[PDF] Association between survival and levetiracetam use in glioblastoma

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Scientific Repo

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www.nature.com/scientificreports

Association between

survival and levetiracetam use in glioblastoma patients treated with temozolomide chemoradiotherapy tae Hoon Roh , Ju Hyung Moon , Hun Ho p ark e ui Hyun Kim c hang-Ki Hong Se Hoon Kim , Seok-Gu Kang & Jong Hee c hang with glioblastoma (GBM) treated with concurrent temozolomide ( t

MZ) chemotherapy. to this end,

dehydrogenase ( IDH wildtype GBM who received tMZ based chemoradiotherapy were analysed. t he patients were divided into two groups based on whether L e

V was used as an anticonvulsant both

methylguanine D n A MGMT

MGMT promoter

o S. i n conclusion, L e V use was associated with prolonged survival in patients with GBM treated with concurrent tMZ chemoradiotherapy. andradiotherapy 1,2 only14.6-20.2 months 2-4 e?ects5 ,andGBMswithmethylated O 6 -methylguanine 5,6

GBMexperience

seizures 7 braintumour surgery 8-11

Korea.

Department of Neurosurgery, Gangnam Severance Hospital,

Department of Pathology, Severance Hospital,

email: changjh@yuhs.ac 2

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Scientific Repo

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www.nature.com/scientificreports/ P450 12 .Currently, interactions

8,9,13-19

ArecentstudyshowedthatLEVinhibited

MGMT andsensitisedGBMcellsto TMZ 20 .Anotherstudyshowed thanthosewhodidnotreceive LEV 21
anysurvivalbene?t.

Methods

p atient recruitment. Seoul,Korea,wereretrospectivelyreviewed.Patientsyoungerthan18 yearsofageandthosewhoreceivedonly IDH1 muta- tion.Asthe IDH2 withGBMswerefoundtohavethe IDH1 astartingdose,1,000 mg/dayofVPAorLEVwasadministered.Ifaseizureeventoccurredtherea?er,500 mg/ neuralgia,900 mg/dayofgabapentinor150 mg/dayofpregabalinwasaddedandescalatedbysymptoms.?at

Surgery and adjuvant treatment.

forallpatientswithin72 ha?erthesurgery.?eextentofresectionwasdeterminedbasedontheMRI?nd regimenwasstartedforall patients 3 .?epatientsreceivedradiationtherapyatatotaldoseof60 Gy,withdaily fractionsof2 Gy.?efollow-upMRIwasperformeda?erCCRT,andthena?erthethirdandsixthcyclesof TMZ.?erea?er,MRIwasperformedevery3-6 monthstoassessthediseasestatus.?eResponseAssessmentin progression 22
.Duringchemoradiotherapyandadjuvant

Molecular analysis.

previously 6 .?e IDH1 mutationwastestedusingimmuno

Statistical analysis.

t

Results

PatientcharacteristicsaresummarisedinTable 1.?emedianageofthepatientswas58(range19-79)years. resection.LEVwasthemostfrequentlyusedAED(169patients,53%)andusedat500 mgtwiceadayinmost cases.?esecondmostfrequentlyusedAEDwasVPA(132patients,42%)atadoseof500 mgtwiceaday.One MGMT promotermethylationstatuswasavail MGMT promoter.?emedian 3

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Scientific Repo

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www.nature.com/scientificreports/ Table 2showsthecharacteristicsofeachgroupofpatients.Onehundredandsixty-nine(52%)patients MGMT promoter Table 1. concurrentchemoradiotherapy,

LEVlevetiracetam,MGMTO

6 -methylguanine-DNAmethyltransferase, CI con?denceinterval.

ParameterNo. of patients (%)

Sex

Male181(56)

Female141(44)

Seizureasapresentingsymptom33(10)

Median KPS score (range)

Preoperative80(30-100)

Postoperative70(10-100)

Extent of resection

Complete171(53)

Incomplete181(47)

AED during CCRT and adjuvant chemotherapy

LEVincluded169(53)

LEVonly157(49)

LEVplusothers12(4)

LEVnotincluded153(48)

Valproicacidonly111(35)

Valproicacidplusothers21(7)

Others20(6)

NoAED1(0)

MGMT promoter methylation

Methylated87(29)

Unmethylated209(71)

Notavailable26

Dead255(79)

Tumourprogression282(88)

Table 2. deviation, KPS

KarnofskyPerformanceStatus,

MGMT O 6 -methylguanine-DNAmethyltransferase.

ParametersNo. of patients (%)

P value

LEV (+)LEV (-)

n

169n = 153

Age:mean

SD55±1257±130.184

Men97(57)84(55)0.652

PreoperativeKPS:mean

SD77±1572±140.001

PostoperativeKPS:mean

SD72±1868±170.044

Completeresection106(63)65(42)<0.001

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www.nature.com/scientificreports/ maintenancewas31.3 months(95%CI19.9-42.6 months)intheLEV(+)group.?emediandurationofAED months,respectively(P

8.9-13.6)months(P=0.017)(Fig. 1a).

(111patients).?emedianOSwas21.9 months(95%CI17.3-26.5)intheformerand18.7 months(95%CI

14.3-23.1)(P

=0.016)inthelatter.?emedianPFSwas13.3 months(95%CI11.6-14.9)intheLEVgroupand

12.7 months(95%CI9.4-16.1)intheVPAgroup(P=0.082)(Fig. 1b).

promoter(P signi?cantprognosticfactorsforOS(Table 3).Age,postoperativeKPSscore,completeresection,andmethyl-

HR0.80;95%CI0.63-1.03).

