Laterapianel«setting»adiuvanteeneoadiuvante

CarloBaroneDirettoreUOCOncologiaMedicaUniversitàCattolicadelS.Cuore

Summary

• Introduction• Adjuvant therapy

– Trialsonchemoradiation– Trialsonchemotherapywithout chemoradiation

• Meta-analyses ofadjuvant therapy• Neoadjuvant therapy• Recommendations• Futuredirections

PancreaticCancerStageDistributionandSurvivalintheUnitedStates

• Relapseoccursinapproximately80%- 85%ofpatientsafterresection,underscoringtheimportanceofadjuvanttherapy4-7

– Amargin-freeresection(R0)isassociatedwithbettersurvivaloutcomescomparedwithinvolvedmargins8,9

– Marginstatushasalsobeenshowntobeassociatedwiththeincidenceoflocalrecurrence,butnotrecurrencetolymphnodes ordistantorgans10

1. SEER Stat Fact Sheets: Pancreas. http://seer.cancer.gov /statfac ts/html/pancreas .html. Accessed September 24, 2015. 2. NCCN Clinical Practice Guidelines in Oncology, V2.2015. 3. Vincent A, et al. Lancet 2011; 4. Liao WC, et al. Lancet Oncol 2013; 5. Siegel R, et al. CA Cancer J Clin 2013; 6. Oettle H, et al. JAMA 2007; 7. Sener SF, et al. J Am Coll Surg 1999; 8. Bilimoria KY, et al. J Am Coll Surg 2008; 9. Winter JM, et al. J Gastrointest Surg 2006; 10. Sugiura T, et al. Surgery 2013.

27,1

10,7

2,44,4

051015202530

Localized Regional Distant Unstaged

Prop

ortio

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Su

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al, %

5-YearRelativeSurvival1 • Surgery is the only potentially curative treatment option for pancreatic cancer2

• At the time of diagnosis ≈ 10% of patients have resectable(Stages 0-IIB) and ≈ 10% have borderline resectable (Stage III) disease3

ClinicalClassificationofPancreaticCancer

1. NCCN Clinical Practice Guidelines in Oncology, V2.2015. 2. Vincent A, et al. Lancet 2011.

Classification1,2 Stage Features Resectable(≈ 10%)

0, IA, IB, IIA, IIB

• No distant metastases• No evidence of SMV or portal vein abutment, distortion, tumor

thrombus, or venous encasement• Clear fat planes around the celiac axis, hepatic artery, and SMA

Borderline resectable(≈ 10%)

III • No distant metastases• SMA encasement < 180°; SMV/portal impingement• Short-segment SMV occlusion • Celiac encasement < 180° (tail)• Abutment/encasement of hepatic artery

LAPC(≈ 30%)

III • No distant metastases• SMA encasement > 180°• SMV/portal vein occlusion• Any celiac abutment (head) or celiac encasement > 180°

(body/tail)• Aortic invasion or encasement; lfn mts beyond field of resection

MPC (≈ 60%) IV • Presence of metastatic disease in distant organs

Chemoradiation vsObservation:GITSG

• Ofthe21treatedpatients,3(14%)hadsevereleukopenia• Nocasesoftreatment-relateddeathsorlife-threateningadverseevents

Kalser MH, et al. Arch Surg 1985.

Efficacy Observation 5-FU + Radiation P ValueMedian DFS, months 9 11 0.01Median OS, months 11 20 0.03

Chemoradiation vsObservation:EORTC40891

• Thirty-fivepatients(44%)received3daysof5-FUinthesecondcourseduetograde1or2acutetoxicity• Nograde≥3leukopenia orthrombocytopeniawasobserved• Theonlymajortoxicitywas1caseofduodenal ulcer2

a Periampullary = tumor in the distal common bile duct, papilla of Vater, or duodenum.b The course of therapy weeks 5 - 6 consisted of 0 (if grade ≥ 3 toxicity), 3 (if grade 1/2 toxicity), or 5 (if no toxicity) days of 5-FU

Efficacy2 Observation 5-FU + Radiation HR P ValueMedian PFS, years 1.2 1.5 0.94 0.663

Median OS, years (primary endpoint) 1.6 1.8 0.91 0.540

1. Klinkenbijl JH, et al. Ann Surg 1999; 2. Smeenk HG, et al. Ann Surg 2007.

**mg/kg

CRTvsCTvsCRT→CTvsObservation:ESPAC-1(2×2FactorialDesign)

