 or Gleason score 9-10/gleasongradegroup5, PSA>20ng/mL.orVeryhighriskprostatecancer i.eT3b-T4orPrimaryGleasonpattern5/Gleasongradegroup5or>4coresGleasonscore8-10/Gleasongradegroup4or5

5. Abilitytoreceivelongtermhormonetherapy/orchidectomy6. KPS≥ 70(seeappendix)7. Nopriorhistoryoftherapeuticirradiationtopelvis8. Patientwillingandreliableforfollow-upandQOL9. Signedstudyspecificconsentform

Exclusioncriteria-

1. Evidenceofdistantmetastasisatanytimesincepresentation2. Lifeexpectancy<2year3. PreviousRTtoprostateorprostatectomy.4. Severe urinary symptoms or with severe IPSS score (>15)inspite of being on

hormonaltherapyfor6monthswhichintheopinionofthephysicianprecludesRT.5. Patientswithknownobstructivesymptomswithstricture.6. Anycontraindicationtoradiotherapylikeinflammatoryboweldisease.7. Uncontrolledco-morbiditiesincluding,butnotlimitedtodiabetesorhypertension8. Unabletofollowuporpoorlogisticorsocialsupport.



Pre-treatmentevaluation:

All patients with biopsy proven Adenocarcinoma of the prostate (TRUS guided) afterscreeningwillundergothefollowinginvestigationspriortoenrolmentandrandomization

• Completehistoryandphysicalexamination• SerumPSA<3weeksofrandomization• Laboratory investigations undertaken routinely (complete blood counts, Renal

functiontest,LiverfunctiontestandSerumElectrolytes)• Staging investigation including CT scan of the abdomen- pelvis / bone scan/ MRI

pelvis/PSMAPETCTtoruleoutdistantmetastasis.• IPSSscoring• Documentationofpre-treatmenturinaryandrectalsymptomsandqualityoflife.

Interventions

Registration

Patientswith high risk carcinoma prostate on presentationwill be screened for eligibilitycriteria.Theymustmeetalloftheinclusioncriteriaandhavenoneoftheexclusioncriteriatobeeligibleforthetrial.Written,informedconsentwillbeobtainedfromallthesepatientsatthetimeofregistration.

Subjectsmustberegisteredbeforestartingstudytreatment.Oncetheregistrationprocesshasbeencompleted, the subjectwill beassigneda subject studynumber. Individualswillonlyberegisteredonceinthistrialfollowingwhichthepatientwouldberandomized.

Randomisation

Patients will be randomized to one of the below mentioned arms using stratified blockrandomizationmethod.

Arm1(Standardarm):Moderatehypo-fractionatedRT68Gy/25#

Arm2(Testarm):Extremehypo-fractionatedRTwithSBRT36.25Gy/5#

Stratification

Stratificationwillbedoneforthefollowingparameters1. Nodalstatus:N0VsN+2. LHRHagonist/antagonistsVsBilateralorchidectomy

RadiotherapydetailsInarm1ofthestudy,patientswhoarerandomizedtoreceivemoderatelyhypofractionatedRTwill receive a total dose of 68Gy in 25# to the primary over 5weeks,with treatmentbeingdelivereddaily.Patientswithnodepositivediseasewillreceiveadoseof50Gyin25#to the pelvis. Boost to gross nodal disease will be considered based on the response tohormonal therapy to a dose of 60-66Gy/25# as a simultaneous integrated boost(SIB). Anoptionofequivalentbiologicaldoseusing60-62.5Gyin20#maybeallowedformulticentricaccrualinthefuture.



InArm2ofthestudy,patientswhoarescheduledtoreceiveSBRTwillreceiveacourseof5fractions of radiation; each fraction size will be 7.25Gy. The total dose will be 36.25Gy.Patientswithnodepositivediseasewillreceiveadoseof25Gyin5#tothepelvis.Boosttogrossnodaldiseasewillbeconsideredbasedontheresponsetohormonaltherapytoadoseof30-35Gy/5#asasimultaneousintegratedboost(SIB).The5treatmentswillbescheduledto be delivered alternate day over approximately 7-10 days. An option of equivalentbiologicaldoseusing35-36.25Gyin5weeklyfractionsmaybeallowedasperinstitutionalpracticeformulticentricaccrualinthefuture.DoseCoverageThe95%isodoselineusedfortheprescriptiondoseshouldcoveraminimumof95%ofthePTV.

