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Original article
Twenty years experience in treating childhood medulloblastoma:
Between the past and the present
Prise en charge d’une cohorte d’enfants atteints de médulloblastome: résultats cliniques sur 20 ans
J. Khalil
a, Z. Qing
b, Z. Chuanying
b, Y. Belkacémi
c, N. Benjaafar
a, J. Mawei
b,∗Q1
aMohamed-VUniversity,avenuedesNations-Unies,8007.N.UAgdal,Rabat,Morocco
bXhinhuageneralhospital,1665KongjiangRd,Yangpu,Shanghai,China
cHenri-MondorInstitute,avenueduMaréchal-de-Lattre-de-Tassigny,94010Créteilcedex,France
a r t i c l e i n f o
Articlehistory:
Received25May2017
Receivedinrevisedform9May2018 Accepted15May2018
Keywords:
Medulloblastoma Treatment Toxicity
a b s t r a c t
Purpose.–Medulloblastomaisthemostcommonprimarymalignantcentralnervoussystemtumourof childhood.Theselastdecades,treatmentmodalitieshavelargelyevolvedresultinginbettersurvivalrates.
Q2
Nevertheless,long-termtoxicityisamajorconcerninthissetting.Thepurposeofthisstudywastoanalyse theclinicalresultsandmedicaloutcomesofacohortofpaediatricpatientstreatedformedulloblastoma inXhinhuaHospitalinShanghai.Theseresultsarecomparedwiththosefromothercentresreportedin literature.
Patientsandmethods.–ThiswasaretrospectivestudyconductedatXhinhuaHospitalinShanghai,China.
Itincluded121patientstreatedformedulloblastomafrom1993toDecember2013.
Results.–Meanageatdiagnosiswas6.7years(range:1–14.3years).Totalsurgicalresectionwasachieved in60%ofthecases.Classicmedulloblastomawasfoundin59%ofthecases.Adjuvantradiotherapywas deliveredinallcasesandchemotherapyconcerned70.2%ofthestudiedcohort.Themedianfollow-up timeofthestudywas84months(range:24–120months).Five-and10yearsprogression-freesur- vivalrateswere83.2%,and69.5%and5yearsand10years.Overallsurvivalrateswere82.5%,and 72.5%.Patient’sagesignificantlyinfluencedsurvival:patientsunder3yearsoldhadtheworseoutcomes (P=0.01).TandMstagesalsosignificantlyimpactedsurvivalrates:advancedstageswereassociatedwith lowerrates(P=0.08and0.05respectively).Finally,patientsreceivingtemezolomidehadbadoutcomes whencomparedtothenewstandardprotocolusedinthedepartment(P=0.03).Themostcommonly reportedlatetoxicitywasgrowthsuppressionin35patients(52.2%).Hypothyroidismrequiringhormone replacementwasrecordedin29%ofthecases.Hearingloss,andproblemsincludingpoorconcentration, poormemoryandlearningdifficultieswerereportedin19%and25%ofthecasesrespectively.Second cancerswerenotedinthreecases.
Conclusion.–Overall,ourresultsarecomparabletothosereportedinliterature.Nevertheless,efforts shouldbemadetoensurelongerfollow-upsandcorrectlyassesstreatment-relatedtoxicity.
©2019PublishedbyElsevierMassonSASonbehalfofSoci ´et ´efranc¸aisederadioth ´erapieoncologique (SFRO).
Motsclés: Médulloblastome Traitement Toxicité
ré s um é
Objectifdel’étude.–Lemédulloblastomeestlatumeurmalignedu systèmenerveuxcentrallaplus fréquentedel’enfance.Lesnouvellesapprochesthérapeutiquesontpermisd’améliorerlestauxdesurvie auprixd’unetoxicitéaccrue.L’objectifdecetteétudeétaitd’analyserlesrésultatscliniquesd’unecohorte d’enfantsatteintsdemédulloblastomeprisenchargeàl’hôpitalXhinhuadeShangaïetdelescomparer àceuxd’autrescentresrapportésdanslalittérature.
Patientset méthodes.– Notre étude rétrospective,menéeàl’hôpital XhinhuadeShanghai, ainclu 121patientstraitéspourmédulloblastomedejanvier1993àdécembre2013.
∗ Correspondingauthor.
E-mailaddress:bensaidbadr8@gmail.com(J.Mawei).
https://doi.org/10.1016/j.canrad.2018.05.008
1278-3218/©2019PublishedbyElsevierMassonSASonbehalfofSoci ´et ´efranc¸aisederadioth ´erapieoncologique(SFRO).
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Résultats.–L’âgemoyenaumomentdudiagnosticétaitde6,7ans(intervallede1à14,3ans).Unerésec- tionchirurgicaletotaleaétéréaliséedans60%descas.Letypeclassiqueaétéretrouvédans59%descas.