Grade≥3AEs:hematologic(2patientsintheCT-alonegroupand5intheCRT→CTgroup),stomatitis(4intheCT-alonegroupand5intheCRT→CTgroup),diarrhea(2intheCT-alonegroupand4intheCRT→CTgroup)

1. Neoptolemos JP, et al. Lancet 2001; 2. Neoptolemos JP, et al. N Engl J Med 2004.

EfficacyRandom Assignment to CRT Random Assignment to CT

CRT (n = 145) No CRT (n = 144) CT (n = 147) No CT (n = 142)Median OS, months(primary endpoint) 15.9 17.9 20.1 15.5

HR (95% CI) 1.28 (0.99 - 1.66) 0.71 (0.55 - 0.92)P value 0.05 0.009

TheESPACstudy withafactorial design

CRT<noCRT CT>noCT

Gemcitabinevs5-FUBeforeandAfterCRT:RTOG97041,2

• Grade4hematologictoxicitywasmorecommoninthegemcitabinearm(14%vs1%;P<0.001);ratesofnonhematologic toxicityweresimilar betweenthe2arms;1patientinthegemcitabinearmdiedofnonneutropenic infection1

a The co-primary endpoints were OS for all patients and OS for patients with tumors of the pancreatic head

Efficacy2,a 5-FU Gemcitabine HR P ValueMedian OS, months NR NR 0.933 0.51

Patients with tumors of the pancreatic head

n = 20117.1

n = 18720.5 0.838 0.12

1. Regine WF, et al. JAMA. 2008;299:1019-1026. 2. Regine WF, et al. Ann Surg Oncol. 2011;18:1319-1326.

TheRTOGtrial:CRTwithFUorGEM?

Surgery

FU ci x 3 w

RT 50.4 Gy + FU ci

FU ci x 3 m(4 + 4 w)

GMC 1000/w x 3

RT 50.4 Gy + FU ci

GMC 1000/w x 3 m

270 pts 268 pts

SM 20.5 vs 17 mSM 18.8 vs 17 m

Nosignificant improvementwithGEMinpancreatic headcancer

Chemoradiation +IFN-2bvs5-FU/Leucovorin

• Theratesofgrade≥3AEswere85%intheCRT+IFN-2barm(primarilyneutropeniaanddehydration)and16%inthe5-FU+leucovorin arm(primarilydiarrhea)

a Patients were challenged with a single dose of IFN-2b 4 - 6 days before therapy

Efficacy CRT + IFN-2b 5-FU/Leucovorin HR P ValueMedian DFS, months 15.2 11.5 NR 0.61Median OS, months(primary endpoint) 26.5 28.5 1.04 0.99

Schmidt J, et al. J Clin Oncol. 2012;30:4077-4083.

GemcitabinevsObservation:CONKO-0011,2

• Twenty-sixpatients(14%)inthegemcitabinearmand15(8%)observationarmexperiencedaseriousadverseevent;5ofthesepatients(19%)hadeventsconsideredtobegemcitabine-related1

Efficacy Observation Gemcitabine HR P ValueMedian DFS, months(primary endpoint) 6.7 13.4 0.55 < 0.001

Median OS, months 20.2 22.8 0.76 0.01

1. Oettle H, et al. JAMA. 2007;297:267-277. 2. Oettle H, et al. JAMA. 2013;310(14):1473-1481.

qw 3/4 = the first 3 of 4 weeks

CONKO– 001trial

13.4mvs6.7mHR0.55(0.44-0.69)

22.8mvs20.2mHR0.76(0.61-0.95)

GemcitabinevsObservation:JSAP-2

• Inthegemcitabinearm,grade≥3leukopeniaandneutropeniaoccurredin25%and70%ofpatient,respectively; nograde≥3AEswerereportedintheobservationgroup

• 2patientsinthegemcitabinearmand1patientintheobservationarmdiedduringtreatment

a Except intraoperative radiotherapy

Efficacy Observation Gemcitabine HR P ValueMedian DFS, months 5.0 11.4 0.60 0.01Median OS, months(primary endpoint) 18.4 22.3 0.77 0.19

Ueno H, et al. Br J Cancer. 2009;101:908-915.