TreatmentPlanningPreparation

• Bladder:Patientswillbeaskedtohaveacomfortablyfullurinarybladderbothduringsimulationand treatment. Consistentbladder fillingprocedureshouldbeused foran individualpatient for simulationand foreach treatment.Bladder fillingmaybeachievedbyaskingpatientstodrink500mlofwater45minutespriortotreatmentandtonoturinatebetweenthistimeandtreatment.

• Bowel:Patientswillbeadvisedtoadheretoalowgas,lowmotilitydietcommencing2daysprior to thesimulationandtreatment.OnetablespoonofMilkofMagnesiawillbetakenthenightbeforethesimulation.

SimulationComputedTomography(CT)

• Patientswillbeaskedtoempty therectumbefore theplanningCTscan.About45min prior of acquiring the helical CT scan; all participants will be asked to voidcompletelyandtodrink500mlofplainwater.Thisprotocolofbladderfillingwillbefollowed during every day treatment to ensure constant partial bladder filling toachievelesservolumeofbowelinirradiatedareaandleastdisplacementofinternalorgansdue to variablebladder filling.Patientswill be simulated in supinepositionwithhandsoverchest.Kneerestwillbeusedforimmobilisationandreproducibility.Threemarkerswillbeplacedoverskinatlaserintersections;oneatsymphysispubisandtwolaterally.CTscanswillbetakenwithcontrastfrom1stLumbervertebrato5cm below ischial tuberosity with a slice thickness of 2.5mm. Lasermarks will bepermanentlytattooedforsetup.

MagneticResonanceImaging(MRI)MRIimagesarenotrequiredbutmaybeusedforfusionifavailable.Contouring:

• TargetVolumes:CTVprostate (andSV):ForpatientswithoutclinicalorradiologicalinvolvementofSV,CTVwillconsistofthewholeofprostateglandincludinganyECE



andthebaseofseminalvesiclesdefinedastheproximal0.5seminalvesicleswillbeincludedintheCTV.

• CTV nodes: For patients with node positive disease, will receive radiotherapy topelvic nodes. Contouringwill begin from the level of L4-5. Contourwill bedrawnaroundthemajorvesselswithmarginsofabout7mmandthenmodifieddependingontheanatomicalboundarieslikebone,musclesandperitoneum.Theexternaliliacvessel contouringwill be stoppedat the top level of the femoral head. Theupperexternal iliac region delineationwill also include the lateral andmedial pre-sacralnodal area from S1-3with a thickness of 8-10mm. The internal iliac lymph nodecontouring(includingtheobturatornode)willstopatthebeginningoftheobturatorforamen.ThecaudalpartofthevolumewillincludethedistalpartoftheSVwhenitisuninvolvedclinico-radiologically.TheprophylacticlymphnodaldelineationsfollowthepatternshownattheRTOG.ThewholenodalCTV(bilateral)willbedrawnasasinglestructureand1cmthickpresacral spacewillbe includedby joiningbilateralnodalCTVuptocaudalborderofS3,posteriorborderbeingtheanteriorsacrumandanterior border approximately 10mmanterior to the anterior sacral bone carvingoutbowel,bladder,andbone.

• PTVnodes:Amarginof5mmwillbegrownisotropicallyoverCTVnodes• PTV Prostate (and SV): A margin of 5mm will be grown in all directions over

theCTVprostate.• Organsatrisk:Wholeofrectumwillbedrawnasasolidstructurestartingfromrecto

sigmoid flexure up to the bottom of ischial tuberosity. The rectalwall will not bedrawn separately. The entire bladder will be drawn as a solid structure from thedometothebaseincludingthewall.

• Bowelwill be representedby a single solid structure encompassing theperitonealcavityandanyloopsofbowelinthepelvis.Theupperextentwillbekeptconstantat2cmsuperiortotheuppermostextentofthePTVtohavecomparabilityofthedosevolumedata.

• Penile bulb will be contoured on the CT image below the pelvic diaphragm withreference to the MRI of pelvis. Both femoral heads will be drawn within theacetabulumwithoutincludingtheneckofthefemur.

