Recent Advances and Trends in the Management of Locally Advanced

Pancrea9c Cancer Incremental Progress

JillLacy,MDFeb2018

Disclosures

CelgeneAstraZenecaNavigantKeyquest

JillLacy,MD

Teaching points

• DefiniAonsand“staging”evaluaAon• Management

•  improvingoutcomes•  consensusguidelines•  unresolvedissues

• ResponseassessmentinpaAentselecAonforsurgery• ChallengesandfuturedirecAons

Locally Advanced Pancrea9c Cancer (LAPC)

•  30-40%ofpaAentswithnewlydiagnosedpancreaAccancerpresentwithnon-metastaAclocallyadvancedunresectabledisease(LAPC)

• Historically,survivalmarginallybeTerthanmetastaAcPC,<12mo• Historically,negligible%ofpaAentswereabletoundergosurgery,<5%• PaAentssuffersignificantmorbidityreferabletolocaltumorburden• PaTernsoffailureandbiologynotwellunderstood*

•  <30%non-metastaAc(5/18)•  >70%metastaAc(13/18)

*JClinOncol2009Apr10;27(11):1806-13

LAPC:DefiniAon

•  Non-metastaAcPCcomprisedofconAnuumfromresectabletounresectablebasedoninvolvementofadjacentvascularstructures

•  ConsensusorganizaAonshavedefinedanatomiccriteriawhichdelineatethreecategoriesofnon-metastaAcPC:–  resectable– borderlineresectable–  locallyadvancedunresectable

•  DefiniAonsprovideguidanceformanagementandneededforclinicaltrials•  BUTarenotuniformandsubjecttointer-observervariability

LocallyAdvancedUnresectablePancreaAcCancer:Weknowitwhenweseeit

EncasementofSMAorceliacaxis* OR

ExtensiveinvolvementofSMVand/orPVthatprecludesresecAonand/orreconstrucAon

AND

NoevidenceofmetastaAcdiseaseincludingmetastaAcnon-regionalLNs*Encasement:>180ocontact

DefiniAonofLAPCNCCNVersion3.2017

•  Nodistantmetastases•  Head/uncinateprocess

–  SolidtumorcontactwithSMAorCA>180o(encasement)–  SolidtumorcontactwithfirstjejunalbranchofSMA–  UnreconstructableSMV/PVduetotumorinvolvementorocclusion(tumororblandthrombus)–  ContactwithmostproximaldrainingjejunalbranchintoSMV

•  Body/tail–  SolidtumorcontactwithSMAorCA>180o(encasement)–  UnreconstructableSMV/PVduetotumorinvolvementorocclusion(tumororblandthrombus)–  ContactwithCAandaorAcinvolvement

BorderlineResectablePancreaAcCancerontheconAnuumofvascularinvolvement

MorelimitedvascularinvolvementthanLAPCandtechnicallymayberesectableBUT:•  HighriskforaposiAvemarginofresecAon(R1resecAon)•  RequiresmorecomplexoperaAonw/vascularresecAonandreconstrucAon,withhighermorbidity

•  MulApleanatomicdefiniAonshavebeenproposedandused•  DefiniAonsareomeninsAtuAonand/oroperatordependent.

Borderline Resectable: Lack of Uniform Criteria

Criteriadiffer:-ExtenttowhichtumorinvolvementofSMV-PVdiscriminatesborderlineresectablefromresectable-ExtenttowhichinvolvementofceliactrunkdiscriminatesborderlineresectablefromLAPC

WhatisBorderlineResectablePancreaAcCancer?ASCOGuidelinesPanelApproach:“punt”

•  CategorizesiniAaldiagnosesasthoseforwhomupfrontsurgeryisrecommendedversusthoseforwhompreoperaAvetherapyisrecommendedbeforeresecAon.