TheJASP-2trial

GemcitabinePlusErlotinib vsGemcitabine:CONKO-005

• Moregrade3/4rashwithgemcitabine+erlotinib vsgemcitabine(7%vs<1%;P <0.001)

a Adjuvant therapy started within 8 weeks after surgical resection

Efficacy Gemcitabine + Erlotinib Gemcitabine HR P Value

Median DFS, months 11.6 11.6 0.89 0.291Median OS, months (primary endpoint) 24.6 26.5 0.90 0.406

Sinn M, et al, ASCO 2015 [Abstract 4007]

5-FUPlusLeucovorin vsGemcitabine:ESPAC-3v2a,1,2

• Differencesingrade≥3toxicityforthe5-FUandgemcitabinearmsincluded,respectively,leukopenia(6%vs10%;P =0.01),thrombocytopenia (0%vs1.5%;P =0.003),stomatitis(10%vs0%;P <0.001),anddiarrhea(13%vs2%;P <0.001)

a Originally a 3-arm trial, but the observation arm was stopped after the results of ESPAC-1 supported CT over observation.

Efficacy 5-FU/leucovorin Gemcitabine HR P ValueMedian PFS, months 14.1 14.3 0.96 0.53Median OS, months(primary endpoint) 23.0 23.6 0.94 0.39

1. Neoptolemos JP, et al. JAMA. 2010;304:1073-1081. 2. Neoptolemos JP, et al. Lancet. 2001;358:1576-1585.

Gemcitabine vsS1:JASPAC-01trial

Resectedhistologically

confirmed PDAC;noneoadjuvantchemotherapy orradiotherapy;PS0-2;adequate bonemarrow function

S180mg/m2/day,d1-28 q6wx4cycles

Gemcitabine 1000mg/m2 d1,8,15every 29days x6cycles

Primary Endpoint:non-inferiority inOS

Treatment Pts 2yrs Survival HR p

Gemcitabine 193 53% 0.56(95%CI.42-.74) <0.0001non-inferiority

S1 192 70% <0.001 superiority

• QoL better withS1;G3/4toxicity similar,except forleukopenia lower inS1Fukutomi A,ASCO2013

5-FUPlusLeucovorin vsObservation:Meta-AnalysisofESPAC-1,ESPAC-1+,andESPAC-31,2

q Theresultsof3ESPACtrialswerepooledtocompareobservationvs5FU/leucovorina

q Allpatientshadresected,histologicallyconfirmedPDAC;noevidenceoflocalspreadordistantmetastasis;lifeexpectancy>3months

q Safetydatawerenotreported

1. Neoptolemos JP, et al. Br J Cancer. 2009;100:246-250. 2. Neoptolemos JP, et al. Lancet. 2001;358:1576-1585.

Trial Observation 5-FU/LeucovorinESPAC-1, n 69 75ESPAC-1+, n 95 97ESPAC-3, n 61 61Total, n 225 233Efficacy Observation 5-FU/Leucovorin HR P Value

Median OS, months 16.8 23.2 0.70 0.003

1 year OS rate, %2 year OS rate, %5 year OS rate, %

633714

774924

— —

SummaryofPhaseIIIAdjuvantStudiesinPCMedian OS, months

Trial CRT Obs 5-FU Gem Gem + Erl S1 P

Value

GITSG 20 11 — — — — 0.03EORTC 40891 21.6 19.2 — — — — 0.540ESPAC-1 15.9 — 20.1 — — — NRa

RTOG 9704 — — 17.1a 20.5a — — 0.12CRT + IFN alfa-2b vs CT 26.5 — 28.5 — — — 0.99CONKO-001 — 20.2 — 22.8 — — 0.01JSAP-02 — 18.4 — 22.3 — — 0.19CONKO-005 — — — 26.5 24.6 — 0.406ESPAC-3 (v2) — — 23.0 23.6 — — 0.39

— — — 53%b — 70%b <.001

a Values reported here are for the set of patients with tumors of pancreatic headb Non-inferiority/superiority trial; reported values refer to 2 year survival

CRTvsCT:Meta-Analysis

Ø Ameta-analysisof10articles(including9trials)examinedtheinfluenceof5adjuvantPCtreatmentsonsurvivalandtoxicityØ Observation(n=670)Ø 5-FU(n=876)Ø Gemcitabine(n=774)Ø Chemoradiation (n=169)Ø CRT+5-FU(n=323)Ø CRT+gemcitabine(n=221)

Ø Authors’interpretationofresultsØ CTwith5-FUorgemcitabineistheoptimumadjuvanttreatmentforPCandreduces

mortalityaftersurgerybyaboutathirdØ CRT+CTislesseffectiveinprolongingsurvivalandismoretoxicthanCT

Liao W-C, et al. Lancet Oncol. 2013;14:1095-1103.