Uneradiothérapieadjuvanteaétéadministréedanstouslescasetlachimiothérapieconcernait70,2% delacohorteétudiée.Laduréemédianedesuiviétaitde84mois(extrêmes:24–120mois).Lesproba- bilitésdesurviesansprogressionà5et10ansétaientrespectivementde83,2%et69,5%etcellesde survieglobalede82,5%et72,5%.L’âgedupatientainfluencésignificativementlasurvie:lespatients demoinsde3ansavaientlestauxdesurvielesplusbas(p=0,01).LesstadesTetMavaientégalement unimpactsignificatifsurlestauxdesurvie:lesstadeslesplusfortsétaientassociéesàdestauxplus faibles(respectivementp=0,08et0,05).Enfin,lespatientsrecevantdutémozolomideavaientdestaux desurviefaiblesparrapportaunouveauprotocolestandardutilisédansledépartement(p=0,03).Latox- icitétardivelaplusfréquemmentrapportéeétaitunretarddecroissancechez35patients(52,2%).Une hypothyroïdienécessitantunremplacementhormonalaétérapportédans29%descas.Unehypoacousie etdesproblèmesdeconcentration,demémorisationetdesdifficultésd’apprentissageontétésignalés dans,respectivement,19%et25%descas.Troiscasdecancersecondaireontéténotés.
Conclusion.–Dansl’ensemble,nosrésultatssontcomparablesàceuxrapportésdanslalittérature.Néan- moins,deseffortsdevraientêtrefournispourassurerunsuivipluslongetévaluercorrectementlatoxicité dutraitement.
©2019Publi ´eparElsevierMassonSASaunomdeSoci ´et ´efranc¸aisederadioth ´erapieoncologique(SFRO).
1. Introduction
Medulloblastomaisthemostcommonprimarymalignantcen- Q3
tralnervoussystemtumourofchildhood,accountingfor16–25%
Q4
ofthecases[20].Somedataintheliteraturesuggestanincrease inits incidencerate whilesome otherstudies reporttrendsto decreaserates[41,24].Itcanoccuratallages,butitspeakofinci- denceisbetween4and7years,andisrarelydiagnosedinadults [20,41,24,18].Medulloblastomasaretypicallylocatedintheposte- riorfossa,inoraroundtheIVventricle,adherenttotheposterior medullaryveluminthemidline.Itcanalsobelocatedwithinthe cerebellarhemispheres.Clinicalfeaturesincludemostlycoordina- tiondeficitsandsignsofincreasedintracranialpressure,lastingin somesituationsthreetofourmonthsbeforediagnosis[22].Itlikely disseminatesalongthecerebrospinalfluidpathway;inapproxi- mately30%ofthecases[32].Metastasisoccursrarelyoutsidethe centralnervoussystem.Formostcases,theaetiologyisunknown [41,24,18].Nevertheless,somegeneticdisorders(i.e.Gorlinsyn- drome,Turcotsyndrome,Li-Fraumenisyndrome,Rubinstein-Taybi syndromeandataxiatelangiectasia)werefoundtobeassociated withanincreasedriskofmedulloblastoma[44].Managementof medulloblastomahaslargelyevolvedoverthelastthreedecades.
Multimodaltreatmentincludingsurgicalresection,radiotherapy andchemotherapy is nowconsidered asthestandard care and hasledtoanimprovement ofoutcomeswithanestimated30%
reductioninmortalityrates[13].Nonetheless,treatment-related toxicityisstillthemainconcernwhentreatingmedulloblastoma, significantlyimpactinglong-termqualityoflife.
Through our study, we present clinical results and medical outcomesofmorethan100paediatricpatientstreatedformedul- loblastomainXhinhuaHospitalinShanghai.Theseresultswillbe comparedwiththosefromothercentresreportedinliterature.
2. Patientsandmethods
Chartswereobtainedforallchildren diagnosedwithmedul- loblastomafromthemedicalrecordsdepartmentattheXhinhua hospitalinShanghai, Chinafrom1993to2013.Nopatientwas excludedfromtheseries.Thefollowingdatawereobtainedfrom thepatients’ chart:age,sex,dateofbirth, signsandsymptoms, lengthofsymptomsbeforediagnosisanddiagnosticimagingtool.
Thelocation,stageandhistologyofthetumour,typeofsurgery (totalvssubtotalresection),and presenceor absenceofhydro- cephalusand/oraventriculoperitonealshuntwererecorded.The
presenceofresidualdiseasewasdeducedfrompostoperativeimag- ing reports, and was accordingly divided in two groups: less than1.5cm2andlargerthan1.5cm2.Radiationandchemotherapy protocols,follow-upneuroimaging,metastaticworkup,treatment- relatedtoxicityandtreatmentmanagementforrelapseswerealso reviewed.