024487296120144

0255075100

Monthsaftersurger

y

Overallsurvival

LEV(+)vsLEV(-)(a)

LEV(+) (n = 169)

LEV(-)(n=153)

21.1months

17.5months

p=0.003

024487296120144

0255075100

Monthsaftersurger

y

Progression-freesurvival

LEV(+) (n = 169)

LEV(-)(n=153)

12.3months

11.2monthsp=0.017

024487296120144

0255075100

LEVmonotherapyvsVPAmonotherapy

Monthsaftersurgery

Overallsurvival

LEV (n = 157)

VPA(n=111)

21.9months

18.7monthsp=0.016

(b)

024487296120144

0255075100

Monthsaftersurgery

Progression-freesurvival

LEV (n = 157)

VPA(n=111)

13.3months

12.7months

p=0.08 6

Figure 1.

patients.?eoverallsurvivalwas21.1 monthsintheLEV(+)groupand17.5 monthsintheLEV(-)group (P =0.003).?eprogression-freesurvivalwas12.3 monthsintheLEV(+)groupversus11.2 monthsinthe

LEV(-)group(P

overallsurvivalwas21.9 monthsinLEVmonotherapygroupand18.7 monthsinVPAmonotherapygroup (P =0.016).Progression-freesurvivalwas13.3 monthsintheLEVgroupand12.7 monthsintheVPAgroup (P

0.082).

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Discussion

historyof seizures 9 whencombinedwithTMZ. 2000s
13,23 withchemotherapy agents 24
interactions 24
.Fur- GBM 25
-30 .?eexactmechanismof thissurvivalbene?tisunclear;somein vitrostudiesrevealed,asahistonedeacetylase,VPApromotestumourcell di?erentiation,apoptosis,andgrowth arrest 31
,32 ofMGMTandsensitisesgliomacellsto TMZ 33
used 34
.Anotherlargestudy withGBM 35
survey,only16%ofneurosurgeonsuseAEDsformorethan6 weeks 9 .Previousstudiesmayhaveinvolvedthe ingwasbasedontheAEDsadministeredduringthe?rst2 months,asthetime-dependentselectionbiascould periodinmostpatients.?emediandurationoffollow-upandAEDusewere60.8 monthsand37.3 months, asfollows:ifapatienthadnotdied,heorshewouldhavebeenfollowedfor60.8 months,andAEDswouldhave beenadministeredfor37.3 months. group.Our?ndingssupporttheresultsofthestudyofKimet al.,inwhichthesurvivalbene?ta?ordedbyLEVin

IDHmutation,whichcanbea

IDH-wildtypeGBMs.GiventhatIDH-

wildtypeGBMshavepooroutcomescomparedwith curveshowedaplateaua?er48 months;the10-yearsurvivalratewasestimatedtobe22%intheLEV(+)group. ItisnotclearhowLEVimprovesthesurvivalofpatientswithGBM.Bobustucet al.reportedthatLEV transcription 20 resultinginTMZtobemoree?ective.Otherin vitrostudieshaveshownLEVenhancesthee?ectofTMZon

GBMstemcellproliferationand

apoptosis 36
inGBM cells 37
synapses 38
,39 glioma. Table 3. freesurvival. HR hazardratio, CI con?denceinterval, KPS

KarnofskyPerformanceStatus,

MGMT O 6 methylguanine-DNAmethyltransferase,

LEVlevetiracetam.

Overall survivalProgression-free survival

P valueHR (95% CI)P valueHR (95% CI)P valueHR (95% CI)P valueHR (95% CI)

Completeresec

Methylated

MGMTpromoter

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www.nature.com/scientificreports/ factors. lowerthanthatreported previously 7,8 useinpatientswithGBM.

Data availability

Allrelevantdataarewithinthepaper.

Received: 26 December 2019; Accepted: 29 May 2020

glioblastomas.J.Neurosurg.115,3-8(2011).

LancetOncol.10,459-466(2009).

ment.LancetNeurol.6,421-430(2007). tumoursinpatientswithoutepilepsy.

J.Clin.Neurosci.

19,99-100(2012).

Epilepsia

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,45-57(2013). systematicreviewandmeta-analysis.

BrainInj.30,1054-1061(2016).

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patients.J.Neurooncol.78,99-102(2006).

Neuro.Oncol.

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group.J.Clin.Oncol.28,1963-1972(2010).

227-235(2008).

(2003). 77
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www.nature.com/scientificreports/ andasystematicreview.

Seizure

23,830-835(2014).

29.
30.
therapyforhigh-gradeglioma.

Eur.J.Clin.Pharmacol.73,357-363(2017).

Natl.Acad.Sci.USA101,18030-18035(2004).

32.Knupfer,M.M.etal.Di?erente?ectsofvalproicacidonproliferationandmigrationofmalignantgliomacellsin vitro.Anticancer

Res.21,347-351(2001).

Biotechnol.2012,987495(2012).

34.
trialsinnewlydiagnosedglioblastoma.

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inglioblastomapatients?.

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129,461-469(2016).

CancerCellInt.18,136(2018).

J.11,43-49(2017).

Acknowledgements

ofMedicinetoTaeHoonRoh.

Author contributions

reviewedthemanuscript. competing interests ?eauthorsdeclarenocompetinginterests.

Correspondence

Reprints and permissions information

isavailableat www.nature.com/reprints

Publisher's note

institutionala?liations.

Open Access

©?eAuthor(s)2020

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