•  ThiscategorizaAoncapturestheoncologyprovider’sintentinreducingtherateofincompleteresecAon

•  Haschosennottousetheterms“resectable”and“borderlineresectable.”•  ConAnuestosupporttheuseofthesetermsinthecontextofclinicaltrials,where

cleardefiniAonsofeligibilityarenecessary.

Khorana,etal.JClinOncol2016Jul20;34(21):2541-56

AJCC Staging vs Prac9cal Clinical Staging

• AJCCstagingsystemdoesnotaddressresectability

• NCCN:Forclinicalstagingpurposes,useafour-AerclinicalclassificaAonsystembasedimagingstudies:(1)Resectable(2)Borderlineresectable(3)Locallyadvancedunresectable(4)Disseminated

•  CTscanchest/abd/pelvis- ProvidesstagingintermsofmetastaAcvsnon-metastaAc

•  Ifnomets:repeatCTwithbiphasic“pancreaAcprotocolCT”toassessvascularinvolvement/resectability- FindingsonpancreaAcprotocolmaychangemanagementin>50%ofpts

•  EUS- ComplementsCTinassessingvascularinvolvement,espportalvein- Biopsy(required)

•  DiagnosAclaparoscopywithperitonealwashingsinselectedpaAents- ConsiderinpaAentswithhighCA19-9inwhomsurgerymaybeconsidered

DiagnosisandEvaluaAon:Imagingiskey

DiagnosisandEvaluaAon:MulAdisciplinaryDiscussionisKey

NCCNGuidelines:BlackBoxWarning!

ManagementofLocallyAdvancedPancreaAcCancer

LAPCManagement:CurrentStateofAffairs

•  OpAmalmanagementiscontroversial•  NointernaAonally-embracedstandardapproach.•  IniAalchemotherapywithacombinaAonregimeninfitpaAentsisthecurrentrecommendaAonofNCCNandASCO*

•  Butnoclearevidencetosupportoneregimenoveranother•  LimitedprospecAvedatawith“modern”chemotherapy

*JClinOncol2016Aug1;34(22):2654-68

LAPCManagement:ManyUnresolvedQuesAons•  WhatisopAmuminiAalchemotherapyregimen?

– FOLFIRINOXvsGem/Abraxanevsotherdilemma?

•  WhatisopAmumduraAonofchemotherapy?– Roleofmaintenancechemotherapy?

•  Whatisroleofpost-chemotherapyradiaAon?– Doesitconferasurvivalbenefit?– DoesitconferaPFSorQOLbenefit?– WhichRTtechniqueanddoseisbest?

LAPCManagement:ManyUnresolvedQuesAons

•  Whatistheroleofsurgery?– WhoshouldundergosurgicalexploraAon(local-onlybiology)?– Canwepredictresectablediseaseamer”neoadjuvant”therapy?– Doessurgeryconferasurvival,PFS,orQOLbenefit?– Doessurgerycureanyone?

LAPCManagement:MeaningfulProgress

•  Priorto2010,survival<11monthswithgemcitabine-basedchemo•  FOLFIRINOX*hashadmeaningfulimpactonoutcomesofLAPC•  MulApleretrospecAveseries,oneprospecAvetrial2andonemeta-analysis3havedemonstratedmediansurvival>24monthswithupfrontFOLFIRINOX

•  25to>40%abletoundergoresecAonamerFOLFIRINOX•  Emergingexperiencewithgemcitabine/nab-paclitaxelencouraging

1Steinetal.BrJCancer.2016Mar29;114(7):737-432Sukeretal.LancetOncol.2016Jun;17(6):801-10

*Folinicacid,Flourouracil,Irinotecan,OxaliplaAn.FOLFIRINOXvGemformetastaAcPC.NEJM.2011;364:1817-25

FOLFIRINOXforlocallyadvancedpancreaAccancer:asystemaAcreviewandpaAent-levelmeta-analysis

Sukeretal.Lancet Oncol 2016; 17: 801–10 .•  13studiesw/315ptswithLAPCwhoreceivedFOLFIRINOX