Treatmentplanning:

This protocol requires the use of IMRT (DMLC or SMLC) or related techniques(Tomotherapy/VMAT). The recommended photon energies for this protocol are 6-15MVwithorwithoutaflatteningfilter.Allpatientswillundergodailyimageguidedradiotherapy.Planningwillbedoneasasinglephasesimultaneousintegratedboost(SIB)technique.Thedose volume constraints are given below in Table 2 and Table 3 for the two dosefractionation schedules and the 2 Gy equivalent doses (EQD2)of each dose fractionationscheduleisgivenintable4.



Table2:DoseconstraintswithmoderatehypofractionationinArm1(Standardarm)Organ V30 V40 V45 V50 V60 V65 V70Bowel(cc)

80 30

Bladder(%)

65 45 25 15

Rectum(%)

80 60 35 25 15 0.1

Table No 3: Dose constraints with extreme hypofractionation with SBRT in Arm 2(Experimentalarm)Organ V14 V17.5 V28 V31.5 V35Bladder <40%

(N+)<20%(<27% inN+)

<3%

Rectum <40% <15% <8% <3%Femoralhead

<5%

Table4:EQD2forthedifferentdose-fractionationschedules.Dose(Gy)

Fractions Dose/Fraction(Gy)

EQD2(Gy)Alpha/beta@3Gy

EQD2(Gy)Alpha/[email protected]

68 25 2.72 78 8166 25 2.64 74.5 7864 25 2.56 70 7460 25 2.4 64.8 66.8650 25 2 50 5062.5 20 3.125 76.56 82.5960 20 3 72 77.1436.25 5 7.25 78 9435 5 7 74 8530 5 6 54 64.2925 5 5 40 46Hormonetherapy



Allpatientswillreceivehormonetherapystartingatleast8weekspriortothebeginningofradiotherapy(LHRHagonist/antagonist).Theywillcontinuethehormonetherapyduringtheradiotherapy and later for a total duration of 2 years. Patients who have undergoneorchidectomywillalsobeeligible inthisstudy.ThefirstLHRHagonist/antagonist injectionwillbecoveredwitha3-4weekcourseofanti-androgentopreventtestosteroneflare.

ClinicalAssessment:

1. Objectivecriteriafortoxicityevaluation.TheRTOGwillbeusedtodocumentacuteandlatetoxicities(appendix2-3)NationalCancerInstitute’sCommonTerminologyCriteriaforAdverseEvents(CTCAE)version 4.03 will also be used for documentation of proctitis, rectal pain, rectalbleeding, rectal ulcer; and urinary tract toxicities such as frequency, urgency,retention,pain,obstruction.a.RTOGtoxicitycriteriaatbaseline,3-6weekspostRTandat6monthlythereafter.

b. Physician assessment during and end of RT with scoring of toxicity and IPSSscoring.

c.QOLwillbeassessedatbaselineand6monthlyusingtheQLQC30andPR25EORTCQuestionnaire.

2. Diseaseevaluation:ClinicalevaluationofthediseasewillbedoneateachfollowupvisitwithaserumPSAandclinicalexamination.

3. Out of pocket expenditure of the patient and caregiver on food, travel,accommodation and for management of treatment related side-effects will becapturedusingastructuredrecordformduringtreatmentandeachfollow-upupto2years.

4. Allpatientswillfollowup3-6weeksfromendofradiotherapy.Thereafterfollowupvisitswouldbescheduledthreetosixmonthlyforthefirsttwoyearsdependingontheclinicalneedand6monthlythereafterasperstandardpractice.ClinicaldatawillberecordedprospectivelyintheCaseRecordForm.

Statisticalconsideration:StudySampleSizeTheprimaryendpointforthisstudyis4yearBFFS.Thepowercalculationsassumea4-yearBFFSof80%inthemoderatehypofractionationarm(Arm1).Onthisbasis,witha5%onesidedsignificanceand80%power,atotalof434patientswillberandomizedtobotharmsequally(217ineacharm)andthetrialwillhavetheabilitytodemonstratenon-inferiorityofextremehypo fractionationwith SBRT arm (Arm2), defining non-inferiority as “noworsethan 12%‟ below moderate hypo fractionation arm. This also accounts for a 5%noncompliancerateasanticipatedfromexperienceinpreviousstudies.



