nct02347618
untitled h2

PILOTSTUDYOFSHORT-COURSEPREOPERATIVESTEREOTACTICBODYRADIATIONTHERAPY
FORRESECTABLEPANCREATICCANCER
PrimaryInvestigator AlanW.Katz,MD,MPH,DepartmentofRadiationOncology,URMC,Box647,Rochester,NY 14642
Co-Investigators HaomingQiuMD,DepartmentofRadiationOncology,URMC,Box647,Rochester,NY14642 VivekKaulMD,FACG,DepartmentofMedicine,DivisionofGastroenterology,URMC,Rochester, NY 14642 ShivangiKothariMDMS,DepartmentofMedicine,DivisionofGastroenterology,URMC, Rochester,NY14642 Sub-investigators:
EvaGalka,MD,DepartmentofSurgery,URMC,Rochester,NY14642 LukeSchoeniger,MD,PhD,DepartmentofSurgery,URMC, Rochester,NY14642 AramHezel,MD,DepartmentofMedicine,DivisionofHematologyandOncology,URMC, Rochester,NY14642 MohamedtakiTejani,MD,DepartmentofMedicine,DivisionofHematologyandOncology, URMC,Rochester,NY14642 SupriyaMohile,MD,DepartmentofMedicine,DivisionofHematologyandOncology,URMC, Rochester,NY14642 MarcusNoel,MD,DepartmentofMedicine,DivisionofHematologyandOncology,URMC, Rochester,NY14642
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1. background

