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Improving survival in recurrent medulloblastoma: earlier detection, better treatment or still an impasse?

E

Bouffet1,

F

Doz2, MC DemaiIle3,

P

Tron4,

H

Roche5,

D

Plantaz6,

A

Thyss7, JL Stephan8, 0 Lejars9,

E

Sariban10,

M

BucIon"1, JM Zucker2,

M

Brunat-Mentigny1, JL Bernard12, and JC Gentet12

'Department of PaediatricOncology, Centre Leon Berard, 28,rueLaennec,69373Lyon Cedex 08,France;2Departmentof PaediatricOncology, InstitutCurie, Paris,France;3Departmentof PaediatricOncology, Centre 0. Lambret, Lille, France;4DepartmentofPaediatrics,H6pitalCharlesNicolle,Rouen,France;

5DepartmentofPaediatric Oncology,Centre ClaudiusRegaud,Toulouse,France;6Departmentof PaediatricOncology,H6pitalde laTronche,Grenoble,France;

7DepartmentofPaediatric Oncology,Centre Antoine Lacassagne, Nice,France;8Departmentof PaediatricOncology,H6pital Nord,SaintEtienne, France;

9Departmentof PaediatricHaematology-Oncology, H6pitalReineFabiola,Brussels,Belgium;'0DepartmentofPaediatrics,CHU ofTours, France;"Unitede Biostatistiques et Evaluation therapeutique, CentreLeonB6rard, Lyon, France; 12DepartmentofPaediatricOncology,H6pitalde laTimone,Marseille,France

Summary Early detection of relapse has been advocated to improve survival in children with recurrent medulloblastoma.

However,

the prognosticfactors and the longerterm outcomeof thesepatients remains unclear. Pattern ofrecurrences wereanalysedinthreeconsecutive protocols of the Societe

Frangaise

d'Oncologie Pediatrique (1985-91). A uniform surveillance programme including repeated lumbar puncturecombined withcomputerized tomography(CT)ormagneticresonanceimaging(MRI)scan wasappliedfor allregistered patients.

Forty-sixoutof 116patients had progressiveor recurrentdisease. The median timefromdiagnosisto recurrence was10.5months and 76%

relapsesoccurredduring the first2years.Seventeen patients had asymptomatic relapses thatweredetected by the surveillanceprotocol.

Forty-one patients were treated at time of progression. Twenty-three responded tosalvagetherapy and 11 achieved asecond complete remission. The median survival time afterprogression was5months(<1-41 months), and onlytwopatients remained aliveattimeof follow- up. Length of survival is primarily related tosomespecific patterns of relapse (time from diagnosistorecurrence,circumstances ofrelapse, extentofrelapse) andtotheresponsetosalvagetherapy. No evidence oflong-term benefitappearedfrom any form oftreatment.

Keywords: medulloblastoma; relapse; prognosis; salvage therapy

Survivalrateinmedulloblastomais now around 60% at 10 years (Evans et al, 1990; Baileyetal, 1995;Gentet etal, 1995). Thus, 40% of children will develop recurrent disease despite surgery, chemotherapy and radiotherapy. Theprognosis ofthese patients has in the past beendismal,withonlyanecdotal reportsdescribing prolongedsurvival after relapse (Miyagamietal, 1993;Mahoney etal,1996).Ithasbeen suggested thatearlyidentification ofrecur- rence wasassociated withalongersurvival (Mendel etal, 1996).

Overthelast years, the value ofsurveillance scanninginchildren with medulloblastoma has generated tremendous interest and controversy (Torres et al, 1994; Friedman and Kun, 1995;

Steinbok etal, 1996). There areseveral reasons whythis debate remains open.First,thepotentialbenefit of such surveillance scan- ningprogrammes hastobe balanced against its economical and psychological impact. Second, differencesin survival may reflect inherent differences in tumour aggressiveness rather than the resultof earlier detection. Finally, other independent factors may influence the outcome of children with recurrent medullo- blastoma.The aim of this study was todeterminethefactors influ- encing the lengthofsurvival in anunselected group of children registered in three consecutive cooperative protocols of the Societe Fran,aise d'OncologiePediatrique (SFOP).