Comparison fortheBayesan networkmeta-analysis

Liao WC,LancetOncol 2013

Width of linesproportional toNumber of trials

Size of nodesproportional toNumber of pts

Pooled hazard ratios fordeath

ØFirst line: crude HRØ2° line (red): HR adjusted for percentage

of LN positivityØBayesan p-values <.05 in blue if crudeØBayesan p-values <.05 in green if adjusted

Liao WC,LancetOncol 2013

Rankingoftreatments interms ofOSbenefitandoverall G3-4toxic effects

ØCT with 5FU or GMC is the optimum adjuvant treatmentØIt reduces mortality by about a thirdØAdding CRT to CT provides little further survival benefit, but increases toxicity

Raigani S,JGastroint Surg 2014

Community Hospitals, 2003-2010 Teaching Hospitals, 2003-2010

SO = Surgery onlySC = Surgery + CTSRC = Surgery + RT + CT

Trendsintreatmentofpancreatic cancerNationalCancer Database– StageI

Trendsintreatmentofpancreatic cancerNationalCancer Database– StageII

Community Hospitals, 2003-2010 Teaching Hospitals, 2003-2010

SO = Surgery onlySC = Surgery + CTSRC = Surgery + RT + CT

Raigani S,JGastroint Surg 2014

• Neoadjuvant therapy– Resectable tumors (RPC)

• Endpoint– Toincrease survival incomparison toadjuvant therapy

– Borderlineresectable tumors (BRPC)• Endpoints

– Toincrease R0resectability andsurvival

• Induction therapy– Locally advanced unresectable tumors (LAPC)

• Endpoints– Toconvert somepatient toresectability– Toincrease local andsystemic disease

Neoadjuvant therapy:aconfounding term

Rationale insupport ofneoadjuvant therapy

• Increasing thelikelihood ofmargin-negativeresection• Increasing thelikelihood ofcompletion ofmultimodality

therapy• Increasing theefficacy ofradiotherapy• Minimizing pancreatic leak (without increasingcomplications)• Determination ofindeterminant lesions• Declaration ofdistantmetastases• Decreasing«open-and-close»rates• Allowing apatient’s functional statustodeclare itself• Improved cost-effectiveness (?)

Concerns inneoadjuvant therapy

• Inaccuracyofstaging• Imprecisecontinuumbetween radiologically andtechnically

resectable andunresectabledisease• Erroneous histology• Difficulty indistinguishingPCfromintrapancreaticbileduct

ADC• Potential increase inoperativemorbidity andmortality• Possibility ofmetastases orunresectability during therapy• Difficult assessmentofresponse

– Clinical criteria:clinical benefit(pain),noCTprogression,Ca19-9• Uncommon radiographicdown-staging inBRPC

Resectable PC:selected prospective studies - CT

Author Pts Treatment Resectionrate

R0 Survival

Palmer‘07 50 GEM 38% - mOS 9.9m

GEM+CDDP 70% - mOS 15.6m

Heinrich‘08 28 GEM+CDDP 93% 71% mOS 19.1 m(res)

Tajima ‘12 34 S1(13pts)vsUpfront surgery (21pts)

100%100%

84.6%85.7%

2yrs 55.6%2yrs 29.6%

Mizuma ‘14 36 GEM+S1 - 87% 2yrs 45.7%

O’Reilly ‘14 38 GEMOX→Surg →GEM 71% - mOS 27.2

Resectable PC:perioperative therapy

O’Reilly EMetal,AnnSurg 2014

Resectable PC:selected prospective studies - CRT

Author Pts Treatment Resectionrate

R0 Survival

Evans‘08 86 GEM+RT 75% 66% mOS 22.7m(res)

Varadhachary ’08 90 GEM+CDDP→GEM/RT 66% 62% mOS 17.4m(res)

LeScodan ‘’08 41 FU+CDDP+RT 67% - mOS 9.4m(res)

Turrini’10 34 TXT+RT 50% 10% mOS 32m(res)

Shimoto ’13 26 CarboionRT 81% - 5yrs 42%

Resectable andBRPC:selected studies

Author Pts Treatment Resectionrate

R0 Survival

Sho ’13* 22res+39BR GEM+CRT 97% 92% NR

VanBuren ‘13 30 res+29BR GEM+Bev +CRT 72.8% 64% mOS 19.7m(res)

*Retrospective study;important biases fromthelack ofpre-neoadjuvanthistological confirmation forsomepatient andtheadministraton ofadjuvant CTtosomeothers