Adenocarcinomaofthepancreasisthefourth mostcommoncauseofcancerdeathsinthe UnitedStates.Mostadenocarcinomasariseintheheadofthepancreasincloseapproximation to theduodenum, celiacaxisandsuperiormesentericartery.Pancreaticoduodenectomy
(Whippleresection)providestheonlycurativetreatment,butonly10-15%ofpatientsare eligibleforupfrontsurgicalresection.Unfortunately,evenwithresection,bothlocoregional anddistantrecurrenceremainsacommonproblemand5yearsurvivalratesis25-30%for patientswithnodenegativedisease.  
1 Bothadjuvantandneoadjuvanttherapyhavebeen studiedinanattempttoimprovecurrentresults. Theoptimaladjuvanttreatment aftersurgicalresectionisnotcurrentlyknown.TheCONKO-001 trialshowedthatadjuvantgemcitabinechemotherapyincreased5yearoverallsurvivalto21% from10%inthosewhodidnotreceiveadjuvanttherapy.  
2 Whethertheadditionofradiation therapytoadjuvantchemotherapyisbeneficialiscontroversial.TheEORTC40013/FFCD9203/GERCORphaseIIstudyof90patientsshowedthatgemcitabinebasedchemoradiotherapy resultedinimprovedlocalcontrolcomparedwithgemcitabinechemotherapyalonewithsimilar mediantimeofdiseasefreeandoverallsurvival.  
3 TheESPAC-1trialwasacomplexstudyin whichpatientswererandomizedtooneof4 adjuvant arms,chemoradiotherapy, chemotherapy,bothornone.Inasubsetanalysisof289patients,intentiontotreatanalysis showedsignificantlyimprovedoverallsurvivalinpatientsrandomizedtoreceivechemotherapy. Ontheotherhand,patientsrandomizedtochemoradiotherapyhadatrendtowardsworse overallsurvival.  
4 Thistrialwasheavilycriticizedduetomethodologicalflawsandforusing outdatedsplitcourseradiationtechniques.AcurrentlyongoingstudyRTOG0848isseekingto furtheranswerthisquestionbyrandomizingpatientswhohavereceivedadjuvant chemotherapytofurtherchemotherapyaloneorchemoradiotherapy.  
5 Althoughupfrontsurgerywithadjuvanttherapyisgenerallychosen,therearemanyreasonsto considertheuseofneoadjuvanttherapy.Themorbidityofsurgicalresectionoftenprevents thetimelydeliveryofadjuvanttherapy.Despitecarefultechnique,therestillremainsa significantfractionofpatientswhohavepositivesurgicalmarginsandthesepatientshavea poorerprognosisthanthosewhoareabletoundergoanR0resection.Lastly,post-operative radiationtherapyresultsintheradiationofsignificantvolumesofbowelwhichoftenfallinto thespacepreviouslyoccupiedbythepancreatichead.ThiscanresultinsignificantGItoxicity. Asaresult, investigatorshaveevaluatedtheuseofneoadjuvantchemoradiationtherapy for resectablepatients.Astudyof50.4Gyofradiationgivenover5.5weeksincombinationwith5-
FUdemonstratedimprovedlocalcontrolversushistoricalcontrols.  
6 However,toxicityfrom preoperativetreatmentresultedinhospitaladmissionforonethirdofpatients.Thisprompted aconsiderationofshortcoursepreoperativechemoradiationtherapyinwhich30Gyin2weeks wasdeliveredwithconcurrent5-FUwhichresultedinsimilarefficacybutdecreasedgrade3 toxicity.  
7,8 As withmostotherstudies,distantmetastasestotheliveraccountedforamajority ofdiseaseprogression.Therefore,effortsweremadetoshortentheintervalofneoadjuvant radiationtherapytoallowpatientstoproceedmorequicklytosurgeryandadjuvant chemotherapywhichwouldpresumablydecreasetherateofmetastaticdisease. Shortcourseradiationof 25Gyin5fractionshasbeenextensivelystudiedinEuropeforthe neoadjuvanttreatmentofresectablerectalcancerandhasbeenfoundto improvelocalcontrol comparedtosurgeryalone.  
9,10 IntheSwedishRectalCancerTrial,patientsunderwentresection within1weekafterradiotherapy. 9 Acomparisonof25Gyin5fractionsto conventional chemoradiationtherapyto50.4Gywith5-FUandLeucovorinshowedsimilarratesofsurvival, localcontrolandlatetoxicity.Inaddition,25Gyin5fractionswasassociatedwithlessgrade3 or4toxicities(3.2%vs.18.2%,p=<0.001)andhighercompliance(97.9%vs.59.2%)compared withconventionalCRT.  
11 Buildinguponthisexperience,a prospectivestudyof15patientsfromHarvard demonstrated thatneoadjuvantshortcourseRTusing 25Gyin5fractionstothepancreaticbedandregional lymphnodesusingprotontherapyandconcurrentcapecitabinewasfeasibleandwelltolerated. Acutegrade3toxicitywasnotedin4of15patients.11of15patientsunderwentsurgical resection butnopatientsexperienceddelaysorexclusionfromsurgeryduetotoxicityfrom neoadjuvanttreatment.Evaluationof30daypost-operativeresultsshowednodeathsor anastomoticleaks.9of11patientswhounderwentsurgeryhadR0resectionsand10ofthese patientswereabletoreceivepost-operativegemcitabine.Afteramedianfollowupof12 months,oneyearoverallsurvivalwas75% fortheentiregroup.Of11surgicalresected patients,10arestillaliveatlastfollowup.Of15patientstreatedwithneoadjuvanttherapy, only1patientwith apositivesurgicalmarginexperiencedlocalprogression.Nopatient experiencednodalorregionalfailurebut 8patientsdeveloped metastaticdisease.  
12 Asimilarstudywasrepeated,alsoatHarvard, usingphoton(conventionalx-rays)insteadof protonradiationtherapy.However, comparedwiththeprotonstudy ahigherrateoffibrosis (63%vs.27%)wasnoted duringsurgeryleadingto a meanincreaseinoperativetimeof69 minutes.Dosimetriccomparisonsrevealedthatpatientsundergoingphotonirradiationhad significantlyincreasedlowdoseradiationexposuretotheabdominalorgans.Duetothis complication,thestudywasterminatedafteraccrualof10of12 planned patients.13
WhiletheHarvardstudywithneoadjuvantprotontherapyachievedexcellentresults,protons arenotwidelyavailableatmostcentersincludingours.Therefore,webelievethatthereisa needfor continued investigation ofneoadjuvant photonradiationtherapyforpancreatic cancer.Wehypothesizethatdeliveringhighdosephotonradiationtothegrossdiseaseusing stereotacticlocalization(SBRT)withoutelectivenodalirradiationcaneffectivelyreducelocal recurrencewhileminimizing thefibrosisnotedintheHarvardPhotonstudy.13 WearenotawareofanyprospectivereportsofusingSBRT aloneasneoadjuvant treatmentfor resectablepancreaticcancer.However,thereareseveralsingleinstitutionexperienceswhich showthatSBRTcanbesafelydeliveredforlocallyadvancedpancreaticcancer(LAPC).Choung etal.reportedtreatingLAPCwithinductionchemotherapyfollowedby5fractionSBRT.Dose paintingtechniqueof7-10Gy/Fractiontotheregionofvesselabutmentand5-6Gy/fractionto thereminderofthetumorwasutilized.Of73patientsevaluated,nopatientsdevelopedgrade 3orhigheracutetoxicityandonly5%developedgrade3orhigherlatetoxicity.  
14 SinceSBRTrequireslargedoses ofradiationtobeaccuratelydelivered,Chuongetalandmany otherauthorshaveutilizedfiducialplacementinthetumorformorepreciseradiotherapy targeting.  
12-14 Althoughbiliarystentshavesometimesbeenusedasasurrogatefortumor location,a studyof11patients demonstratedthatbiliarystentsarenotreliableenough to substitute forfiducialsin SBRTtargeting.  
15 Fiducialplacementusingendoscopicultrasound
(EUS)hasbeendemonstratedtobebothfeasibleandsafe.16 Basedondatafromtheaforementionedstudies,webelievethatourprotocolwhichuses photonirradiationof 25Gyin5fractionstothegrossdiseasealoneusingfiduciallocalization andstereotacticguidancewithoutchemotherapywill beabletoachieveafavorable therapeuticratio.Therationaleistodeliveradoseofradiationthatwillsterilizemicroscopic diseaseatthemarginsthusdecreasingtheriskoflocalrecurrence.Bytargetingthegross diseasealone,wehopetominimizethevolumeoftissuetreatedandavoidtheincreasein fibrosisnotedintheHarvardphotonstudy. Usingradiationtherapyalonewithout chemotherapywilldecreasethedurationandtoxicityofneoadjuvanttherapytherebyallowing patientstoproceedquicklytodefinitivesurgicalresection.After,resection,fulldose chemotherapycanthenbedeliveredwithoutinterruptionwiththeaimofreducingdistant metastaticdisease.
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2.2 primary objectives