InterimAnalysis

Aplannedinterimanalysisfortoxicityisbuilt in.Thetimingoftheinterimanalyseswillbebasedonaccrualofpatients(25%,n=108)completing2yearsoffollowup.Attheplannedinterim analysis, the p-value from the chi-square or fisher exact test assessing treatmentefficacy with respect to grade III or higher combined GI and GU RTOG toxicity will becomparedinthetwoarmsatonesidedalphaof2.5%andapowerof80%.Ifthecomputedp-value is less thanor equal to 0.025,then accrual to the trialwill be discussedwith theDSMCforstopping(ifapplicable).Otherwise,accrualtothetrialorfollow-up(asapplicable)willcontinueuntiltheplannedsamplesize(n=434)

Datacollectionmethods

Thedataofthestudywouldbecollectedinapredesignedcaserecordform.ThedatawillbefilledinexcelsheetsandthenwouldbetransferredinSPSSand/orRstudioforrequisiteanalysis.

Datamonitoring–

Theinstitutionaldatamonitoringandsafetyboard(DSMSC)willberesponsibleforoversightofthedata.

Analysisofpopulation

Patientdispositionandefficacyanalyseswillbeperformedondatafromtheintent-to-treat(ITT) population and per protocol analysis. All patients randomized into the studywill beclassified according to their assigned treatment group, regardlessof the actual treatmentreceived.TheprimaryefficacyanalysiswillbeontheITTbasisandperprotocolbasis.

StatisticalAnalysis

Qualitative datawill be expressed as percentages and compared between the treatmentgroups using the chi-square test (or the Fisher exact test). Quantitative data will beexpressedasmeansandstandarddeviation(ormediansandrange)andcomparedbetweenthetreatmentgroupsusingtheStudentttest(ortheWilcoxontest).

Prostate cancer specific survival and overall survival will be estimated using the Kaplan-Meiermethodwith95%confidenceIntervals.Thelog-ranktestwillbeusedtocomparethetreatment groups. The comparisonwill beadjustedon stratification factorsusing theCoxmodel.Themedianfollow-upwillbeestimatedusingthereverseKaplan-Meiermethod.

Outcomemeasures

Freedomfrombiochemicalfailure[BFFS]:FreedomfrombiochemicalfailurewillbedefinedasdurationfromdateofnadirPSAtoPSA>2ng/mloverthenadirPSA

Overallsurvival(OS) isdefinedasthetimefromrandomizationtothetimeofdeathfromanycause

Theprostatecancer-specificsurvivalwillbecalculatedfromthedateof randomizationtothedateofthedeathduetoprostatecancer.



QualityoflifewillbeassessedusingtheEORTCQLQc30andPR25questionnaire

Patientaccrual

Patientswill be identified and checked for eligibility from theOPDs at TMHandACTREC.Suitablepatientswill be considered for the studyby amemberof the investigating teamafterthoroughlyexplainingthestudyprocessandgivingatleast24hoursforthinkingoveriftheyneed.

Weexpect 65patients tobe accruedper year in theprojectwith total studydurationofabout8years,witha4-yearfollowupperiodandauniformaccrualrate.

Multicentricapproach:ThetrialwillbeopenedtoothercenterswithaccesstoIMRT/IGRTwho may be encouraged to join the study in due course. The choice of conventionalfractionation to 60-62.5 Gy in 20# will be allowed with appropriate stratification forindividualcentres.

AdverseEventreportingguidelines

In order to assure prompt and complete reporting of toxicities, the following generalguidelinesaretobeobserved.

The principal Investigator will report the details of any unusual, significant, fatal or life-threatening protocol treatment reaction to the Data Monitoring Committee and DataManagement Staff in theCRSwithin24hoursofdiscovery.When reporting it is requiredthat thePrincipal Investigator shouldhavea relevantmaterial available.Awritten report,includingallrelevantstudyforms,containingallrelevantclinicalinformationconcerningthereported eventwill be sent to the DSMSC by the Principal Investigator. Thiswill be sentwithin 10 working days of the discovery of the toxicity unless specified sooner by theprotocol. The Principal Investigator in consultation with other Investigators will takeappropriate and prompt action to inform the IEC of any protocol modifications and/orprecautionarymeasuresifthisiswarranted.