3. Statisticalanalysis
A Statistical Packagefor Social Sciences package (SPSS) was used for analysis. Means and standard deviations were calcu- lated.TheKaplan–Meiermethodwasusedtoanalyseoveralland progression-freesurvival.Univariateanalysiswasperformedusing thelog-ranktest.Multivariateanalysiswasperformedusingthe Coxproportionalhazardsmodel.Outcomeswerebasedonthefol- lowing factors:age,sex, tumourlocation (midlineorcerebellar hemisphere,orboth),tumourandmetastasisstageasperChang’s classification[6],postoperativeresidualtumour,treatmentwith radiationorchemotherapy,orboth,timeintervalbetweensurgery andadjuvanttreatment,developmentofhydrocephalus,presence ofVPshuntandpathologicalcharacteristicsofthetumour.
4. Results
Between1993and December2013,121children werediag- nosed with medulloblastoma at Xhinhua hospital and were accordinglyincludedinthestudy.
4.1. Clinicalandpathologiccriteria
Themeanageforthewholegroupofpatientsinthisstudywas 6.7years(range1–14.3years),andthemedianagewas5.5years (Table1).Nearly91%ofthestudiedcohortwasabove3yearsold, whileonly11patientswerelessthan3yearsoldatthetimeof thediagnosis.Mostofthepatientswereboys,whoaccountedfor 67.5%ofallthecases.Amaximumdurationofsymptomspriorto presentationof7months,andaminimumof2monthswithamean durationof3±1.4monthswerenoted.Themostcommonpresent- ingsymptomsincluded:vomiting(96patients,80%),headaches(91 patients,76%)andbalancedifficulties(59patients,45%).Convul- sionsweretherevealingsymptomin2.5%ofthecases.Physical examinationrevealedasatisfactoryperformancestatusin95%of thecasesusingLanskyscore.Themostcommonsymptomswere
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Table1
PaediatricpatientstreatedformedulloblastomainXhinhuaHospitalinShanghai:
clinicalandpathologiccriteriaofthestudiedcohort(N=121).
Criteria N(%)
Age
<3years 11(9.2%)
>3years 110(90.8%)
Sex
Boy 82(67.5%)
Girl 39(32.5%)
Revealingsymptoms
Vomiting 96(80%)
Headache 91(76%)
Balancedifficulties 54(45%)
Convulsions 3(2.5%)
Imagingmodalities
MRI 115(95%)
MRIalone 50(41.3%)
MRIincombinationwithCT 65(53.7%)
CTwithoutMRI 6(5%)
Physicalexam
Papilloedema 62(47%)
Ataxia 43(32%)
Dysmetria 17(13%)
Tumourlocation
Vermis 69(0.57%)
Cerebellarhemisphere 31(0.1%)
Hemisphere+vermis 21(0.17%)
Table2
PaediatricpatientstreatedformedulloblastomainXhinhuaHospitalinShanghai (N=121):treatmentmodalities.
Treatmentmodalities N(%)
Surgery 121(100%)
Radiotherapy 121(100%)
Alone 36(30%)
Incombinationwithchemotherapy 85
Q10
Chemotherapy 85(70.2%)
Preradiotherapyalone 0(0%)
Preradiotherapy+concurrent 2(1.6%)
Preradiotherapy+adjuvant 15(12.3%)
Concurrent+adjuvant 12(10%)
Adjuvantalone 56(46.3%)
None 36(29.8%)
papilloedema(62patients,47%),ataxia(43patients,32%),anddys- metria(17patients,13%).
4.2. Initialworkup 4.2.1. Imagingmodalities
Magneticresonanceimaging(MRI)wastheprincipalimaging modalityusedforthediagnosis;itconcernedboththebrainand thespine,andwasemployedin95%ofthestudiedcohort.Itwas performedeitheralone(50patients,41.3%)orincombinationwith braincomputedtomography(CT)(65patients,53.7%).
In57%ofthecases,tumourwaspresentinthevermis,while31 patientspresentedatumoursolelyinthecerebellarhemisphere, andbothofthehemisphereandvermiswereinvolvedin17%ofthe cases.Hydrocephaluswasfoundin78%ofthecases.
4.2.2. Lumbarpunction
Lumbarpunctionwasperformedin29%ofthestudiedcohort.
Cerebrospinalfluidcytologywasanalysedanddidnotrevealabnor- malitiesinanycase.
4.3. Treatmentmodalitiesandresults
Treatment modalities are presented in Table 2. Pathological findingsandtumourstagingarepresentedinTable3.
Table3
PaediatricpatientstreatedformedulloblastomainXhinhuaHospitalinShanghai (N=121):pathologicalfindingsandtumourstaging.