Received11April1997 Revised1July1997 Accepted25September1997

Correspondenceto: EBouffet,Institute of Child Health, Bristol Royal Hospital forSickChildren, St Michael's Hill, Bristol BS2 8BJ, UK

PATIENTS AND METHODS

One-hundred and sixteen patients aged less than 20 years were registered in the M7, M8 and M9 protocols, three consecutive protocols for medulloblastoma of the SFOP. Eleven institutions participated.

All patients underwentcraniotomy with removal of as much disease as possible. The pathological diagnosis of medullo- blastomawas mandatory before initiation of the protocol. Initial staging procedure included clinical examination, review of the operative notes, cranial computerized tomography (CT) or

magneticresonanceimaging (MRI) scanatday 20 aftersurgery,

and CSF examination at day 21 attime ofmyelogram. Patients

wereclassified intwogroups:high-risk patients with either brain steminvolvement, incomplete resectionormetastasis andlow-risk patients with localized disease and complete resection. Thirty- three of the 116patients hadinitially metastatic disease.

TheM7protocol (1985-88) (Gentetetal, 1995) includedtwo coursesof the '8 in 1'regimen(Pendergrassetal, 1987)onday 8 andday 21 aftersurgery.High-dose methotrexate (12gm-2) with subsequent folinic acidrescue was given atday 35 and 42. Four additionalcoursesof'8 in1'weregivenoncemonthly afterradia- tion therapy for high-risk patients. The M8 protocol (1988-89) includedthreecoursesof'8 in1, before radiation therapy and three additionalcoursesof'8 in 1F afterradiationtherapy for high-risk

This work has been presented at the SIOP XXVII Meeting in Montevideo (October 1995).

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patients.

The M9

protocol (1989-91)

included sixcoursesof'8 in 1' followed

by

radiation

therapy

for both low-risk and

high-risk patients.

Radiationwas either initiated

during

the

chemotherapy, overlapping

with the two

high-dose

methotrexate coursesin the M7

protocol,

afterthree coursesof'8 in 1' in the M8

protocol

or after sixcoursesof '8 in1, inthe M9.Radiationwasadministered tothe cranial fieldat a

daily

dose of 1.8

Gy

withfive

weekly

frac- tions up to arecommended dose of27

Gy.

A

27-Gy

boost was

given

tothe

posterior

fossa.

Spinal

irradiationwasdeliveredwitha

posterior

field at the same

fractionation,

up to 35

Gy.

An addi- tional

10-Gy

boostwas

given locally

in thecaseof

spinal

orsupra- tentorialmetastases.

All

patients

werefollowed

clinically during

andaftertreatment.

CTor MRIscan of the head with and without administration of contrast

material,

wasobtained 2months afterthe

completion

of the

radiotherapy,

and thenevery 4months

during

thefirst2 years unless additional examinations were indicated

clinically.

The scanswerethen

repeated

at6

monthly

intervals.CSFwas exam-

ined 2 months after the

completion

of

radiotherapy,

every 2 months

during

the first year, and every 4 months

during

thesecond year.

Progression

wasdefinedasanynewlesion detected inanyof the examinations. A

complete restaging (CSF examination,

CT scan orMRI of the

brain,

and

myelogram

or MRIofthe

spinal axis)

was

performed

for

relapsing patients.

Failureswere

analysed

intwo different ways:

(a) according

tothe site into

local,

distant and combined

relapses;

and

(b) according

totheextent

they

were classifiedas 'isolated' when the

staging

revealeda

single

site of

progression,

and 'combined' in all other situations. Over this

period, guidelines

for

salvage therapy

werebasedon thecurrent SFOP

protocols,

i.e.

phase

II studies of ifosfamide or

etoposide

and

carboplatin

as described

previously (Chastagner

et

al, 1993;

Gentet et

al, 1994),

and

high-dose chemotherapy

followed

by autologous

bone marrow rescue for

responding patients. Sixty- eight patients

were treated

according

to the M7

protocol,

19

according

tothe M8 and 29

according

tothe M9.

Thirty-three

out ofthe116

patients

had

initially

metastaticdisease.

Weexamined the

following

factors for

prognostic significance:

ageat

diagnosis,

sex,initial

staging,

site of

failure,

time from

diag-

nosis to

relapse, patterns

of detection and response to salvage

therapy.

Forallthe variables

examined,

theresultsare

reported

in termsofsurvival. Survivalwasmeasuredfromthe time ofrelapse

tothe date of deathorlast

follow-up.