TranslationalResearch

Theaccrualofpatientsintheprospectiverandomizedtrialwillbeanexcellentopportunitytocollectbio-specimen(urine,serum,andparaffinblocks)fromthepatientsforcorrelativestudiesinthefuturewiththeoutcomeandtoxicitydata.PatientswillbeconsentedforthesameandIECwillbe informedbeforeundertakinganyfuturecorrelativestudiesusingthebio-specimen.

Research ethics approval - This protocol and the template informed consent formscontainedinAppendixwillbereviewedandapprovedbytheinstitutionalIRBwithrespectto scientific content and compliance with applicable research and human subjects’regulations.Theprotocol,site-specific informedconsent forms(local languageandEnglishversions), participant education and recruitment materials, and other requesteddocuments—andany subsequentmodifications—alsowill be reviewedandapprovedbytheIRB.Subsequenttoinitialreviewandapproval,theIRBwillreviewtheprotocolatleastannually.The Investigatorwillmakesafetyandprogress reports to the IRBat12monthlyintervals andwithin threemonths of study termination or completion. These reportswill



include the total number of participants enrolled and summaries of each DSMSC [datasafetyandmonitoringcommittee]reviewofsafetyand/orefficacy.

Protocol amendments - Any modifications to the protocol which may impact on theconductofthestudy,potentialbenefitofthepatientormayaffectpatientsafety,includingchanges of study objectives, study design, patient population, sample sizes, studyprocedures, or significant administrative aspectswill require a formal amendment to theprotocol.Anyandall suchamendmentswill be communicated to the institutional IRB forreviewandapproval.Administrativechangesoftheprotocolareminorcorrectionsand/orclarifications thathavenoeffecton theway the study is tobe conducted. ThesemaybecommunicatedtotheIRBattheinvestigator's’discretion.

Consent

Patientswillbegiventhepatient informationsheetbythetrial investigators/nurses.Thepurposeandreasonsbehindthestudywillbecommunicatedtothepatient.Allpatientswillbeprovidedwithacopyofthewritteninformedconsentaswellasthepatientinformationsheet.ConsentwillbeonasperinstitutionalIRBguidelines.

Confidentiality

All study-related information will be stored securely at the study site. All participantinformationwillbestoredinlockedfilecabinetsinareaswithlimitedaccess.Alllaboratoryspecimens,reports,datacollection,process,andadministrativeformswillbeidentifiedbyacodedID[identification]numberonlytomaintainparticipantconfidentiality.Allrecordsthatcontain names or other personal identifiers, such as locator forms and informed consentforms, will be stored separately from study records identified by code number. All localdatabaseswillbesecuredwithpassword-protectedaccesssystems.Forms, lists, logbooks,appointment books, and any other listings that link participant ID numbers to otheridentifying information will be stored in a separate, locked file in an area with limitedaccess.

Accesstodata

ThePrincipalInvestigatorandCoinvestigatorswillbegivenaccesstothedatasets.Projectdatasetswillbehousedontheprojectspecificdatabasecreatedforthestudy,anditwillbepasswordprotected.



15. KatzAJ,SantoroM,AshleyR,DiblasioF,WittenM:Stereotacticbodyradiotherapyfororgan-confinedprostatecancer.BMCUrol2010,10:1.

16. King CR, Brooks JD, Gill H, Pawlicki T, Cotrutz C, Presti JC Jr: Stereotactic bodyradiotherapyforlocalizedprostatecancer:interimresultsofaprospectivephaseIIclinicaltrial.IntJRadiatOncolBiolPhys2009,73:1043-1048.

17. Madsen BL, Hsi RA, Pham HT, Fowler JF, Esagui L, Corman J: Stereotactichypofractionated accurate radiotherapy of the prostate (SHARP), 33.5 Gy in fivefractionsforlocalizeddisease:firstclinicaltrialresults.IntJRadiatOncolBiolPhys2007,67:1099-1105.

18. Tang CI, Loblaw DA, Cheung P et al. Phase I/II study of a five-fractionhypofractionated accelerated radiotherapy treatment for low-risk localisedprostatecancer:earlyresultsofpHART3.Clin.Oncol.(R.Coll.Radiol.)20(10),729–737(2008).