•  63%alsoreceivedradiotherapy•  26%underwentsurgery(74%R0resecAons)•  Medianoverallsurvival24.2mo•  SurvivalsubstanAallybeTerthanhistoricalcontrolswithLAPC•  SurvivalcomparesfavorablywithsurvivalofresectedpaAents

FOLFIRINOXinLAPC:YaleTrialDesignStein.BrJCancer2016

LocallyAdvancedandBorderlinePC(NCCNcriteria)

ConAnueFOLFIRINOX*

RadiaAonwithconcurrent

chemotherapy*SurgicalResecAon

mFOLFIRINOXx8cyclesCTscanamercycle4and8*

Ifstableorrespondingamer8cycles,addiAonaltreatmentperinvesAgator’sdiscreAon

*SurgeryallowedifdeemedresectablebeforecompleAonofinducAonFOLFIRINOXorameraddiAonaltherapy

Primaryendpoint:PFSSecondaryendpoints:•  RR•  OS•  ResecAonrate

FOLFIRINOXinLAPC:YaleResultsStein.BrJCancer2016

DisconAnuedFOLFIRINOXpriortocompleAng8cycles CompletedFOLFIRINOXinducAon

ReasonsforFOLFIRINOXdisconAnuaAon:-Withdrew,2paAents-OptedforchemoRT(stabledisease),4pts-Treatmentdelays,5ptsUnresolvedinfecAon,2ptsAdverseevents,3pts

11pts35%

20pts*65%

PaAentDisposiAonDuringFOLFIRINOXInducAon

*Includes4ptsdeemedresectablepriorto8cycles

FOLFIRINOXinLAPC:YaleResults

•  31paAentsinlocallyadvancedcohort•  ResponsetoinducAonFOLFIRINOX(RECIST):

– 17.2%parAalresponse;82.7%stabledisease– NopaAentsprogressed

•  Surgery:41.9%(13)underwentsurgery(allR0resecAons)– 6of13hadchemoRTpriortosurgery– 9hadnode-negaAvedisease(stage0,I,IIAin1,2,and6pts)

•  Medianprogressionfreesurvival17.8mo•  Mediansurvival26.6mo

Stein.BrJCancer2016

ABSTRACT204

Phase2LAPACTTrialofnab®-PaclitaxelPlusGemcitabineforPa9entsWithLocallyAdvanced

Pancrea9cCancerPascalHammel,1JillLacy,2FabiennePortales,3AlbertSobrero,4RobertoPazo-Cid,5JoseL.ManzanoMozo,6EricTerrebonne,7ScotDowden,8Jack

ShiansongLi,9TengJinOng,9ThomasNydam,9PhilipA.Philip10

1HôpitalBeaujon,Clichy,France;2YaleCancerCenter,NewHaven,CT;3InsAtutrégionalduCancerdeMontpellier(ICM),Montpellier,France;4AziendaOspedalieraUniversitariaSanMarAno,Genova,Italy;5HospitalMiguelServet,Zaragoza,Spain;

6HospitalUniversitariGermansTriasiPujol,Barcelona,Spain;7HospitalHautLeveque,Giround,France;8TomBakerCancerCenter,Calgary,Canada;9Celgene

CorporaAon,Summit,NJ;10KarmanosCancerInsAtute,Detroit,MI

nab®isaregisteredtrademarkofCelgeneCorporaAon.