a) Toevaluatethefeasibilityandtolerability ofshortcoursepreoperativestereotacticbody radiationtherapyforresectablepancreascancer b) TodeterminetherateofGrade2orgreateracutetoxicity ofneoadjuvantstereotactic bodyradiationtherapy c) Todetermineintraoperativeandpostoperative surgicalmorbidity following neoadjuvanttreatmentincludingtheamountoffibrosisandtotaloperativetime.  
2.3 Secondary Objectives a) Todeterminelocalcontrolandrecurrencepatternsoftreatedpatients relativeto historicalcontrols.  
b) Todetermineprogressionfreesurvivaloftreatedpatients c) Todetermineoverallsurvivaloftreatedpatients
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3.2 inclusioncriteria

a) Patientwithpathologicallyprovendiagnosisofadenocarcinomaoftheheadofthe pancreas b) CT w/contrastorMRIof theabdomenwithcontrast within6weekspriortoregistration c) CTchestorPET/CTwithin6weekspriortoregistration d) Clinicallydeterminedtoberesectablebased onNCCNCriteria: e) Noradiographicevidenceofsuperiormesentericveinorportalveindistortion f) Noevidenceofdistantmetastasis g) Clearfatplanesaroundtheceliacaxis,hepaticartery,andsuperiormesentericartery h) NoenlargedlymphnodesperCTcriteriaorPETavidlymphnodes i) Nolymphadenopathyoutsidethesurgicalfield(i.e.celiacorpara-aorticadenopathy) j) Adequatecardiopulmonaryreservesto toleratesurgery k) Karnofskyperformancestatus ≥70 l) Age≥18 m) Adequatebonemarrowfunctiondefinedasfollows:
- Absoluteneutrophilcount(ANC)≥ 1800cells/mm3 - Platelets≥100,000cells/mm3
- Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieveHgb≥ 8g/dlisacceptable.)
n) Pregnancytestmustbenegativeforwomenofchildbearingpotential within7daysprior tostudyentry o) Patientmustsignstudyspecificinformedconsentpriortostudyentry
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3.3 exclusioncriteria

a) Priorsurgicalresectionofanypancreaticmalignancy b) Priorinvasivemalignancy(exceptnon-melanomatousskincancer)unlessdiseasefree foraminimumof3years c) Anypriorchemotherapyorradiationfortreatmentofthepatient'spancreatictumor. d) Priorradiotherapytotheregionofthestudycancerthatwouldresultinoverlapof radiationtherapyfields e) Severe,activecomorbidity,definedasfollows:
1. Unstableanginaand/orcongestiveheartfailurerequiringhospitalizationwithin thelast12months 2. Transmuralmyocardialinfarctionwithinthelast6months 3. Acutebacterialorfungalinfectionrequiringintravenousantibioticsatthetime ofregistration 4. Chronicobstructivepulmonarydiseaseexacerbationorotherrespiratoryillness requiringhospitalizationorprecludingstudytherapywithin30dayspriorto registration.  
f) Severe,uncorrectablehepaticinsufficiency and/or coagulationdefects duetoliver failure g) Anyevidenceofdistantmetastases(M1) h) Pregnancyorwomenofchildbearingpotentialandmenwhoaresexuallyactiveandnot willing/abletousemedicallyacceptableformsofcontraception;thisexclusionis necessarybecausethetreatmentinvolvedinthisstudymaybesignificantlyteratogenic
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4. methodsandstudyprocedures