19. BolziccoG,FavrettoMS,ScreminE,TamboneC,TascaA,GuglielmiR.Image-guidedstereotactic body radiation therapy for clinically localized prostate cancer:preliminaryclinicalresults.Technol.CancerRes.Treat.9(5),473–477(2010.

20. BoikeTP,LotanY,ChoLCetal.PhaseIdose-escalationstudyofstereotacticbodyradiation therapy for low- and intermediate-risk prostate cancer. J. Clin. Oncol.29(15),2020–2026(2011).

21. KatzAJ,SantoroM,AshleyR,DiblasioF,WittenM.Stereotacticbodyradiotherapyasboostfororgan-confinedprostatecancer.Technol.CancerRes.Treat.9(6),575–582(2010).

22. Jabbari S, Weinberg VK, Kaprealian T et al. Stereotactic body radiotherapy asmonotherapy or post-external beam radiotherapy boost for prostate cancer:technique, early toxicity, andPSA response. Int. J. Radiat.Oncol.Biol. Phys.DOI:10.1016/j.ijrobp.2010.10.026(2010).

23. FreemanDE,KingCR.Stereotacticbodyradiotherapyforlow-riskprostatecancer:five-yearoutcomes.RadiatOncol,6,3(2011.

24. TownsendNC,HuthBJ,DingW,GarberB,MoorevilleM,ArrigoS,LamondJ,BradyLW: Acute toxicity after Cyber Knife-delivered hypofractionated radiotherapy fortreatmentofprostatecancer.AmJClinOncol2010.

25. DearnaleyDP, SydesMR, LangleyRE,et al. Theearly toxicityofescalatedversusstandard dose conformal radiotherapy with neo-adjuvant androgen suppressionfor patients with localised prostate cancer: results from the MRC RT01 trial(ISRCTN47772397).RadiotherOncol2007;83:31–41..

26. DearnaleyD,SyndikusI,SumoG,etal.Conventionalversushypofractionatedhigh-dose intensity-modulated radiotherapy for prostate cancer: preliminary safetyresultsfromtheCHHiPrandomisedcontrolledtrial.LancetOncol2012;13:43–54.

27. Stephen Stapleton. Distress During Radiation Therapy - Assessment amongpatients with breast or prostate cancer. Clinical Journal of Oncology Nursing21(1):93-98·February2017.DOI:10.1188/17.CJON.93-98.



Appendix1:KarnofskyPerformanceScale

100-Normal,nocomplaints,noevidenceofdisease90-Abletocarryonnormalactivity:minorsymptomsofdisease80-Normalactivitywitheffort:somesymptomsofdisease70-Caresforself:unabletocarryonnormalactivityoractivework60-Requiresoccasionalassistancebutisabletocareforneeds50-Requiresconsiderableassistanceandfrequentmedicalcare40-Disabled:requiresspecialcareandassistance30-Severelydisabled:hospitalizationisindicated,deathnotimminent20-Verysick,hospitalizationnecessary:activetreatmentnecessary10-Moribund,fatalprocessesprogressingrapidly

Appendix2:RTOGAcuteToxicity

Organ Grade0 Grade1 Grade2 Grade3 Grade4

LOWER G.I.INCLUDINGPELVIS

Nochange

Increasedfrequency orchangeinqualityof bowel habitsnot requiringmedication/rectaldiscomfortnot requiringanalgesics

Diarrhea requiringparasympatholyticdrugs (e.g.,Lomotil)/ mucousdischarge notnecessitatingsanitary pads/rectal orabdominal painrequiringanalgesics

Diarrhea requiringparenteralsupport/ severemucous or blooddischargenecessitatingsanitarypags/abdominaldistention (flatplate radiographdemonstratesdistended bowelloops)

Acute or subacuteobstruction, fistulaor perforation; GIbleeding requiringtransfusion;abdominal pain ortenesmus requiringtube decompressionorboweldiversion

GU Nochange

Frequency ofurination ornocturia twicepretreatmenthabit/ dysuria,urgency notrequiringmedication

Frequency ofurination ornocturia which isless frequent thanevery hour.Dysuria, urgency,bladder spasmrequiring localanesthetic (e.g.,Pyridium)