BRPC:selected prospective studies

Author Pts Treatment Resectionrate

R0 Survival

Patel ‘11 17 GTX→FU/RT 64.7% 47% mOS 15.6m

Stokes ‘11 40 Cap/RT 46% 40% mOS 23m

Landry ‘10 10 GEM/RT 30% 19.4% -

11 GEM+CDDP/RT 22% 13% -

Leone‘13 39 GEMOX→GEM/RT 28% 28% mOS 16.7m

Christians ‘14 18 FOLFIRINOX→CRT 67% 67% 2yr S:39%

BRPC:selected retrospective studies

Author Pts Treatment Resectionrate

R0 Survival

Faris ‘13 25 FOLFIRINOX 33% 10% -

Boone ‘13 22 FOLFIRINOX 26% - -

Christians ‘14 18 FOLFIRINOX 67% - -

Hattori ‘14 28 S1 76% - -

Rose‘14 64 GEM+TXN orFU+OXA 48% - mOS 23.6m(res)

Katz‘08 160 CT→CRT 63% --

mOS 18mmOS 40m*

*66out160patients who completed theprogram

LAPC:selected prospective studies

Author Pts Treatment Resectionrate

R0 Survival

Kunzmann ‘13 8 NabT →FOLFIRINOX 37% - -

Huguet ‘07 167 PCTseq vsGEMOX→RT - - mOS 13.1m

Reni’09 91 PEFG/PEXGorPDXG→RCT

14%ORR47%

- mOS 16.2m

Polistina ‘10 23 GEM→GEM+RT 8% 0.9% mOS 10.6m

Mukerjee ‘13 3836

GEM→CRTCap→CRT

--

--

mOS 15.2mmOS 13.4m

Sherman ‘15 34(art)11(ven)

GTX→CRT→SurgGTX→Surg (R1→CRT)

85.3%100%

69%7.5%

mOS 29mmOS n.r.*

*n.r.=not reached

LAPC:selected retrospective studies

Author Pts Treatment Resectionrate

R0 Survival

Gunturu ‘13 16 FOLFIRINOX ORR50% - -

Nitsche ‘15 14 FOLFIRINOX 29% - -

Greer ‘08 102 FU+CDDP→GEM+RT 41% - -

Khushman‘15

51 FOLFIRINOX→CRT(not res)FOLFIRINOX→CH(res) 53% 40% mOS 35.4m*

*All patients

MixedPC:selected prospective studies

Author Patients Treatment Resectionrate

R0 Survival

Sahora ‘11 BR12+LA13 GEM+TXT 32% 28 mOS 16m(res)

Sahora ‘11 BR15+LA18 GEMOX 39% 25% mOS 22m(res)

Lee‘12 BR18+25LA GEM+Cap 39.5% 36% mOS 23.1m(res)

Vasile‘13 32 mFOLFOXIRI 41% - mOS 24.2m

Massucco ‘06 BR18+LA10 GEM+RT 39% - mOS 15m

Pipas ‘12 R4+BR23+LA6 Cet+GEM+RT 76% - mOS 24.3m(res)

Kim ‘13 R23+BR39+LA6 GEMOX+RT 63% - mOS 18.2m

MixedPC:selected retrospective studies

Author Patients Treatment Resectionrate

R0 Survival

Hosein ‘12 18(BR+LA) FOLFIRINOX 39% 20% 1yr PFS83%

Lee‘12 BR18+25LA GEM+Cap 39.5% 36% mOS 23.1m(res)

Peddi ‘12 23(BR+LA) mFOLFIRINOX ORR34% - 1yr PFS75%

Blazer‘14 43(BR+LA) mFOLFIRINOX 53.8% 42% mPFS 18.4 m(res)

Nanda‘15 BR14+15LA FOLFIRINOX→CRT 41.3% 31% 1yr S65.5%Kharofa ‘14 R 30

BR39CRT→Surg →RTCT→CRT→Surg →RT

70% 65% mOS 20m

Mellon‘15 BR110+49LA CT(FOLFIRINOXin21LA) 51% 48% mOS 34.2(res)

Blazer‘15 BR18+25LA FOLFIRINOX→CRT 51% 45% -

Retrospective analysis ofsurvival inneoadj therapy vssurgery-firstapproach – MDAnderson2002-07