Pathologicalfindings
Classichistology 71(59%)
Medulloblastomawithextensivenodularity 15(12%)
Desmoplastichistology 10(8%)
Anaplastichistology 2(1.6%)
Medulloblastomanototherwisespecified 23(19%) Tstages
T1 2(1.6%)
T2 3(2.5%)
T3a 14(11.6%)
T3b 85(70.3%)
T4 17(14%)
Mstages
M1 0(0%)
M2 1(0.8%)
M3 11(9%)
M4 0(0%)
Riskstratification
Averagerisk 51(41.7%)
Highrisk 70(58.3%)
4.3.1. Surgery
Ventriculostomywasrequiredpriortosurgeryin19casesto restoreanormalcerebrospinalfluidflow,whileitwasperformed duringoraftersurgeryintwentycases.Theremaining55patients with hydrocephalus were relieved only by the use of steroids thatwereadministeredintravenouslyimmediatelyafterdiagno- sis.Surgerywascarriedout3to4daysafterventriculostomywhen thelastwasperformedfirst.Surgeryconsistedonamidlinesuboc- cipitalcraniectomywithresectionofthearchofC1inmostcases.
In60%ofcases,thechildrenhadtotalresections;whilesubtotal resectionwasperformedin40%ofthecases.Thetypeoftumour wasconfirmedbypathologicaldiagnosisinallcases.Classicmedul- loblastomawasfoundin59%ofthecases,desmoplastictypeand medulloblastomawithextensivenodularitywerefoundin8and 12% of the casesrespectively. Anaplastic medulloblastoma was reportedintwocases,andin19.3%ofthecases,pathologicalfind- ingsonlyreportedmedulloblastomawithnootherspecification.All patientswerestagedaccordingtotheChang’sclassificationusing bothofoperativeandimagingreports.StagesT1andT2grouped togetherwerereportedinonlyfivecases,whilethemajorityofthe patients(96%)presentedstagesT3andT4.Infact,stagesT3a,T3b, andT4presented11.6%,70.3%and14%ofthecasesrespectively.
AstotheMstage,11patientshadaM3stagediseaseandonlyone patienthadaM2stage,nocasesofeitherM1orM4stagewere reported.Riskstratificationwasalsoappliedtoallpatients,and 58.3%ofthepatientsweredescribedashavingahigh-riskdisease.
4.3.2. Adjuvanttreatment
Allpatientsreceivedtreatmentfollowingsurgery;itconsisted ofeitherradiotherapyalonein30%ofthecasesorassociatedto chemotherapyin70%ofthecases.
4.3.2.1. Radiotherapy. Allpatientsunderwentcraniospinalirradi- ation withathree-dimensional techniquein proneposition.CT simulatorscanwasobtainedforallpatientsandthedevicesusedfor immobilizationincluded:necksupport,afive-pointfixationmask insuringtheimmobilizationfortheheadandacastforbodyfix- Q5 ation.Forthetreatmentplanning,EclipseandXiosoftwarewere used.Volumesdelineationwasperformedbyaradiationoncolo- gist;forthecranialpartclinicaltargetvolume(CTV)comprised theentirebrainandmeninges.ThespinalCTVcomprisedofthe spinalcanalasobservedonCT-scanincludingthecerebrospinal fluidextensiontothespinalganglia.Theinferiorlimitofthespinal CTVwasdefinedusingMRIfindings,andwaslocatedatthecaudal extentofthecalsac.Theplanningtargetvolume(PTV)wasdefined
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bymedicalphysicists,andincludedmarginsof8mminthecaudal directionand5mminthelateral,anteriorandposteriordirections.
Radiationtherapywasdeliveredamongtwotreatmentseries;the firstseriesdeliveredatotaldoseof3000–4000cGytothecran- iospinalaxis(18–20fractions),andthesecondonewasaboostof 1400–2000cGytotheposteriorfossa.
Mostpatients(97%)receivedradiationtothecraniospinalaxis witha boost tothe posterior fossa.Four patients stopped the treatmentbeforethesecondseriesofradiotherapytreatment.For patientsbeyondthree years,themedian time intervalbetween surgeryandradiotherapywasofdays(range:2–30days).Asto patientsunder3years,radiotherapywasdelayedtillcompletion of3yearsandthemediantimeintervalbetweenradiotherapyand chemotherapywas10days(range:1–25days).
4.3.2.2. Chemotherapy. Eighty-fivepatientsreceivedpostoperative chemotherapy,ofwhich13%receivedchemotherapypriortoradi- ation while 77% had medical treatment after radiotherapy. In general,chemotherapywasdeliveredatameantimeintervalfrom completionofradiotherapyof10days(range:2–20days).
Temozolomide-basedregimenwasprescribedin40.5%(N=35) of the cases witha mean number of cyclesof 8 (range: 5–18 cycles).Protocols including vincristine,cisplatin,and lomustine and/orcyclophosphamidewereprescribedin59.5%(N=50)ofthe studiedcohort.Ameannumberofsevencycles(range:4–9cycles) wasnoted.