LAPCTStudydesign:mulAcenter,singlearm,phase2trial

aEligibilitydeterminedonthebasisofvascular(SMV,PV,SMA,andCA)involvementorunresectablelymphnodes.bSurgicalintervenAonwasallowedpriortocompleAonof6cyclesofnab-paclitaxel+gemcitabineifdiseasewasdeemedoperablebythetreaAngmedicalteam.cForpaAentswithoutPDorunacceptabletoxicityamerinducAon.dConcurrentcapecitabineorgemcitabine+radiaAonaccordingtoinsAtuAonalpracAce.eTimefromfirstdoseofstudytherapytotreatmentfailure,definedasdisconAnuaAonofstudytherapyduetoPD,deathbyanycause,orthestartofanon–protocol-definedanAcancertherapy.fAmer6cyclesoftherapy;CR,PR,andSD(for≥16weeks).gQOLoutcomeswereassessedusingtheEuropeanOrganizaAonforResearchandTreatmentofCancer(EORTC)quality-of-lifequesAonnaires(QLQ),EORTCQLQ-C30andQLQ-PAN26.

1.VonHoffDD,etal.NEnglJMed.2013;369:1691-703.

Objec9ve:Toassessthesafetyandefficacyof6cyclesofinducAontherapywithnab-paclitaxel+gemcitabinefollowedbyInvesAgator’sChoice(IC)oftreatmentinpaAentswithnewlydiagnosedLAPC

Previouslyuntreated,

unresectableaLAPC

PlannedN=110

Induc9onPhase

nab-Paclitaxel125mg/m2qw3/4+

Gemcitabine1000mg/m2qw3/4

Maximumof6cyclesb

Inves9gator’sChoice(IC)TreatmentOp9onsc

•  nab-Paclitaxel+Gemcitabine•  Chemoradia9ond•  Surgicalresec9on

Periodicfollow-upforPFSandOS

•  PrimaryEndpoint:TTFe

•  SecondaryEndpoints:DCR,fORR,PFS,OS,safety,andQOLg•  PosthocEvalua9on:AnalysisofinvesAgator’schoiceoftreatment,includingresecAonrateandquality(R0vsR1)

•  KeyExclusionCriteria:Endocrine/mixed-originpancreaActumors,borderlineresectabledisease

•  SampleSize:AnesAmated100paAents(assumes10%dropoutrate)intheITTpopulaAonprovides80%powertodetecta30%increaseinthemedianTTFfrom5.1(medianTTFfromtheMPACTtrial1)to6.6months

ABSTRACT204:nab-PaclitaxelplusGemcitabine–PascalHammel,MD

LAPACT:PaAentdisposiAonDuringNab/GemInducAona

aPercentagesarebasedonthe107enrolledpaAents;1paAentenrolledbutdisconAnuedpriortotheinducAonphase.bPaAentsdesignatedforsurgerypriortocompleAng6cyclesofinducAonwereconsideredtohavecompletedtheinducAonphase.

57.0% 42.1%

ReasonsforDiscon9nua9onofInduc9on

Adverseevent(n=20;18.7%)Progressivedisease(n=8;7.5%)Physiciandecision(n=6;5.6%)WithdrawalbypaAent(n=3;2.8%)ProtocolviolaAon(n=4;3.7%)Nonadherencetostudydrug(n=1;0.9%)Death(n=2;1.9%)Other(n=1;0.9%)

CompletedinducAontreatment(n=61)bDisconAnuedinducAontreatment(n=45)

N=107

LAPACT:EfficacyduringinducAonBestResponseDuringtheInduc9onPhase(nab-Paclitaxel+GemcitabinetreatmentOnly)BestResponsebyRECISTv1.1a ITTPopula9on(N=107)b

Completeresponse,n(%) 0

Par9alresponse,n(%) 35(32.7)

Allstabledisease,n(%)Stabledisease≥16weeksStabledisease≥24weeks

62(57.9)48(44.9)35(32.7)

Diseasecontrolrate(completeresponse+par9alresponse+stabledisease),n(%)Diseasecontrolratebasedonstabledisease≥16weeksDiseasecontrolratebasedonstabledisease≥24weeks

83(77.6)70(65.4)

Progressivedisease,n(%) 5(4.7)

27

aExcludingtumorassessmentsamernon-protocol-definedanAcancertherapyorsurgery.b1paAent(0.9%)wasnotevaluableand4paAents(3.7%)didnothaveapostbaselineassessment.ITT,intenttotreat;RECIST,ResponseEvaluaAonCriteriaInSolidTumors.