Frequency withurgency andnocturia hourly ormore frequently/dysuria,pelvispainor bladder spasmrequiring regular,frequentnarcotic/grosshematuria with/without clotpassage

Hematuria requiringtransfusion/ acutebladder obstructionnotsecondarytoclotpassage, ulcerationornecrosis



Appendix3:RTOGLateToxicity

Organ Grade0 Grade1 Grade2 Grade3 Grade4

Small/

Largeintestine

Nochange

Mild diarrhoea;mild cramping;bowelmovement 5times daily;slight rectaldischarge orbleeding

Moderatediarrhoea andcolic; bowelmovement > 5times daily;excessive rectalmucus orintermittentbleeding

Obstruction orbleeding, requiringsurgery

Necrosis /perforationfistula

Bladder Nochange

Slight epithelialatrophy; minortelangiectasia(microscopichematuria)

Moderatefrequency;generalizedtelangiectasia;intermittentmacroscopichematuria

Severe frequency& dysuria; severetelangiectasia(often withpetechiae);frequenthematuria;reduction inbladder capacity(<150cc)

Necrosis/contractedbladder (capacity <100 cc); severehemorrhagiccystitis



Appendix4:CommonTerminologyCriteriaforAdverseEvents(CTCAE)version4.03Adverseevent 1 2 3 4 5ProctitisDefinition: Adisordercharacterized byinflammation oftherectum.

Rectaldiscomfort,interventionnotindicated

Symptoms (e.g.,rectaldiscomfort,passingbloodormucus); medicalinterventionindicated; limitinginstrumentalADL

Severe symptoms;fecalurgency or stoolincontinence;limitingself-careADL

Life-threateningconsequences;urgentinterventionindicated

Death

RectalhemorrhageDefinition: Adisordercharacterized bybleeding fromthe rectal walland dischargedfromtheanus.

Mild;intervention notindicated

Moderatesymptoms;medicalintervention orminorcauterizationindicated

Transfusion,radiologic,endoscopic, orelectiveoperativeinterventionindicated


Death

RectalmucositisDefinition: Adisordercharacterized byinflammation ofthe mucousmembrane oftherectum.

Asymptomatic ormildsymptoms;interventionnotindicated

Symptomatic;medicalinterventionindicated;limitinginstrumentalADL

Severe symptoms;limitingselfcareADL

Life-threateningconsequences;urgent operativeinterventionindicated

Death

RectalpainDefinition: Adisordercharacterized bya sensation ofmarkeddiscomfortintherectalregion

Mildpain Moderate pain;limitinginstrumentalADL

Severe pain;limitingselfcareADL

- -

RectalulcerDefinition: Adisordercharacterized bya circumscribed,inflammatoryand necroticerosive lesiononthe mucosalsurface of therectum.

Asymptomatic;clinicalordiagnosticobservationsonly;intervention notindicated

Symptomatic;alteredGIfunction (e.g.altereddietaryhabits, vomiting,diarrhea)

SeverelyalteredGIfunction;TPNindicated;electiveoperative orendoscopicinterventionindicated;disabling

Life-threateningconsequences;urgent operativeinterventionindicated

death

UrinaryfrequencyDefinition: Adisordercharacterized byurination atshortintervals.

Present LimitinginstrumentalADL;medicalmanagementindicated

- - -



UrinaryincontinenceDefinition: Adisordercharacterized byinability tocontrol the flowofurinefromthebladder.

Occasional (e.g.,withcoughing,sneezing, etc.),padsnotindicated

Spontaneous; padsindicated limitinginstrumentalADL

Interventionindicated(e.g.,clamp, collageninjections);operativeinterventionindicated;limiting self careADL

- -

UrinaryretentionDefinition: Adisordercharacterized byaccumulation ofurine within thebladder becauseoftheinabilitytourinate.

Urinary,suprapubicorintermittentcatheterplacementnot indicated;abletovoidwithsomeresidual

Placement ofurinary,suprapubic orintermittentcatheterplacementindicated;medicationindicated

Elective operativeorradiologicinterventionindicated;substantial loss ofaffectedkidney function ormass

Life-threateningconsequences;organ failure;urgentoperativeinterventionindicated

Death

UrinaryurgencyDefinition: Adisordercharacterized bya suddencompelling urgetourinate.

