PREVENTIONANDMANAGEMENTOFFEBRILENEUTROPENIA

JeanKLASTERSKYMD,PhDUniversitéLibredeBruxelles(ULB)

InsHtutJulesBordetInsHtutBrussels-Belgium

PREVENTION

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FEBRILENEUTROPENIARISK

Kudereretal,JCO,2007

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DURATIONOFPROPHYLAXISFORNEUTROPENICCOMPLICATIONSOFCHEMOTHERAPYINPATIENTSWITHPRIMARYSOLIDTUMORS

RECEIVINGFILGRASTIM

Weyckeretal.,JClinTher,2009

Pa#entsreceivingfilgrastrimforasolidtumorinUS(12/2003-01/2015),n=1193Pa#entsreceivingpegfilgras#m,n=14570Riskofhospitaliza#onforneutropeniccomplica#ons:2.1%versus1.2%,p<0.05

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TIMETORECOVERYOFANC

Parketal.,SupportCareCancer(2017)25:505-511

Pa#entswhowererandomizedtofilgras#mreceiveddailysubcutaneousinjec#onsoffilgras#m

100μg/m2/daybeginningapproximately24haTerchemotherapyandcon#nuedun#lANCwas

documentedtobe5x109/LaTernadir,orforupto10days.Pa#entswhowererandomizedto

theDA-3031groupreceivedasinglesubcutaneousinjec#onofDA-3031atfixeddosesof6mg

onday2ofeachchemotherapycycleapproximately24haTercomple#onofchemotherapy.

Breastcancerpa#entsreceivingTACchemotherapy(docetaxel,doxorubicin,cyclophosphamide)74pa#entsNonsignificantdifferencebetweenarms

PEGFILGRASTIMVSFILGRASTIM

Cooperetal.,BMCCancer,2011

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PATIENTASSESSMENTALGORITHMTODECIDEPROPHYLACTICG-CSFUSAGE

AaproMSetal.,EurJCancer,2011

TruongJetal.AnnOncol.2016

FNIncidence

GapBetweenClinicalTrialsandRealLifePrac#ce

(randomizedcontrolledtrials)(n=110)

n=50,069Breastcancerpts(1996-2014)(n=65)

FNrates:significantlyhigherintheobservaHonalstudycomparedwithRCTcohorts(OR=1.74;95%CI1.15–2.62;p=0.012).

Thismeantthata13%(95%CI8.7%to17.9%)FNrateinRCTwouldtranslateinto20%FNrateinobservaHonalstudy.

MANAGEMENT

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RELATIONSHIPBETWEENFN,RISKOFMORTALITYANDCOMORBIDITIES–USdischargedatabase–155academiccentres

KudererNMetal.,Cancer,2006

Overall Nomajor 1major >1major(n=41,779) comorbidity comorbidity comorbidity

(n=21,386) (n=12,398) (n=7,995)

25

20

15

10

5

0

9.5

2.6

10.3

≥21.4

Inpa

Hentm

ortality

(%paH

entsadm

iied

forF

N)

MortalityfollowinghospitaladmissionforFN*(1995–2000)

*DatabasedonasingleadmissionperpaHent

Higherrateinpa#entswithleukemias,followedbylymphomaandsolidtumors

SeymourCWetal.NEnglJMed2017;376:2235-2244.

. In patients with sepsis

AMASCCscoreindex≥21predicts

alow(5-10%)riskofcomplicaHonsanddeath(<2%)

Risk of complication : low risk prediction

PredicPnghighrisk?

0

10

20

30

40

50

60

5-16(n=70)

17-18(n=64)

19-20(n=100)

21(n=165)

22-23(n=171)

24(n=109)

25-26(n=115)

Mascc score

Rat

e of

ser

ious

com

plic

atio

ns/d

eath

Serious complicationDeath

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Initial management of febrile neutropenia

Temperature >38.5° and ANC <0.5x10°/L

CalculateMASCCscore

Highrisk Lowrisk

Inpa#entbroadspectrumintravenousan#bacterialtherapyVigorousresuscita#onifneeded

InpaHentoralanHbacterialtherapyEarlydischargeforsomecases

Klasterskyetal.,JClinOncol,200615

Reasons for not administering oral treatment to patients predicted at low-risk of serious complication

development (MASCC score ≥ 21)*

Klasterskyetal,JClinOncol,2000

Reason N°ofpaHents %

AnHbacterialprophylaxisand/ortreatment 179 71Inabilitytoswallow 27 11ContraindicaHon(s)tooraltherapy 17 6ProtocolviolaHon 16 6Refusal(bypaHentorphysician) 11 5Allergytopenicillinorquinolones 2 1

*Astudyof611consecu#vepa#entswithFNattheIns#tutJulesBordet

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Reasons for prolonged hospitalization more than 24 hours in predicted low-risk patients receiving oral

empiric treatment*

Klasterskyetal,JClinOncol,2006

Reason N°ofpaHents

%ofcomplicaHons

Persistentfeverandneedfortreatmentchange 19 21

ObjecHvemedicalreason 42 9

Reasonnotrelatedtoamedicalevent 38 2

*Astudyof611consecu#vepa#entswithFNattheIns#tutJulesBordet

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CRAWFORD(1991)