ABSTRACT204:nab-PaclitaxelplusGemcitabine–PascalHammel,MD

28

Bestchangefrombaselineintargetlesionsa

aInvesAgatorassessed.SLD,sumoflongestdiameters.

• Medianbestpercentagechangefrombaselineinsumoflongestdiameteroftargetlesionswas18.5%•  39of102paAents(38.2%)hada>30%reducAoninsumoflongestdiameteroftargetlesions

Maxim

umCha

ngeFrom

Baseline,%

Pa9ents(n=102)

100

80

60

40

20

0

−20

−40

−60

−80

−1000 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105

ABSTRACT204:nab-PaclitaxelplusGemcitabine–PascalHammel,MD

29

Progression-freesurvivala

Events/N Median,mo(90%CI)

Allpa9ents 80/107 10.8(9.26–11.63)

No.atRisk

100

80

60

40

20

00 3 6 9 12 15 18 21 24

97 85 68 40 23 14 7AllPaAents 107

Months

Percen

tageofP

a9en

ts

With

outD

iseaseProgression

,%

aAsofmonth12,27paAentshavenotprogressedordied.ABSTRACT204:nab-PaclitaxelplusGemcitabine–PascalHammel,MD

Allpa9entsEvents/N Es9mated12-monthOS

58/107 72%(90%CI,64.5%–78.9%)

30

Overallsurvivala

aAsofmonth12,49paAentsweresAllalive.

No.atRisk

100

80

60

40

20

00 3 6 9 12 15 18 21 24 27

101 96 86 73 40 28 17 5AllPaAents 107

Percen

tageofS

urvival,%

Months

ABSTRACT204:nab-PaclitaxelplusGemcitabine–PascalHammel,MD

EORTCQLQ-C30Measurements

31

Global Health Status/ QoL

EORTC QLQ-C30

Functional Scales Symptom Scales/Items

•  How would you rate your overall health during the past week?

•  How would you rate your overall quality of life during the past week?

a Scales have been revised since version 1.0

•  Physical functioninga •  Role functioninga •  Emotional functioning •  Cognitive functioning •  Social functioning

•  Fatigue •  Nausea and vomiting •  Pain •  Dyspnea •  Insomnia •  Appetite loss •  Constipation •  Diarrhea •  Financial difficulties

The QLQ-C30 QoL was completed by patient: screening, on day 1 of each A+G cycle, and at the 28-day follow-up visit during the induction phase

QualityoflifeduringinducAona

aPaAentswereaskedtoratetheiroverallhealthandqualityoflifeduringthepastweek.

•  PaAents’overallglobalhealthstatusandoverallQOLwasmaintainedthroughday1ofcycle6

Baseline C2, D1 C3, D1 C4, D1 C5, D1 C6, D1

99 85 73 70 53 42 Cycle, Day

Mea

n C

hang

e fr

om B

asel

ine

± SE

All Patients

10

5

0

−5

−10

ABSTRACTID204(200537):nab-PaclitaxelplusGemcitabine–PascalHammel,MD

Gem+Nab-paclitaxelinLAPC:LAPACTSummary•  FirstprospecAvestudytoevaluateNab/GeminLAPC

•  Nonewsafetysignals•  ResponsetoinducAonNab/Gemencouraging

–  32.7%parAalresponse;57.9%stabledisease–  4.7%progression

•  R0orR1resecAonrate15%•  QualityoflifemaintainedinmostpaAents•  Medianprogressionfreesurvival10.8mo(TTF8.8mo)•  Mediansurvivalunavailable(72%aliveatoneyear)

ABSTRACT204:nab-PaclitaxelplusGemcitabine–PascalHammel,MD

CrossTrialComparisonsofInducAonChemotherapyinLAPCInduc9onRegimen

Completedinduc9on

DCRduringinduc9on

RRduringinduc9on

PFS(mo)

OS(mo)

12mosurvival

Resec9onRate

SCALOPN114

Gem/Cape13mo

64.9% ? ? ? 12.7 53% ?