4.1 PretreatmentEvaluation(pleasesee scheduleinAppendixBfortablelayout) Within6weekspriortostudyenrollmentpatientsmustundergothefollowingevaluations:
a) Historyand physical byRadiationOncologist,GastroenterologistandSurgicalOncologist b) CTorMRIscanoftheabdomenandpelviswithIVcontrastorPET/CT c) CTchestorPET/CTwithin6weekspriortoregistration d) InformedConsent obtainedbyamemberofthestudyteam e) Labstudies[CBCwithdiff,Na,K,BUN,Cr,Glucose,Phosphorous,Calcium,Albumin,AST,
ALT,Totalbilirubin,Alkalinephosphatase,CA19-9,CEA, INR andapregnancytest(urine orserumHCG) forwomenofchildbearingpotential].  
f) Ifclinicallyindicated,fiducialplacementin/near the tumorviaendoscopicultrasoundby gastroenterologyserviceatleastoneweekpriortoCTsimulation g) Patientswillbeplacedonprotonpumpinhibitors1weekpriortoSBRTtocontinueuntil thedayofsurgerytominimizeboweltoxicity.
h) Anybilestentmanipulationshouldbedone7-10dayspriortoSBRT
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4.2 evaluationduringstudy period

a) History,physicalandvitalsigns duringtheweekly"ontreatmentvisit" duringradiation therapy b) History,physicalandvitalsignsandlaboratoryevaluationobtained bysurgeryteam priortoresection.Specifictestsneededwillbedeterminedbysurgicalteam.  
c) Followingresection,patientswillbeassessedwithin30daysafter dischargeforpostoperativemorbidity bythesurgeryteam.  
d) Patientswillbefollowedatleastevery6months foraminimumof5years bya physicianfromeitherradiation,surgicalormedicaloncologyservice.Closerfollowup maybeneededbasedonclinicalsituation.
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4.3 treatment 4.3.1 radiationtherapy

4.3.1a SimulationandPlanning Patientsshouldabstainfromoralintakefor2hourspriortoCTSimulation. Waterand medicationsareacceptable.PatientswillbesimulatedsupineandExac-tracbodymarkerswill beplacedontheskinforpatientpositioningandrespiratorymanagement.Inordertominimize treatmentvolume,patientswillbeaskedtoperformend-expiratorybreathholdduring simulationandtreatment.Ifpatientisunable totolerateand/orcomplywithbreathhold, simulationandtreatmentwillbedoneusingshallowfreebreathing. A Vac-bag custom immobilizationdevicewillbemade. Withthepatientin thetreatmentpositionandin end-expiratorybreathhold,anon-contrastCT willbefirst performed.Thiswillbe followedbyacontrastCTscan(ifnocontraindications)also usingbreathhold technique.Themaximumslicethicknesswillbe2.5mm.Ifintravenous contrastisnotused during CTSimulation,adiagnosticCTorMRIusingintravenouscontrastor PET/CTmustbeavailableasareference fortargetdelineation. Grosstumorvolume(GTV)willbedefinedonthebasisofCTandMRIimagingfindings. The GTValonewillbetreatedwithaplanningtargetvolume(PTV)marginof-5mmtoaccountfor setupinaccuracyandpatientandorganmovement.Ifneeded,PTVcanbereducedto3mm or less in ordertoavoidhighdosestotheduodenumandstomach. 25Gyin5fractions willbe prescribedtothe70-90% isodoseline.Patientswillbetreatedin5fractionsdeliveredover5-7 days.
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targetdose

25Gyin5 fractionswillbeprescribedtothe70-90% isodoseline. Theprescriptionisodoseline willbechosensothatatleast95%ofthePTV isconformallycoveredbytheprescription isodosesurface. Targetdoseslessthan95%ofprescriptiondosearelimitedtoareasadjacent toanorganatrisk(OAR). Figure1.SchematicofRadiationPrescription  
  
1. Prescriptiondose25Gy 2. Prescriptionisodose70-90% 3. Atleast95%ofPTVcoveredbyprescriptionisodose 4. Normalizationtobeatisocenter NormalTissueTolerance adaptedfromChuongetal.14:
- Meankidney dose <10Gy - Duodenum/small bowel/stomach: maximumdose(0.5cc)<35 Gy, meandose<20Gy, volumereceiving30Gy<5cc
- Liver:volumereceiving30 Gy <10%
- Spinalcordmaximumpointdose-20Gy
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4.3.1c qualityassurance

Theprescriptionisodoselineselectedwillbe70-90%ofthemaximumdosewithinthePTV.As aresulta"hotspot"willexistwithinthePTVthatisequaltotheprescriptiondosedividedby theprescriptionisodoseline(e.g.25Gy/0.8=31.25Gywhen25Gyisprescribedtothe80% isodose line).Doseshigherthantheprescriptiondose (i.e. hotspots)mustoccurwithinthe targetandnotwithinanOAR. 4.3.1d Treatment PatientswillbeimmobilizedintheVac-Bagdevice.Theywillbetreatedinthemannerinwhich theyweresimulated;eitherexpiratorybreathholdorshallowbreathing.Theywillinitiallybe positionedusingExacTracbodymarkers.Treatmentpositionwillthenbeconfirmedbyfiducials alignmentviaExacTracKVimaging.Finalanatomicconfirmationwillbemadebycone-beamCT
immediatelypriortotreatment.
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4.3.3 surgery