4.4. Therapeuticresults 4.4.1. Radiotherapycompliance
Allofthe121patientsincludedinthecurrentstudyreceived adjuvantradiotherapy. Onlyfourpatientsdidnot completethe planned treatment; in two cases, it was relative to infectious meningitisthatrequiredhospitalizationintheintensivecareunit, andinthetwoothercasesitwasduetotheparents’refusaloncom- pletionofthetreatment.Themediantimetostartradiotherapywas 18days(range:2–30days).Themedianoveralltreatmentdura- tionwas42days(range:36–55days).Onehundredandseventeen patients(96.6%)completedexternalbeamradiotherapyasplanned, withoutanyinterruptions.Threepatientsinterruptedtreatment becauseofacutegrade3haematologicaltoxicity,andonepatient experiencedagrade3vomiting,constraininghimtogoalongwith thetreatmentplan.
4.4.2. Chemotherapycompliance
Before2002,temozolomidewastheonly prescribeddrugin theadjuvantsettingforbothintermediateandhigh-riskpatients;
inourseries,thisregimenwasprescribedin40.5%ofthecases.
Ninety-threepercentcompletedtheplannedtreatment.Sixtreat- mentinterruptionswerereported;haematologicaltoxicitywasthe mainreasoninallcases.
Since2002,protocolsincludingvincristine,cisplatin,andlomus- tine and/or cyclophosphamide were prescribed; this protocol concerned59.5%ofthestudiedcohort.Only9.5%casesoftreat- mentinterruptionusingthisprotocolwerereported.Intwocases, itwasrelatedtograde3febrileneutropeniarequiringtreatment;
inthreecases,itwasduetoagrade3thrombopenia;andinthe threeremainingcases,grade3vomitingwasthemainreason.
4.5. Treatmenttoxicity
TreatmenttoxicityresultsarepresentedinTable4.
4.5.1. Acutetoxicity
4.5.1.1. Postoperative toxicity.Immediate postoperative toxicity wasrecorded in55patients(45.5%);infectionsand hematomas
Table4
PaediatricpatientstreatedformedulloblastomainXhinhuaHospitalinShanghai (N=121):treatment-relatedtoxicitiy.
Toxicity N(%)
Acutetoxicity
Postoperativetoxicity 55(45.5%)
Infection 32(26%)
Hematoma 32(26%)
Cerebellarmutismsyndrome 25(20.5%)
Nervedamage 10(8.3%)
Radiotherapy-relatedtoxicity 62(51%)
Vomiting(grade3–4) 34(28%)
Headaches 23(19%)
Hearloss(grade2–3) 18(15%)
Abdominalpain 9(7.4%)
Dermatitis(grade2–3) 36(29.7%)
Haematologicaltoxicity Anaemia
Grade1–2 21(17.3%)
Grade3–4 18(14.8%)
Neutropenia
Grade1–2 18(14.8%)
Grade2–3 29(24%)
Thrombopenia
Grade1–2 11(9%)
Grade2–3 21(17.3%)
Chemotherapy-relatedtoxicity Haematologicaltoxicity
Anaemia
Grade1–2 21(17.3%)
Grade3–4 38(31.4%)
Neutropenia
Grade1–2 71(58.8%)
Grade2–3 43(35.5%)
Thrombopenia
Grade1–2 27(22.3%)
Grade2–3 44(36.4%)
Vomiting
Grade1–2 41(34%)
Grade3–4 63(52%)
Latetoxicity
Endocrine:hypothyroidism 50(41.3%)
Grade2 35
Grade3 15
Grade4 0
Sensory
Hearingloss 29(24%)
Grade2 18
Grade3 11
Visualdisturbance 19(15.7%)
Grade2 10
Grade3 9
Neurologic
Cognitivedisturbance(NS) 17(25%)
Seizures(grade2) 3(3.5%)
Other
Secondarymalignancy 3(3.5%)
Grade3 1
Grade4 2
Radionecrosis NR
Cerebrovascular NR
Total 58(83.5%)
Grade2 30
Grade3 10
Grade4 2
NS:notspecified;NR:notreported.
werethemostcommonlyreportedin26%ofthecases.Twenty-five patients(20.6%)presentedpostoperativecerebellarmutismsyn- dromeandtenpatients(8.2%)presentednervedamage,secondary tosurgicalresection.
4.5.1.2. Adjuvant treatment-related toxicity. Eighty-two cases (67.7%) of either radiation or chemotherapy-related toxicities were reported. The National Cancer Institute (NCI) Common TerminologyCriteriaforAdverseEvents(CTCAE),version4.0was
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Fig.1.Paediatricpatientstreatedformedulloblastoma:survivalratesofthestudiedcohort(N=121).a:5yearsoverallsurvival;b:5yearsprogression-freesurvival.
usedtoevaluateandgrade toxicity.Nauseaandvomitingwere the most recorded toxicity (Table 4), vomiting was commonly associatedwiththeuseofvincristine.Headachestartedthreedays followinginitiationofradiotherapyandwasobservedin19%ofthe cases.Othertoxicityrelatedtoradiotherapywerenoted,suchas, hairloss(15%ofthecases)andabdominalpain(7%ofthecases).