Tzeng CWetal,JGastroint Surg 2014

Summary ofmeta-analyses:localized,BRandLAPC

Author Studies Treatment Patients Resection rate Survival

Petrelli’14 2phase II11retrosp

FOLFIRINOX+CRT

BR+LA 43% -

Xu ’14 1prosp2retrosp

Adj CRTvsNeoadj CRT

LPC - P =0.62

Festa’13 5phase II5prosp

CT± RT BR 80%(of69%*)

1yr S61%2yr S44%

Andriulli ’13 7phase I/II10phase II3prosp

GEM± RTGEM± RT

LPCBR+LA

82%(of91%*)68%(of39%*)

2 yr S67.2%2yr S54.2%

Assifi ‘11 14phase II CT± RTCT± RT

LPCBR+LA

65%31%

mOS 23mmOS 22.3m

*Percentage ofexplored patients

Limitsofmeta-analyses forneoadjuvant therapy• Different types ofstudies

– Phase IIorI– Retrospective– Cohort– Casereports

• Different settings– Resectable tumors– Borderlineresectable tumors– Locally advanced uresectable tumors

• Low size samples– Less than 50patients inprospective studies

• Different schedules– Monotherapy (FluoropyrimidineorGemcitabine orTaxanes)– Combinationtherapy (GEMOX,GEM+CDDP, FOLFIRINOX,GTX,S1+GEM,others)

• Different measures ofoutcome• Mixedtreatmentstrategies

– CTalonefollowed bysurgery followed ornot byRTorCT– CTfollowed byRTorRCTfollowed bysurgery– CRTfollowed bysurgery followed ornot byCT

RecommendationsforAdjuvantPCTreatment

• Forsurveillance, theNCCNrecommendshistoryandphysicalexam(cat2A),CA19-9(cat2B),orCTscan(cat2B)every3- 6months for2years,andthenannually

a For NCCN guidelines, chemotherapy before or after chemoradiation. Chemoradiation can be fluoropyrimidine- or gemcitabine-based.b The ESMO guidelines state that chemoradiation in the adjuvant or additive setting should only be performed within randomized controlled trials (cat IB).c Not specified in guidelines whether leucovorin should be included or whether the recommendation differs by bolus vs continuous infusion.1. NCCN Clinical Practice Guidelines in Oncology, V2.2015; 2. Ducreux M, et al. Ann Oncol 2015; 3. Yamaguchi K, et al. Jpn J Clin Oncol 2011.

NCCN 20151 ESMO 20152,b JPS 20113

Chemotherapy alone

Gemcitabine 1 I A B5-FU/leucovorin 1 I Ac —Continuous infusion 5-FU 2A I Ac —Capecitabine 2B — —

Chemotherapy plus chemoradiationa

Gemcitabine 2A — —5-FU/leucovorin 2A — —Continuous infusion 5-FU 2A — —

Chemoradiation alone Gemcitabine — — C1

Linee-GuidaAIOM- 1Qualità

dell’evidenzaSIGN

Raccomandazioneclinica Forzadellaraccomandazione

clinica

C NeitumoriBLèraccomandabileunastrategiaterapeuticacontrattamentoneoadiuvante seguitodaristadiazione edeventualeresezionechirurgica

Positivadebole

D Inmancanzadistudiprospetticineitumoriresecabiliconfattoriprognosticiassociatialimitatasopravvivenzapost-operatoriapuòessereconsiderato untrattamentoneoadiuvante

Positivadebole

A IpzaffettiaADCduttaledelpancreasstadioIa-IIIresecatoR0-R1 conKarnofsky ≥50devono rievere unaCTadiuvanteconFPoGEM

Positivaforte

D* LaRCTpuòessereconsideratadopochirurgiaR0oR1conunadosedialmeno50Gy

Positivadebole

*Opinionediespertiinassenzadistudiconunadeguatolivellodiqualità

Linee-GuidaAIOM– 2MalattialocalmenteavanzataQualità

dell’evidenzaSIGN

Raccomandazioneclinica Forzadellaraccomandazione

clinica

D* IpzconmalattialocalmenteavanzatanonresecabilepotrebberoesseretrattaticonCTsistemica,conglischemidellamalattiaavanzata,seguitadaRCT

Positivadebole

*Opinionediespertiinassenzadistudiconunadeguatolivellodiqualità

Qualitàglobaledelleevidenze

GRADE

Raccomandazioneclinica Forzadellaraccomandazione

clinica

Molto bassa NeipzaffettidaADCnonresecabiledelpancreasinstadioIIIpotrebbeessereeffettuataunaCTcometerapiainiziale

Positivadebole

Bassa Neipz affettidaADCnonresecabiledelpancreasinstadioIIIlacapecitabina puòesseresomministratainconcomitanzaallaRT

Positivadebole

CRTforAdjuvantTreatmentisControversial1

1. Twombly R. J Natl Cancer Inst 2008; 2. NCCN Clinical Practice Guidelines in Oncology. V2.2105. 3. Kalser MH, et al. Arch Surg 1985; 4. Ducreux M, et al. Ann Oncol 2015; 5. Klinkenbijl JH, et al. Ann Surg 1999; 6. Neoptolemos JP, et al. Lancet 2001.