Surgerywillbeperformed nomorethan 3 weeksaftercompletionofradiationtherapy. A pancreaticoduodenectomy(Whippleprocedure)withstandardlymphadenectomywillbedone.
Restagingisnotrequiredpriortosurgery.Howeverifre-stagingscansareobtainedand demonstratemetastaticdisease,surgerywillnotbeperformed. Anattemptedresectionmayalsobeabortedwhenmoreadvancedormetastaticdiseaseis foundatthetimeoflaparotomy.Ifsurgicalresectioncannotbecompleted duetothepresence ofadvanceddisease,thepatientwillbewithdrawnfromtheprotocolatthattimeandwill continuetheircarewithstandardtreatmentandfollowupbasedontheirclinicalcharacteristic.
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4.3.4 adjuvanttherapy

Adjuvantchemotherapymaybegivenafterpancreaticoduodenectomyatthediscretionofthe medicaloncologist. Postoperative radiotherapywouldnotroutinelybegivenafterSBRT. 4.4 CostofTreatmentstotheSubject Someofthetests/procedures/examsinvolvedinthestudysuchasimagingandlaboratory analysisforoncologicstagingandthesurgicalresectionarestandardcare.Thepatientand/or his/herinsurancecompanywillberesponsibleforpayingforanytests/procedures/examsthat aredoneaspartofthestandardofcare.Thepatientandhis/herinsurancecompanywillalso berequiredtopayfortheSBRTradiationreceivedthroughthisstudy.Theproviderwillattempt toobtainpriorauthorizationfortheradiationtreatmentfromthesubject's insuranceprovider. Anydifficultiesobtainingauthorizationwillbediscussedwiththesubjectpriortoyour treatment. Thepatientwillbeencouragedtodiscusstheircoveragewiththeinsuranceproviderpriorto initiatingtreatment.ThecostofSBRTwillbeoffsetbyomittingfractionatedradiotherapythat wouldotherwisebegivenasthestandardofcareaftersurgeryandchemotherapy. Therewillbenopaymentsmadetopatientsonthestudy.
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5.2.2 post-treatmentsurveillance

NCCNguidelineswillbefollowed.Surveillancewill beevery3-6monthfor2yearsthenannually thereafterandwillinclude:
- HistoryandPhysical - CA19-9Levels
- CTorMRIimagingwithIVcontrast 6. **ADVERSEEVENTS** 6.1 DefinitionofAdverseEvent Anadverseeventisanysymptom,sign,illness,orexperiencewhichdevelopsorworsensduring thecourseofthestudy,whetherornottheeventisconsideredrelatedtothestudy intervention. Theinvestigatorwillberesponsibleforassessingtheetiologyofanyadverseeventsand determiningifthesecanbeconsideredatreatmentrelatedadverseevent(TRAE)whicharose directlyorindirectlyasaresultofSBRT.AdverseeventswillbegradedaccordingtotheNCI CTCAEVersion4.0.TRAEwillbeconsidered"acute"iftheyoccurwithin1-4weekspostSBRT andpriortosurgicalresectionand"late"iftheyoccurafterthistimeperiod. 6.2 EvaluationofAdverseEvents Patientswillbeassessedfortreatmentrelatedadverseeventsweeklyduringontreatmentvisit duringradiationtherapy,atthepre-operativeevaluationvisitandatfollowupvisits foratleast 5years.Additionalpatientvisitsmaybeneededasclinicallyindicated.Atthesevisits,study staffwillassessadverseeventsbyrecordingallvoluntarycomplaintsofthesubjectandby assessmentofclinical,radiologicandlaboratoryfeaturesasindicatedbytheschedulein AppendixBandasclinicallywarranted.Ateachstudyvisit,thesubjectshouldbequestioned directlyregardingtheoccurrenceofanyadverseexperiencesincehis/herlastvisit. 6.3 DocumentationofAdverseEvents Alladverseevents,whetherobservedbytheInvestigator,elicitedfromorvolunteeredbythe subject,will bedocumented.Eachadverseeventwillincludeabriefdescriptionofthe experience,thedateofonset,thedateofresolution,thedurationandtypeofexperience,the severity,andthe relationshiptoSBRT,contributingfactors,andanyactiontakenwithrespect totheplannedradiationtherapy. Inaddition,anytoxicityleadingtoradiationtreatmentbreak anddelayinsurgicalresectionbeyond3weekspostSBRTwillnoted. Allpatientsareexpectedtoundergosurgicalresectionwithin3weeksafterradiationtherapy. AnyIntraoperativecomplicationsincludingbloodloss,totaloperativetimeandamountof fibrosisnotedbythesurgeonwillberecordedintheoperativereport.Post-operative complicationsincludingdelayedwoundhealing, bloodloss,infection,lengthofhospitalstay, incidenceofpancreaticleak,hospitalreadmissionsforcomplicationswillalsoberecorded. AppendixAliststhedatathesurgicaloncologyteamisresponsibleforrecording. Treatmentrelatedlatecomplicationsincludingbutnotlimitedtoduodenalandintestinal ulceration,perforation,gastritis,boweladhesionsandobstruction, willberecordedatfollow upsupto5yearsaftertreatment.
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6.4 seriousadverseevents (saes)