(n=59SCLC)

LALAMI(2001)(n=48breastca)

IncidenceofFNaTerthefirstcycleofchemotherapy(withoutCSF)

100% 100%

IncidenceofFNaTerthesecondcycleofchemotherapy(withCSF)

23% 6%

SECONDARYPREVENTIONOFSUBSEQUENTFNINPATIENTSWHOHADAFIRSTEPISODE

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REDUCEDDOSEINTENSITYANDIMPACTONSURVIVAL

OS,overallsurvival;(A)RDI,(average)relaHvedoseintensity;DLBCL,diffuselargeB-celllymphoma

1ChirivellaIetal.,BreastCancerResTreat,20092BoslyAetal.,AnnHematol,2008

A reduced dose intensity results in reducedoverall survival in paHents with primarybreast cancer and anthracycline containingchemotherapy1

A reduced dose intensity results in reducedoverall survival in DLBCL-paHents with CHOP-21chemotherapy2

Diseasefreesurvival(years)

CumulaH

vesu

rvival

RDI≥85%

<85%

1.0

0.8

0.6

0.4

0.2

0.00 2 4 6 8 10

Breastcancer

EsHm

ated

survival

0 1 2 3 4 5 6 7 8Yearspostchemotherapy

0.0

0.2

0.4

0.6

0.8

1.0

≤85%86–≤90%>90%

ARDI

NHL

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THE RISK OF NEUTROPENIC EVENTS IS GREATEST IN THE FIRST CYCLE

1.  AdaptedfromCrawfordJetal,fortheANCStudyGroup.Posterpresentedat:46thAnnualMee@ngoftheAmericanSocietyofHematology;December4-7,2004;SanDiego,Calif.Poster2210.

2.  DaleDCetal.,JNatlComprCancerNetw.2003

Grade3-4neutropeniceventsotenleadtodosedelaysordosereducHons.2

OverallN=1,925

Breastn=820

Lymphoman=235

Ovariann=171

Lungn=453

Colorectaln=246

60

50

40

30

20

0

PaHe

nts(%)

10

FirstcycleSecondcycleThirdcycleFourthcycle

70

*Grade3-4neutropenia=ANC<1.0x109/L.

• Morethan50%ofalliniHalGrade3–4neutropenia*occursinthefirstcycleacrossmanytumortypes

•  The past two decades have witnessed major progress in the supportive management of cancer patients who develop fever and neutropenia. Morbidity and mortality have been dramatically reduced, and for many patients therapies are more simple, less toxic and more appropriately delineated according the patient’s risk status.

•  Primary prophylaxis with granulopoiesis colony-stimulating factors has proven to be a major tool for reducing infectious complications from febrile neutropenia and allowing the administration of optimal relative dose intensity of chemotherapy.

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GENERAL CONCLUSIONS

PrinciplesfortheuseofGCSF’sfortheprevenHonofchemotherapy-inducedneutropenia(CIN)

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•  UseofG-CSFsignificantlyreducesthemortalityandmorbidityassociatedwithCIN

•  Long-acHng(pegylated)G-CSFoffersamoreconvenientapproachandmightpossiblybemoreeffecHvethanshort-acHngagents

•  Forshort-acHngagents,theopHmalnumberofdailyadministraHonsis≥7forpaHentswithasignificantriskofdevelopingCIN;theopHmalstrategyinlowerriskpaHentsispresentlyunknown.

•  OtherfactorsthantheintensityofchemotherapymustbetakenintoaccounttoevaluatetheriskofCIN,namelyageandthepresenceofco-morbidiHes

CONCLUSIONS

PrinciplesfortheuseofGCSF’sfortheprevenHonofchemotherapy-inducedneutropenia(CIN)

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•  G-CSFshouldbegivenasaprimaryprophylaxis,i.e.atercycle1ofchemotherapy,inpaHentswithsignificantriskofCIN

•  UseofG-CSFisagoodclinicalpracHceinpaHentswithsignificantriskofCIN,especiallyifchemotherapyisgivenwithacuraHveintent(includingneo-adjuvantandadjuvantsituaHons)

•  FuturestudiesshouldconcentrateonthedefiniHonof«significant»riskofCINandontheopHmalschedulesofG-CSFcorrespondingtothatrisk

•  Short-termsideeffectsofG-CSFarerareandusuallymild;long-termconsequencesincancersurvivorshavetobeevaluated

CONCLUSIONS

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CONCLUSION

IfFNhits

•  FNispreventableinthemajorityofchemotherapy-treatedpaHents

•  EvaluatetheriskofcomplicaHons(MASCCscore)

•  StartanHbioHcsearly(within1hour)

•  Forlowrisk:observe12to24hoursbeforesendingbackhome

•  Fornon-lowrisk:evaluateforseveresepsis/sepHcshockandconsiderICU

•  Monotherapyisadequateinmostcases(!considerlocalmicrobiologicalepidemiology)

•  CriHcallyre-evaluateater48hours

•  CheckwithmicrobiologicallabandIDspecialist

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INSTITUTJULESBORDET

Thank you for

your kind attention

See you later !