AdjuvantAfterNeoadj TherapyandResection

• AccordingtotheNCCN,datasupportingtheuseofadjuvanttherapyforpatientswhoreceivedneoadjuvanttherapyarelacking1

• Patientswhoreceivedneoadjuvantchemotherapyorchemoradiationmayconsideradjuvanttreatmentanoption pendingmultidisciplinaryreview(responsetoneoadjuvanttherapymayguidetreatmentchoice)

• Apatientwhoundergoesresectionforinitiallyborderlineresectablediseasemayconsideradjuvanttherapy(sametherapyoptionsasforinitiallyborderlineresectable disease)2

1. NCCN Clinical Practice Guidelines in Oncology, V2.2015: 2. Vincent A, et al. Lancet2011.

KeyOngoingPhaseIIIAdjuvantPCTrials- 1

Trial Pts Experimentalarm

Comparator arm PrimaryEndpoint

CONKO-006 NR GEM+SOR GEM DFS

PACT-15(NCT01150630)

370* Adj PEXG±Neoadj PEXG

GEM(adj) OS

NCT01072981 722 GEM± CRT+algenpantucel

GEM± CRT OS

PRODIGE/ACCORD24(NCT01526135)

490 FOLFIRINOX GEM DFS

RTOG08481° randomRTOG08482° random(NCT01013649)

950 GEM+ERLGEM± ERL

GEMGEM± ERL +CRT

OSOS

*This is aphaseII/III trial.N refers tothephase II,which compares adj PEXGwithadj+neoadj PEXC

KeyOngoingPhaseIIIAdjuvantPCTrials- 2

Trial Pts Experimentalarm

Comparator arm PrimaryEndpoint

GIP-2(NCT02355119) 310 FOLFOXIRI GEM DFS

NEPAFOX*(NCT02172976)

126 FOLFIRINOXneoadj andadj

GEM OS

NCT00994721 265 GEM+CRT GEM DFS

ESPAC-4 732 GEM+CAP GEM DFS

APACT(NCT01964430) 800 GEM+NabTXL GEM DFS

*This is aphaseII/III trial.N refers tothephase II

ABI-007-PANC-003(APACT)

nab-P 125 mg/m2 qw 3/4 + Gem 1000 mg/m2 qw 3/4

× 6 cycles

Gem 1000 mg/m2 qw 3/4× 6 cycles

Confirmed resected PC with macroscopic complete

resection (R0 and R1) and no evidence of metastases

Planned N ≈ 800

Treatment should begin within 12 weeks of surgery

Randomized 1:1

Schema

• Stratification factors:resection (R0vsR1);nodal status(LN+vsLN-);geographicregion (NorthAmerica,Europe,andAustraliavsAsiaPacific)

• Primary endpoint: independently assessed DFS• Secondary endpoints: OS,safety• Exploratory analysis

– Molecular profiling oftumor tissue tocorrelatetumor heterogeneity withclinicaloutcome

– Quality oflifeasmeasured EORTC-QLQ30anEORTCQLQ-PAN26

• Tocomparedisease-freesurvivalbetweenpatientsrandomizedtonab-P+GemvsGemalone

ClinicalTrials.gov:NCT01964430

PrimaryObjective

Rationale• NoadjuvantPCregimenshavereceivedregulatoryapprovalintheUS1

• TheNCCNandESMOrecommend5-FU(NCCN:+leucovorin) orGemasadjuvantchemotherapyoptions2,3

• RecurrencerateswithadjuvantGemwere77%and81%inphaseIIItrials,suggesting aneedforimproved therapies4,5

• nab-P+GemdemonstratedsuperiorefficacyvsGemalonefortreatmentofmetastaticPCinthephaseIIIMPACTtrial6

1.LiaoW-Cetal.LancetOncol 2013; 2.TheNationalComprehensiveCancerNetwork.NCCNGuidelinesinOncology,v1.2013.3.Seufferlein Tetal.AnnOncol 2012; 4.Oettle Hetal.JAMA 2013;5.UenoH,etal.BrJCancer 2009; 6.VonHoffDD,etal.NEngl JMed 2013.