Aseriousadverseeventisanyadverseeventthatresultsinanyofthefollowingoutcomes:
- death; - islife-threatening; - requiresinpatienthospitalizationorprolongationofexistinghospitalization; - resultsinpersistentorsignificantdisability/incapacity; - isacongenitalanomaly/birthdefect;or
- requiresmedicalorsurgicalinterventiontopreventpermanentimpairmentordamage.  
Anyseriousadverseeventswillbecommunicateddirectlytotheprimaryinvestigator(Dr.Alan Katz)within24hoursanddocumentedin thepatient'smedicalchart.Dr.Katzwilldetermine howtorespondtotheeventandwhetherthepatientwillcontinueonthestudy.
AllSAEswillbereportedtotheIRBperlocalinstitutionalpolicy.
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6.5 treatmentmodificationduetoadverseevents

We donot anticipate anyserioustreatmentrelatedadverseeventswilltakeplaceduringor immediatelyfollowingSBRTtreatment.Weexpectthat themostcommonacutetoxicitiesof radiationtherapywillbemildnausea,fatigueandloosebowelmovements. Patientswillfinishplannedradiationiftheyexperienceuptograde2treatmentrelatedtoxicity. Ifpatientsdevelopanyseriousadverseeventoranygrade3orhighertreatmentrelated toxicity, SBRTradiationwillbestoppedandthepatientswillproceeddirectlytosurgical resectionifdeemedappropriatebysurgicaloncology.
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7. risk/benefitassessment

Thisstudyisbeingconductedbecausetheinvestigatorsbelievethattreatingpancreatic adenocarcinoma withpreoperativeSBRTmayimproveoutcomecomparedwithmore conventionaltreatment.Therehavebeenseveralsmall-scale studiesatotherinstitutions(as documentedintheintroduction)whichhaveshowndeliveringSBRTtothepancreascanbesafe andeffective.However,thistechniquehasnotbeenattemptedatURMC.Weaimtostudy whetherneoadjuvantSBRTisfeasibleatURMC.Therearebenefitsandrisksassociatedwith thisstudyasdocumentedbelow.Theinvestigatorsbelievethatthebenefitsoutweigh the potentialrisksforpatientsenrolledonthisstudy. 7.1 BenefitsofParticipation a) Inconventionaltreatment,radiationisdeliveredtothesurgicalbedwhichcontainsa largeofbowelthathasbeensurgicallymanipulated.Thisstudycallsforradiationtobe deliveredpriortosurgery.Thisallowstheradiationtobetargetedatthegrosstumor directlywhichwilldecreasetheamountofnormalbowelthatistreated.Inaddition, thetumorvascularsupplypreoperativelyisgenerallymorerobustthanpostoperatively allowingbetteroxygenationtothetissuewhichiscriticalforthetumoricidaleffectof radiation.  
b) Inconventionaltreatment,radiationisdeliveredinconjunctionwithradio-sensitizing chemotherapyoveraperiodof5-6weeks.This chemotherapyisgenerallynotas effectiveatcontrollingmicrometastaticdiseasecomparedtodefinitivechemotherapy whichmayincreasetheriskofmetastaticprogression.Thisstudycallsforashorter courseofradiationtreatmenttobedeliveredover1-2weekspreoperatively.Thiswill allowthepatienttoreceivefulldosechemotherapywithoutinterruptionaftersurgery. Thiscouldreducetheriskofmetastaticdiseasewhichisamajorprobleminthe treatmentofpancreaticcancer.  
c) Conventionalradiationtreatmentdeliversasmalldoseofradiationspreadover5-6 weeks.Itisknownthatpancreaticcancerisrelativelyresistanttoradiationtherapy.The radiationinthisstudyisdeliveredinlargerdosesoverashorterperiod oftimewhich mayhelpto overcomesomeoftheresistanceofpancreaticcancer.  
7.2 RisksofParticipation a) Preoperative SBRTcouldcausetoxicities thatcoulddelayorevenpreventsurgical resection whichisthemostimportanttreatmentfor resectable pancreaticcancer. However,previousstudieshavedemonstratedthatthevastmajorityofpatientswho undergopreoperativeradiationcansafelyundergosurgeryinatimelyfashion.  
b) Radiationtherapycancausebothacuteanddelayedsideeffects.Acutesideeffectsthat takeplaceduringorimmediatelyaftertreatmentcanincludefatigue,nausea,vomiting, diarrhea,lossofappetiteandweightloss.Theseeffectsareexpectedtobeuncommon andcanbemanagedwithsupportivecaresuchasanti-nauseaoranti-diarrheal medicines.Delayedsideeffectscantakeplacemonthstoyearsafterradiationandcan includedelayedwoundhealing,scartissueformationandbowelobstructionand structuring.Theseeffectsareexpectedtobeveryrare.Theseeffectsareexpectedtobe similarordecreasedcomparedwiththetoxicitiesassociatedwithconventional radiation.
c) Thereisariskofinvasionofpatientprivacy.Alltheinformationgatheredfrompatient chartorrecords,includingnameandanyotheridentifyinginformationwillbestrictly confidentialandwillbekeptunderlockandkey.Thepatientswillnotbeidentifiednor willanyinformationthatwouldmakeitpossibleforanyonetoidentifythepatientbe usedinanypresentationorwrittenreportsaboutthisstudy.Only summarizeddatawill bepresentedatmeetingsorinanypublications.
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8. confidentialiatyofdataandinformationstorage