Chemotherapywasresponsibleforacutehaematologicaltoxicity in58%ofthecases,ofwhich,35%weregradedasgrade3.
4.5.2. Latetoxicity
Analysisoflatetreatmenttoxicityincludedonlydatafrom86 patients(71%),theremaining35patientswereeitherlosttofollow- up(20patients,16.5%)orhadpassedawayatthetimeofanalysis (15patients,12.3%).TheNCICTCAE,v.4.0wasusedtoevaluateand togradetoxicity.LatetreatmenttoxicityissummarizedinTable4.
Routine follow-up included physical exam and assessments Q6
of height and weight, as well as regular testing for growth hormone, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulatinghormone and adrenocorticotropic hormone.
Themostcommonlyreportedsequelawasgrowthsuppressionin 50 patients(41.3%), this complicationwasdeducedfrommedi- calpatients’recordsindicatingareductioningrowthvelocityor decreasedpercentilecomparedtoa priorgrowthcurve.Twenty patients required growth hormone supplementation. Hypothy- roidismrequiring hormone replacementwas recordedin 16.5%
ofthecases(N=20);allaffectedpatientsreceivedeuthyroid on levothyroxine. Hearing loss was reported in 24% of the cases (N=29).Problemsincludingpoorconcentration,poormemoryand learningdifficultieswerereportedbytheparentsin 25%ofthe treatedpatients(N=17).Secondcancerswerenotedinthreecases;
braintumourwasdiagnosedintwocasesafteramedianfollow-up of5.2yearsand,onecase,ofthyroidcarcinomawasreportedduring thefourthyearfollowingtreatmentcompletion.
4.6. Diseaseoutcomes
Themedianfollow-uptimeofthestudywas84months(range:
24–120months).Thirty-fivepatients(29%)werelostforfollow- up;analysisincludedonlypatientsforwhomdatawasavailable.
Ninepatients(10.5%) relapsedlocally;meanrelapsetime inter- valfrominitialdiagnosiswas27 months(range: 8–36months).
Infive cases,localfailurewaswithinthetumour bed,dissemi- natedleptomeningealrelapseoccurredintwocasesandisolated supratentorialfrontalrelapsewasreportedintwocases.Patients withlocalfailure withinthetumour bedreceivedradiotherapy alongwithchemotherapy;Gammaknifewasusedintwocases.In thecasesofdisseminatedleptomeningealrelapse,cisplatin-based chemotherapy, along with palliation, was the main treatment.
Finally,patientspresentingsupratentorialfrontalrelapsereceived radiotherapy.Alloftheaforementionedpatientspassedawayata meanintervaltimeof16months(range:8–24months).
Metastaticrelapseoccurredin17cases(19.8%),ofwhich,six casesoccurredoutside thecentralnervoussystem.Tenpatients receivedactivetreatmentwhiletherestbenefitedfrombestsup- portivecare.
Kaplan–Meiermethodwasusedtoestimateprogression-free andoverallsurvival(Fig.1).Progression-freesurvivalratesat5and 10yearswere83.2%(95%confidenceinterval[CI]),and69.5%(95%
CI)respectively.Overallsurvivalratesat5and10yearswere82.5%
(95%CI),and72.5%(95%CI)respectively.
4.7. Prognosticfactors
Uni-andmultivariateanalysesoffactorsimpactingprogression- freeoroverallsurvivalarepresentedinTable5.
4.7.1. Univariateanalysis
Factorsincludingage,sex,tumourstageandlocation,presence ofmetastasisatthetimeofdiagnosis,presenceofhydrocephalus andresidualdisease,patient’sriskgroupandthetypeofthepre- scribed chemotherapywereanalysed. Patient’sagesignificantly influencedsurvival:patientsunder3yearsoldhadtheworseout- comes(P=0.01).Tand Mstages significantlyimpactedsurvival rates:advancedstageswereassociatedwithlowerrates(P=0.08 and 0.05 respectively).Finally,patientsreceivingtemezolomide had badoutcomeswhen comparedtothenewstandard proto- colusedinthedepartment(P=0.03).Fig.2illustratedifferences insurvivalratesaccordingtotheaforementionedfactors.
4.7.2. Multivariateanalysis
Inthemultivariateanalysis,wecouldnotidentifyanyindepen- dentlysignificantvariableimpactingsurvivalrates.
5. Discussion
Although medulloblastoma could be considered as a rare tumour,itisthemostcommonbraintumourinchildhood;infact, oneoffivepatientswithbraintumourshasmedulloblastoma[36].
Ourstudyrelatesa20years’experienceintreatingmedulloblas- toma.