APACT:AdjuvantPancreaticAdenocarcinomaClinicalTrial(ABI-007-PANC-003)

ABI-007-PANC-003(APACT)

• HistologicallyconfirmedresectedPCwithmacroscopiccompleteresection(R0andR1)

– Noneuroendocrinetumors• StageT1-3,N0-1,M0• Abletobegintreatment≤12weeksafterresection• Age≥18years• ECOGPS0or1• Adequatehematologicandbloodchemistryparameters,including

– Absoluteneutrophil count≥1500cells/mm3

– Totalbilirubin ≤ULN(patientswithGilbertsyndrome, ≤1.5×ULN)• CA19-9<100U/mLassessedwithin14daysofrandomization

1.CelgeneDataonFile.ProtocolABI-007-PANC-003.2.ClinicalTrials.gov:NCT01964430.

SelectedInclusion Criteria

ABI-007-PANC-003(APACT)

• Assumptionbasedon2previousphaseIIItrials:GemwillresultinamedianDFSof14months1,3,4

• Theestimatedenrollmentofthistrialis800patients1,2– Ifnab-P+GemresultsinamedianDFSof19months,this

wouldrepresentanHRof0.74– Atleast489DFSeventsfrom800patientswouldallow90%

powertodetecttheHRof0.74ata2-sidedsignificancelevelof0.05

1.CelgeneDataonFile.ProtocolABI-007-PANC-003. 2.ClinicalTrials.gov:NCT01964430.3.Oettle H,etal.JAMA 2007;4.Neoptolemos JP, etal.JAMA 2010.

StatisticalDesign

KeyOngoingNeoadjuvantPCTrials- 1

Trial Pts Treatmentgroups PrimaryEndpoint

NEONAX(NCT02047513)

166 Neoadj GEM+NabTXL x2Adj GEM+NabTXL x4Adj GEM+BabTXL x6

DFS

NCT02047474 46 Neoadj FOLFIRINOXx3+AdjFOLFIRINOXx3

DFS

NEOLAP(NCT02125136)*

168 Neoadj GEM+NabTXL x3+NeoadjFOLFIRINOXx2+Adj GEM+NabTXL x3Neoadj GEM+NabTXL x4+Adj GEM+NabTXL x3

Conversionrate

*Including LAPC

KeyOngoingNeoadjuvantPCTrials- 2

Trial Pts Treatmentgroups PrimaryEndpoint

NCT01314027 - Neoadj GEMOX+Adj GEMAdj GEM

DFS

NCT01065870 - Neoadj GTX+RTNeoadj GTX

DFS

NEOPA 410 Neoadj CRT+Adj GEMAdj GEM

DFS

Summaryü Resectionistheonlypotentiallycurativetreatmentoption forPC1

ü Atthetimeofdiagnosis,≈10%ofpatientswithPChaveresectablediseaseand≈10%patientshaveborderline resectable disease2

ü TheuseofCRTforadjuvantPCiscontroversial3ü CurrentUSrecommendationslistCT(Gemor5-FU/leucovorin)asacategory1optionand

CRTacategory2Aoption1ü CurrentESMOguidelines listCT(Gemor5-FU/leucovorin)asacategory1Aoptionbutdo

notrecommendCRToutsideofaclinical trial4ü Resultsofarecentmeta-analysissupportCToverCRT5

ü AnumberofphaseIIItrialsarecurrentlyexploringdifferentadjuvantPCtreatmentoptions6

ü Theroleofneoadjuvantorconversiontherapyispresentlyuncertain;thisstrategyhastobeevaluatedinwell-designedclinicaltrial,butinthepracticemightbeconsidered inBRPCandinLAPCpendingmultidisciplinary review

1. NCCN Clinical Practice Guidelines in Oncology. Pancreatic Adenocarcinoma. Version 2.2015. 2. Vincent A, et al. Lancet. 2011:378:607-620. 3. Twombly R. J Natl Cancer Inst. 2008;23:1670-1671. 4. Ducreux M, et al. Ann Oncol. 2015;23(suppl 5):v56-v68.

5. Liao W-C, et al. Lancet Oncol. 2013;14:1095-1103. 6. Neoptolemos JP, et al. Presented at: ASCO 2013 [abstract 4006].

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