LAP07N442

Gem+/-ErloAnib24mo

60.9%

? ? 7.5 12.8 54% 4%

YaleN31

ModifiedFOLFIRINOX34mo

65% 100%

17.2% 17.8 26.6 86% 42%

LAPACTN106

Gem/nab-paclitaxel46mo

57% 77.6%(at4mo)

32.7% 10.8 72% 15%

1Post-inducAon:randomizedtoRTwthCapeorGem(LancetOncol2013Apr;14(4):317-26)2Post-inducAon:randomizedtoRTorconAnuedchemo(JAMA2016May3;315(17):1844-53)3Post-inducAon:invesAgatorschoicechemo,RT,orsurgery(BrJCancer2016Mar29;114(7):737-43)4Post-inducAon:invesAgatorschoicechemo,RT,orsurgery(Abs204ASCOGISymposium2018)

LAPCManagement:

•  WhattodoamerinducAonchemotherapyinnon-progressors?– ConAnuechemotherapy– RadiaAonandifsowhattechnique

•  LAP07trialshowednosurvivalbenefitforRTamergemcitabine+/-eroloAnibinducAoninnon-progressor1

•  AdvancesinchemoandRTlimitapplicaAonofLAP07tocurrentpracAce

– Surgery(?precededbyRT)–  IrreversibleelectroporaAon(?)

1Hammeletal.JAMA2016;315(17):1844-53

LAPCManagement:

•  WhattodoamerinducAonchemotherapyinnon-progressors?– ConAnuechemotherapy– RadiaAonandifsowhattechnique

•  LAP07trialshowednobenefitforRTamerGemcitabine1

•  AdvancesinchemoandRTlimitapplicaAonofLAP07tocurrentpracAce

– Surgery(?precededbyRT)–  IrreversibleelectroporaAon(?)

1Hammeletal.JAMA2016;315(17):1844-53

LAPC:WhoshouldundergosurgicalexploraAon?LimitaAonsofCTImagingAmerInducAonTherapy

•  MayshowpersistentsignificantvascularinvolvementinptswhoachieveR0resecAon

•  OflimitedvalueindifferenAaAngresidualtumorfromfibroinflammatoryAssueamerpre-optreatment.

•  Usualsizecriteriaforresponse(RECIST)areinsufficienttoevaluate“biologic”responseofLAPC

CassinoTo.Radiology2014;273(1):108-16(Bordeaux,FR).DonahueArchSurg2011Jul;146(7):836-43(UCLA).Ferrone.AnnSurg.2015;261(1):12(MGH).Wagner.EurRadiol2017Jul;27(7):3104-3116(French).Michelakos.AnnSurg2017Dec7(MGH)

CTevaluaAonamerneoadjuvantFOLFIRINOXforborderlineandlocallyadvancedpancreaAcadenocarcinoma:FrenchExperience

•  36ptswithBR/LAPC(NCCN)resectedamerFFX(+RT,12):31R0,5R1•  CriteriaforexploraAon:improvingPS,decreasingCA19-9,noprogression•  SignificantresponsetoFFXbyRECISTonCT:PRin17/36(47%)•  StablediseasevsresponsebyRECISTunabletopredictR0resecAon•  Decreasedarterial/venousinvolvementunabletopredictR0resecAon•  NCCNclassificaAonpost-inducAonFFXunabletopredictR0resecAon:R0resecAonpossibleinptswithpost-treatmentLAPCbyNCCN

Wagneretal.EurRadiol2017Jul;27(7):3104-3116.

ResecAonStatusAccordingtoNCCNClassificaAon

Wagneretal.EurRadiol2017Jul;27(7):3104-3116.