Present

LimitinginstrumentalADL;medicalmanagementindicated

- - -

Urinary tractpainDefinition: Adisordercharacterized bya sensation ofmarkeddiscomfortintheurinarytract.

Mildpain Moderate pain;limitinginstrumentalADL

Severe pain;limitingselfcareADL

- -

Urinary tractobstructionDefinition: Adisordercharacterized byblockage of thenormal flow ofcontents of theurinarytract.

Asymptomatic;clinicalordiagnosticobservationsonly

Symptomatic butnohydronephrosis,sepsisorrenaldysfunction;urethraldilation,urinary orsuprapubiccatheterindicated

Symptomatic andalteredorganfunction (e.g.,hydronephrosis,or renaldysfunction);electiveradiologic,endoscopicoroperativeinterventionindicated


Death



Appendix5:IPSSscoreInternationalProstateSymptomScore(I-PSS)Patient Name: ______________________ Date of birth: ________ Date completed_______

Inthepastmonth: Notatall

Lessthan 1in5times

Less thanhalf thetime

Abouthalf thetime

Morethanhalf thetime

Almostalways

Yourscore

1.IncompleteEmptying Howoftenhaveyouhadthe

0

1

2 34

5

sensationofnotemptying

yourbladder? 2.Frequency How often have you hadtourinatelessthaneverytwohours?

0

1

2 34

5

3.Intermittency Howoftenhaveyoufound

0

1

2 3

4

5

you stopped and startedagain severaltimeswhenyou urinated?

4.Urgency Howoftenhaveyou found itdifficult to postponeurination? 0 1 2 3 4 5

5.WeakStream

0

1

2 3

4

5

How often have you had aweakurinarystream

6.Straining

0

1

2 3

4

5

How often have you had tostraintostarturination?

None 1Time 2Times 3Times 4Times 5Times

7.Nocturia Howmanytimesdidyou

0

1

2 34

5

typically get up at night tourinate?

TotalI-PSS

Score

Score: 1-7:Mild 8-19:Moderate 20-35:Severe



QualityofLifeDuetoUrinarySymptoms

Delighted Pleased

MostlySatisfied

Mixed MostlyDissatisfied

Unhappy Terrible

Ifyouweretospendtherestof

yourlifewithyoururinaryconditionjustthewayitisnow,howwouldyoufeelaboutthat?

0 1 2 3 4 5 6

AbouttheI-PSSThe International Prostate Symptom Score (I-PSS) is based on the answers to sevenquestions concerningurinary symptomsandonequestion concerningquality of life. Eachquestionconcerningurinarysymptomsallowsthepatienttochooseoneoutofsixanswersindicating increasing severity of theparticular symptom. The answers are assignedpointsfrom 0 to 5. The total score can therefore range from 0 to 35 (asymptomatic to verysymptomatic).Thequestionsrefertothefollowingurinarysymptoms:

Questions Symptom1 Incompleteemptying2 Frequency3 Intermittency4 Urgency5 WeakStream6 Straining7 Nocturia

Questioneightreferstothepatient’sperceivedqualityoflife.The first seven questions of the I-PSS are identical to the questions appearing on theAmerican Urological Association (AUA) Symptom Index which currently categorizessymptomsasfollows:

Mild(symptomscorelessthanofequalto7)Moderate(symptomscorerange8-19)Severe(symptomscorerange20-35)

The International Scientific Committee (SCI), under the patronage of the World HealthOrganization (WHO) and the InternationalUnionAgainst Cancer (UICC), recommends theuseofonlyasinglequestiontoassessthequalityoflife.Theanswerstothisquestionrangefrom “delighted” to “terrible” or 0 to 6. Although this single question may or may notcapturetheglobalimpactofbenignprostatichyperplasia(BPH)Symptomsorqualityoflife,itmayserveasavaluablestartingpointforadoctor-patientconversation.TheSCIhasagreedtousethesymptomindexforBPH,whichhasbeendevelopedbytheAUAMeasurement Committee, as the officialworldwide symptoms assessment tool forpatientssufferingfromprostatism.Appendix6:QOLquestionnaire(Attached)Appendix7:Outofpocketexpenditure(Attached)

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