Allprotectedhealthinformationwillbede-identifiedpriortostorageintheresearchdatabase. SubjectsintheresearchdatabasewillbeonlyidentifiedbyanIDnumberbasedontheirorder ofenrollment(i.e.Subject1,Subject2etc.).Theprimaryinvestigator,Dr.Katzwillmaintaina password-protected filethatwilllinkthesubjectIDcodetothepatient'smedicalrecord numberintheelectronicmedicalrecordsystematURMC.Allresearchdatawillbekeptin securedataservers inthedepartmentofradiationoncology.Allresearchspreadsheetswill havepasswordsprotectionthatwillonlybeknowntothestudyinvestigators.  
Thepatient'senrollmentonthetrialandanyclinicaldatarelevanttothepatient'scarewillbe documentedinthepatient's electronic medicalrecordatURMC.
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9. dataanalysisandmonitoring

Thepurposeofthispilotstudyistodeterminefeasibility ofpreoperativeSBRTfollowedby surgicalresectionatURMCandtodetermineitssafetyandtolerabilityinasmallpopulationof patients. Forthisphase1trial,weplantoenroll18 patientsover1-2years withagoalof12 evaluablecases. Thisisagenerallyacceptednumberofpatientsforphase1trialsandwill minimizetheriskstopatientsincasethetreatmentisfoundtobeunsafe.Wewillstop recruitmentandanalyzethesafetydataifthereappearstobeanygrade 3orgreatertoxicityon anysubjectthatcanbedirectlyattributedtoSBRTorifanypatientsaremadeineligiblefor surgicalresectionsolelyduetotoxicitiesfromSBRT. Inthecasewhereanypatientbecomes ineligibleforresectionduesolelytotoxicityfromSBRT, thestudywillbeimmediatelyclosed toaccrual.Wewillstoprecruitmentandanypatientwho hasnotstartedradiationtherapywillhavetheirplannedradiationtreatmentcanceled.A patientwhohasstartedradiationtherapywillundergoanindividualdiscussionwithDr.Katz abouttherisksandbenefitsofcontinuedtreatment. Ifapatientexperiencesgrade3orgreatertoxicitydirectlyattributabletoSBRTthatisreversible andultimatelyabletoundergoresection,wewillanalyzetheeventandattemptto prevent/reducetheadverseeventfromtakingplaceagain.Wewilldiscusstherisksand benefitsofcontinuedrecruitmentintothestudywithourco-investigatorsanddetermine whetherornot tocontinuethestudy.Ifwebelievethatmodificationscanbemadethatwill reasonablyreducetheriskofafutureeventfromoccurring,wewillcontinuerecruitmenttothe study. Theinvestigatorsplantoevaluatetheratesofacutetoxicityafter12patientshavebeen enrolledandundergoneSBRTandsurgicalresection.Longtermsafetyandefficacywillbe evaluatedafterall12patientshaveundergonesurgicalresectionandhaveeitherbeenfollowed foratleast6monthorhavedied.Theprimaryinvestigator,Dr.AlanKatzwillhaveaccesstoall ofthestudydata. TheCancerCenterData&SafetyMonitoringCommitteewillmonitorthestudyforsafety. Study Investigatorswillconductcontinuousreviewofdataandpatientsafety. TheInvestigatorwill submitquarterly progressreportsofthesedatatotheClinicalTrialsMonitoringCommitteefor review[AppendixC]. Thereviewwillincludeforeachtreatment arm/doselevel: thenumber ofpatientsenrolled,withdrawals,significanttoxicitiesasdescribedintheprotocol,serious adverseeventsbothexpectedandunexpected,doseadjustments,andresponses observed. ThePImaintainsadatabaseofalladverseeventswithtoxicitygradeandinformation regardingtreatmentrequired,complications,orsequelae. TheInvestigatorwillsubmitacopy oftheAEspreadsheetalongwiththeProgressReporttotheClinicalTrialsMonitoring Committeeforreview.Actualreviewdateswillbeassignedwhenthe1stpatientisaccrued.  
- Anyseriousadverseeventthatisserious,relatedANDunexpectedmustbereported within10calendardaystoboththeSafetyCoordinatorandtheRSRB(seeRSRB guidelines). TheDSMCChairwilldeterminewhetherfurtheractionisrequired,and whenpatientsafetyisofconcern,aninterimmeetingmaybecalled.  
- SeriousadverseeventsthatarerelatedANDexpectedorunrelatedANDunexpectedwill bereportedtotheCommitteeforreviewatthequarterlymeeting. SAEreportsare expectedtoincludesufficientdetailsothattheDSMCcandeterminetheseverity, toxicitygrade,expectedness,treatmentrequired,andafollowupreportdocumenting resolutionoriftherearesequelae. Unlessotherwisespecifiedintheprotocol,serious adverseeventsthatrequiredetailedreports(butnotnecessarilyexpedited)are expected,related,non-hematologictoxicitiesofgrades3,4or5.  
Weplantopublisha descriptiveanalysisofthe resultsincluding acuteandlatetoxicity including surgicalmorbidity. Weplantoreportoncologicoutcomesincludingmedianoverall survival,progression freesurvival,localprogressionfreesurvivalanddistantprogressionfree survival.AnalysiswillbeusingKaplan-Meiermethod.Survivaltimewill bemeasuredfromthe dateofdiagnosis. Alocalrecurrencewillbedefinedasanyevidenceoftumorrecurrencewithin thePTV.Whetherlocalrecurrenceoccurredinconjunctionwith,beforeorafterdistant recurrencewillbenoted.
schema
appendixa