MGHExperience

•  40ptswithBR/LAPC(AHPBAguidelines)whounderwentsurgeryreceivedpre-opFOLFIRINOX

•  19ptssAllclassifiedasLAand9asBRamerFOLFIRINOX•  92%hadR0resecAonsamerFOLFIRINOX•  FOLFIRINOXassocw/lowlymphnodeposiAvity(35%)•  Conclusions:

– Amerpre-opFOLFIRINOX,imagingnolongerpredictsunresectability– Amerpre-opFOLFIRINOX,pathologicpredictorsofsurvivalareimproved

Ferrone.AnnSurg.2015;261(1):12

MGHExperience

•  141pts(BR/LA)surgicallyexploredamerFFX(10%)orFFXf/bRT(90%)*•  110pts(78%)resected(R080.6%,R119.4%)•  Nopre-opfactorsaccuratelypredicAveofresectabilitywereidenAfied•  Predictorsofshortsurvivalinresectedpts

–  highpre-opCA19-9–  tumorsize>3cm

•  MedianOSofallFOLFIRINOX-treatedpts34.2andand37.7moforresectedpts(vs25.1moforupfrontresectedpts)

*ExcludedptswhoprogressedordiedonFOLFIRINOX Michelakos.AnnSurg2017Dec7.[Epubaheadofprint]

SelecAonofPtsforSurgery:Authors’RecommendaAons

Ø  “SurgeryshouldbeconsideredamerneoadjuvantCRTinptswhohaveshownaparAalregressionoftumor-tovesselcontact,irrespecAveofthedegreeofdecreaseintumorsizeorthedegreeofresidualvascularinvolvement”1

Ø  “PaAentsshouldbechosenforsurgeryonthebasisoflackofdiseaseprogression,goodfuncAonalstatus,anddecreaseincanceranAgen19-9”2

Ø  “InabilityofimagingtopredictresectabilityamerneoadjuvanttherapymayleadtooperaAngsystemaAcallyonallptswithoutobviousprogressionamerneoadjtherapy”4

Ø  “Onthebasisoftheabsenceofreliableimagingand/orclinicalmarkersofresectability,weadvocateforsurgeryofallborderlineresectableandLAPCpaAentsamerneoadjuvantFOLFIRINOXinabsenceofmetastaAcdisease”3,5

1.CassinoTo.Radiology2014;273(1):108-16(Bordeaux,FR).2.DonahueArchSurg2011Jul;146(7):836-43(UCLA).3.Ferrone.AnnSurg.2015;261(1):12(MGH).4.Wagner.EurRadiol2017Jul;27(7):3104-3116(French).5.Michelakos.AnnSurg2017Dec7(MGH)

LimitaAons•  RetrospecAvestudiesofonlythoseFFX-treatedptswhowentontosurgicalexploraAon

•  StrongselecAonbias•  MixofLAPCandBRandlackofuniformdefiniAons•  RoleofRTimpossibletoteaseout•  Long-termdisease-freesurvivalrateunknown•  Studiesneededto

–  beTerdefinecriteriathatpredictR0vR1resecAonvunresectabledisease–  toidenAfypredictorsoflong-termdisease-freesurvivalamersurgery

StandardofCareforLocallyAdvancedandBorderlinePancreaAcCancer:Convergence

FOLFIRINOX4-12cyclesorto

maximumresponse*

ConAnueFOLFIRINOX+

RadiaAon+ SurgicalExploraAon

*Gemcitabineandnab-paclitaxelespinolder,lessfitpts;CTscanevery6-8weeks+FollowedbysurgicalexploraAoninappropriatecandidates

Distantmets:alternatechemotherapy,trialLocalprogression:RTvsalternatechemotherapy