Medulloblastomacanoccuratallagesbutitspeakofincidenceis between4to7yearsold[20,41,24,18].Similarly,themedianageat diagnosisofourpatientswas5.5years.Italsoappearsthatmedul- loblastomaaremorefrequentlydiagnosedinboys[41,24,18];our seriesreflectsthisfindingas67.5%oftheincludedpatientswere boys.
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Table5
PaediatricpatientstreatedformedulloblastomainXhinhuaHospitalinShanghai(N=121):univariateandmultivariateanalysisoffactorsimpactingprogression-free-or overallsurvival.
% Univariateanalysis Multivariateanalysis
P P Hazardratio 95%confidenceinterval
Age 0.01 0.04 0.18 0.38–0.39
<3 9.2%
>3 90.8%
Sex 0.5 Notincluded
Male 67.5%
Female 32.5%
Tumourlocation 0.44 Notincluded
Bifocal 90.0%
Multifocal 10.0%
Hydrocephalus 0.19 0.91 0.93 0.27–3.15
Yes 78.3%
No 21.7%
Tstage 0.08 0.28 0.28 0.28–2.90
T1-T2 0.1%
T3-T4 98.3%
Mstage 0.05 0.007 5.2 1.58–17.24
M0-M1 16.8%
M2-M3 83.2%
Residualtumour 0.73 Notincluded
Present 18.9%
Absent 81.1%
Risk 0.74 Notincluded
Standard 41.7%
High 58.3%
Chemotherapy 0.03 0.19 0.5 0.17–1.43
Temozolomide 40.5%
Other 59.5%
Themostrevealingsymptomsnotedinourserieswere:vomit- ing(105patients,80%),headaches(100patients,76%)andbalance difficulties(59patients,45%).Thesesymptomswerealsothemost reportedinliterature,withatimeintervalbetweenthefirstreveal- ingsymptomsanddiagnosisof3to4months[22];inourcasethe meandurationofsymptomswasof3±1.4months.MRIisamanda- toryfollow-upimagingthatshouldbecarriedoutbeforetumour surgery.ItisimperativetoperformboththebrainandspinalMRI, asspinalmetastasesmightoccurupto40%ofthecases[12].In ourseries,bothbrainandspinalMRIwereperformedin95%ofthe includedcohortandrevealedmetastaticdiseaseintwelvecases (10%).
MRIfeatures are typicalof medulloblastoma, and surgery is oftencarriedoutaccordingtoitsfindings.Primarygoalsofsurgery are,ononehand,torestorenormalcerebrospinalfluidflowincase ofanobstructivehydrocephalus,andontheotherhand,tomax- imallyresecttheprimarytumor.Someneurosurgeons advocate carryingoutthesurgeryin twophases; thefirst stepwouldbe torelieveobstructivehydrocephalusviaathirdventriculostomy [4],andthesecondonewouldbethesurgicalexcisionofthepri- marytumor.Inourseries,ventriculostomywasrequiredpriorto surgeryin19cases(15.7%),andaftersurgery,in20cases(16.5%).
Alloftheincludedpatientsunderwentprimarytumourresection andcompleteresectionwasaccomplishedin60%ofthecases.
Asidefrominfectionsandmechanicalcomplications,posterior fossamutismsyndromeisthemostfearedcomplication[33,43];in ourstudy,thissyndromewasreportedin20.6%ofthecases.
Pathological findings guidetumours’ classification according tothecurrenteditionoftheWorldHealthOrganization(WHO), and are also used to establish tumour risk stratification. The WHOclassification recognizes theclassic medulloblastoma and fourhistological variants of medulloblastoma: anaplastic,large cell,nodulardesmoplasticandmedulloblastomawithextensive nodularity[21].Inourseries,classicmedulloblastomawasfound in 59%of the cases,desmoplastictype was foundin 8%of the cases,medulloblastomawithextensivenodularitywasreportedin
12%ofthecaseswhileanaplasticmedulloblastomawasreported intwocases.Recently, thepresenceof widespreadanaplasiaor largecellmorphologywasfoundtobeassociatedwithdecreased progression-freesurvivalandtherebywasaddedtoriskstratifica- tioncriteria[9,23,26].Inouranalysis,wewerenotabletoidentify the anaplastic type as a prognosis factor as only two cases of anaplastictumourwerereported.Nodulardesmoplastictumour has, inthecontrary,beenshown tobea favourableprognostic marker[34].Nevertheless,onceagainwecouldnotfindprognostic significationforthishistologicaltype.Sincethe1990s,riskstrat- ificationofmedulloblastomahasbeenused,andisbasedonage, metastaticstatusatdiagnosis,extentofsurgicalresection,andwide spreadanaplasiaorlargecellmorphologythathasbeenrecently added[29,35].Thisstratificationispracticallyusedasatooltoguide treatmentoptionsandalsotopredictclinicalevolution.Thislatter wasappliedtoallofourpatients;accordingly58.3%ofthepatients hadahigh-riskdisease.