AssessmentofAcuteToxicityFormtobecompletedbySurgicalTeamimmediatelyafter resectionandatthePostOpVisit.  
| Field   | Result   |
|---------|----------|
| TobeRecordedintheOperativeNote OperatingTime(min) EstimatedBloodLoss (ml) Surgeon'sAssessmentofFibrosis (Expected,Increased,MarkedlyIncreased) TobeRecordedatthePostOpVisit         | DateofVisit:          |
| LengthofHospitalizationpost-surgery includinganyre-admissions(days).Described anyre-admissions AnastomoticLeak(yes/no) Ifsodescribed Post-SurgeryInfectionRequiringAntibiotics (yes/no) Ifsodescribed Woundhealingcomplicationsthatareworse thanusual?(yes/no)Ifsodescribed Nameofpersoncompletingtheform:         |          |  
Dateformcompleted:  
| TestsandObservation    | Within6weeks priortoStudy enrollment    | OnTreatment   | Post-OpToxicity   |    |
|----|----|---|---|----|
| visitduringRT    | Evalbysurgery team    | ClinicalFollowUp every3-6monthsfor 2years,thenannually perNCCN   |   |    |
| Signedinformedconsent    | X  |   |   |    |
| History+PhysicalExamination    | X  | X | X | X  |
| Completeblood countwith differential,Comprehensive metabolicpanel,creatinine clearance,Phosphorous,INR    | X* |   |   |    |
| Pregnancytest**    | X  |   |   |    |
| CA19-9Level    | X  | X |   |    |
| CEALevel    | X  |   |   |    |
| a) | CTorMRIscanoftheabdomen andpelviswithIVcontrastor PET/CT.    | X | X |    |
| CTchestorPET/CT    | X  |   |   |    |
| *Otherlaboratorytestssuchascoagulationstudiesmaybeorderedbysurgicalteamasneeded ** Pregnancytestresults needtobeobtainedwithin7daysofstudyentryforthoseofchildbearingpotential.    |    |   |   |    |
appendixc
appendixa

James P. Wilmot Cancer Center (JPWCC)
Data Safety Monitoring Committee (DSMC)
Study Progress Summary Report Study name and URCC \#
PI:
DSMC Review Date:
Date of 1st **accrual: _______Status: open___ closed to accrual___ closed _______**
(date)
DATA SUMMARY:
appendixc
1. enrollment

Since last Report: Total to Date: Total Planned:  
  
  
Comments:  
| 2.                                                                                                                         | ADVERSE EVENTS Serious / Related /  Unexpected1 :   | Other Serious2 :   | Non-Serious:   |
|----------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------|--------------------|----------------|
| Since Last Report: Total: Comments:                                                                                        |                                                     |                    |                |
| 1 Serious, possibly/probably/definitely related events that are considered unexpected require prompt reporting to RSRB and |                                                     |                    |                |  
Comments: 1Serious, possibly/probably/definitely related events that are considered unexpected require prompt reporting to RSRB and DSMC.  
2Serious events which are unrelated and/or expected require reporting to the RSRB at least annually and to the DSMC per DSMC
reporting requirements.
appendixc
3. subject withdrawals

| Investigatorinitiated:                           | Reason(s):   | Subjectinitiated:   | Reason(s):   |
|---------------------------|--------------|---|--------------|
| Since last report: Total: |              |   |              |  
DMSC RECOMMENDATIONS: <indicate DSMC recommendations, if any - i.e., requested actions or *state 'No recommendations at this* time; study should continue as planned.'>
appendixc
10. references

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