StandardofCareforLocallyAdvancedandBorderlinePancreaAcCancer:Convergence

FOLFIRINOX4-12cyclesorto

maximumresponse*

ConAnueFOLFIRINOX+

RadiaAon+ SurgicalExploraAon

*Gemcitabineandnab-Paclitaxelespinolder,lessfitpts;CTscanevery6-8weeks+FollowedbysurgicalexploraAoninappropriatecandidates

Distantmets:alternatechemotherapy,trialLocalprogression:RTvsalternatechemotherapy

StandardofCareforBRandLAPC:UnansweredquesAons

•  Whichchemo?FOLFIRINOXvGemplusnab-paclitaxel•  RoleofRT(orotherlocalablaAvetherapies)?•  OpAmumRTmodality?•  ResponseassessmentamerchemotherapyandchemoRT?•  SelecAonofpaAentsforresecAon?

– PredictorsofR0resecAonANDlong-termdisease-survival??

LAPC:Challenges

– Needforreliablebiomarkerstosortlocal-onlybiologyfrommetastaAcbiology(?SMAD4)

– NeedforwelldesignedRCTstoopAmizecurrentstandardofcare– StrongbeliefsonvalueofcomponentsoftreatmenthashamperedtrialdesigntoanswerkeyquesAons

– NeedforclinicaltrialswithnovelagentsfocusedonLAPC

ClinicalTrialsinLAPCPhaseIIIRCTs

Ø  FOLFIRINOXvsFOLFIRINOXfollowedbySBRT(US)Ø  Chemotherapy(FOLFIRINOXorGemmonotherapy)vsChemotherapyfollowedby

chemoradiaAon(GermanCONKO-007)Ø  IrreversibleElectroporaAonvsSBRTamerFOLFIRINOX(CROSSFIRETrial)(Netherlands)Ø  FOLFIRINOXvsGemcitabine(NEOPAN)Ø  Gem/CapvsGem/Cap+GV1001vaccine(LAPCandmetastaAc)Ø  GemcitabinevsGemcitabine+micellarcisplaAnNC-6004(LAPCandmetastaAc)

ClinicalTrialsinLAPCPhaseIandII

Ø SBRT:12studies•  DoseescalaAon•  Withimmunecheckpointinhibitors•  Withvaccine•  Withconcurrentchemotherapy

Ø IrreversibleelectroporaAon:4studiesØ StandardradiaAonwithalternaAveconcurrentchemotherapy(Abraxane,nelfinivir,S-1)

Ø Approvedchemotherapydrugs(withorwithoutRT)

ClinicalTrialsinLAPCPhaseIandII

Ø NovelagentswithorwithoutRTorchemotherapy•  Theragene(ReplicaAon-competentAdenovirus-mediatedDoubleSuicideGeneTherapy)•  Oregovomab(anA-CA125)•  Intra-tumoralgenedeliveryofCYL-02(plasmidDNAencodingmousesomatostaAnreceptorand

fusionproteinofhumandeoxycyAdinekinaseanduridinemonophosphatekinase)•  CG200745PPA(hypomethylaAngagent)•  ATRA(stromalablaAonstrategy)•  Intra-tumoralNanoPac(NanoparAculatePaclitaxel)•  CeriAnib•  Tocilizumab(targetsIL6receptor)•  Nelfinavir(radiosensiAzer)

LAPC:Summary

•  DisAncAons/definiAonsofborderlineresectableandLAPCaresomewhatarbitraryanddifficulttoimplementaccuratelyandconsistently

•  TherapeuAcapproachforptswithvascularinvolvementhasconverged->upfrontcombinaAonchemotherapyfollowedbyphysician’sdiscreAon

•  Responseassessment/paAentselecAonforsurgeryamerchemotherapy+/-RTremainsachallenge

•  SurvivalandresecAonratesareincreasingwith“modern”chemotherapy•  Arewecuringmoreptswith”modern”neoadjuvantapproaches??•  Needforbiologicalpredictorsofdisseminateddisease•  NeedforhighqualityRCTsandevaluaAonofnovelagents

ThankYou