Asalreadymentioned, patientsarestratifiedfortherapyinto standardandhigh-riskgroups,infact,thosetwogroupshavediffer- entprognosisandtherebyareoffereddifferentadjuvanttreatment.
Nevertheless,todate,radiationtherapyisthemostimportantadju- vant treatmentproviding cure for both groups [30,3,14,42]. All patientsincludedinthestudyreceivedadjuvantradiotherapy.For average-riskdisease,thewholebrainandspineweretreatedwith ameandoseof23.4Gy,withposteriorfossameanboostdoseof 30.6Gy tototal doseof 54Gy. Asto advanced-stage disease, a meandoseof36Gywasdeliveredtothewholebrainandspine, withaposteriorfossameanboostdoseof18Gytoatotaldoseof 54Gy.Whenindicatingadjuvantradiotherapy,themainconcern istreatment-relatedtoxicityespeciallythelatetoxicitythatmight manifestmonthstoyearsaftercompletionofirradiation.
Neuroendocrinedeficiency following craniospinal irradiation for medulloblastoma is the most known toxicity, long-term endocrinesurveillanceaftercraniospinal irradiationistherefore mandatory. Growth hormone deficiency is the most common endocrinopathyresultinginshortstature asa commonsequela
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Fig.2. Progression-freesurvivalratesofpaediatricpatientstreatedformedulloblastoma,asfunctionsofvariousfactors(N=121).a:patient’sage;b:Tstage;c:Mstage;d:
typeofchemotherapy.
[11];thistoxicitywasreportedin41.3%ofthepatients,forwhom follow-updatawasavailable.Nevertheless,only29%ofthecases receivedhormonalsupplementation,which indicateseitherthe subjectivenatureofourdataorsuboptimalintervention.Paulino etal.,intheirseriesof32patientsevaluatedthyroidfunctionafter craniospinalirradiationformedulloblastoma,andreported56%of casesdevelopinghypothyroidism[31].Inourseries,41.3%ofthe cases(N=50)developedhypothyroidism;hormonalreplacement therapywasprescribedin20cases.Secondarymalignanciesare alsoanimportantconcerninlong-termfollow-up;infact,their relativeriskfollowingradiotherapyinmedulloblastomahasbeen estimatedtobearound4.59and20,anddoesnotseemplateauor declineafter10years[37,15,2].Inourseries,secondarytumours werereportedinthreecases.
Anothermajorlateeffectofradiotherapyinmedulloblastoma is neurocognitive dysfunction; abundant data correlate medul- loblastoma’streatmentwithadeclineinneurocognitivefunction [31,27,8].Inourseries,thistoxicitywasonlydeducedfrompar- ents’observationwhichisextremelysubjective.Tests,suchasthe minimental statusTest,Hopkins VerbalLearningTestorPaced AuditorySerialAdditionTestwerenotusedinourstudytoassess neurocognitiveimpairment;thisisoneofourstudy’smajorpitfalls.
Anotherpitfallintheevaluation oflateradiotherapy-related toxicityisthehighnumberofpatientslosttofollow-up.Initially, dataof 72 patientswasmissing;we wereabletocontact only 18 patients, which left a total of 54 patientslost tofollow-up.
These patients represent 29% of the studied cohort, which we
admitishigh.Becauseoftheneurologictoxicityassociatedwith thishighdoseofradiotherapy,many ongoingtrialsareevaluat- ingthepossibilityofreducingradiationdoses;Children’sOncology GroupACNS0331,forexample,isarandomizedstudyforpatients withstandard-risk medulloblastoma,that evaluates lower dose craniospinal irradiation and a smallerboost target. SJYC07 is a risk-stratified study where patients with standard-risk medul- loblastomareceivehigh-dosemethotrexate-basedchemotherapy followedbyfocalradiationalone.Newerstudies,suchasSJMB12, offerarisk-adaptedapproachtocraniospinalradiotherapybased onmolecularsubgroup.Resultsareawaitedtochangeourpractice andtherebychanginginfants’withmedulloblastomafuture.
Meanwhile,newradiotherapytechniquesprovidemanyadvan- tages in lowering acute toxicity; in fact, intensity-modulated radiotherapy and volumetric-modulated arc therapy provide highlyconformaltargetradiationdoses,whileminimizingirradi- atedvolumesof healthytissue [17,7,10].Protontherapy is also a fascinating technique permitting better normal tissue spar- ing[39,19].Anothertechniquethatshowedpromisingresultsin preventingneurocognitiveimpairmentishyperfractionatedradio- therapy[28].
Chemotherapyisanothertreatmentmodalityusedintheadju- vant setting for medulloblastoma; in fact, many multicentric randomizedtrialsintegratedchemotherapyalongwithradiation therapy,followingsurgicalresection[39,19,28,40].Nevertheless, randomizedtrials didnotdemonstratea statisticallysignificant benefit to overall survival [25]. Fewer analyses suggested that
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