Survivalcurves weredrawn

using

the

Kaplan

andMeier method

(Kaplan

and

Meier,

1958).As

nearly

all

patients

died of

progression,

length ofsurvival rather than survivalwasconsidered with

regard

tostatisticalanalysis.In theunivariate

analysis

the

prognostic

factorswerecompared using the

log-rank

test. Multivariate

analysis

was

performed

usingthe Cox

proportional

hazard model. Statistical analyses were conducted

according

to the

procedure

of the BMDP package

(BMDP

Statistical

Software,

LosAngeles, CA, USA).

RESULTS

Patterns

ofrecurrences

The median

follow-up

forrecurrence-freepatientsis 102 months.

Forty-six patients

relapsed. The age and sexofpatientswith and withoutrecurrence weresimilar.Consideringthedisease extent at thetime of initial

diagnosis,

23patientshad metastaticdisease and 23hadlocalized disease.Relapses occurredwithin amedian time of315

days

from surgery, ranging from 41 days to 81 months.

Table 1 Total number of sites in 45 relapsingpatients and distribution of sites in 22patients with isolated site of relapse

Total Isolated

Local 20 10

CSF 20 4

Spinal 15 0

Supratentorial 19 8

Extraneural 3 0

Numberof occurrences 77 22

CSF, cerebrospinal fluid.

There was no significant difference between the timing ofrelapse between the threeprotocol groups. Twenty-five patients (54%) had tumour recurrence during the first year afterdiagnosis, ten(22%) duringthe second year, threeduring the third year, four during the fourth year and three later on. Overall, 76% of recurrences occurredduring the first 2 years. Six patients developed progres- sive disease during treatment. Subclinical recurrences were detected in 17patients (37%)duringsurveillanceprocedures ata median time of 15 months from diagnosis (mean 21 months, range 5-30months). Clinical recurrences occurred earlier, with a median timing of 9 months from diagnosis (mean 17.5 months, range 1.5-81 months), although this difference was not statistically significant (P = 0.41). Extensive restaging was performed in 42 out of the 46 patients, but sites ofrelapse were reported and analysed in 45 patients, three patients having had incomplete investigations (Table 1).Localrelapsewasreportedin tenpatients, distant relapsein 25 patients and local + distant in ten patients.

Twenty-two patients had isolated relapses: ten in the primary tumoursite, eightin thesupratentorialareaand four had isolated CSFrelapse. Twenty-three patientshad a combinedrelapse.This includedposteriorfossa in ten, CSF in 16, supratentorialareain

11,

spinalaxis in 15 andsystemicmetastasesinthree patients.

Treatment of relapse

Treatment attime of relapse variedaccording toeach institution, takinginto account thepotentialforresectionorreirradiation,and the wishes ofthefamily. Treatmentmodalitiesaresummarizedin Table 2. Fivepatients receivedonlysteroidsandanalgesics. Seven patients had an attempt to excisional surgery for local (four patients), supratentorial (two patients) or spinal (one patient) relapse. Eight received radiotherapy. Two patients with early progression during sandwich therapy received craniospinal radio- therapy,four had asupratentorialboost(includingtwopatients after surgical removal), onereceived a 15-Gy spinal reirradiation, and onepatient with a local relapsehad radiosurgery using 'gamma- knife'. Thirty-six patients were treated using chemotherapy.

Twenty-threeofthem(64%) receivedetoposideand carboplatin as first- or second-line salvage treatment. Other regimens included etoposide and cyclophosphamide, '8 in 1', MOPP, etoposide and cisplatin, orifosfamide. Response to chemotherapy was assessed according to theSIOP criteria (Gnekow, 1995).Eighteenpatients (50% of chemotherapy-treated patients) achieved partial or complete response with chemotherapy. Nine responding patients (two complete and seven partial responders) received high-dose chemotherapyfollowed by bone marrow rescue. Regimens for high dosechemotherapywereeitherBCNU, carboplatin and melphalan (fourpatients), etoposide,carboplatin and melphalan (three patients) oretoposideandthiotepa(twopatients).

BritishJournalofCancer

(1998) 77(8),

1321-1326 . CancerResearch

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Table 2 Treatment modalities and response tosalvagetherapyaccordingtothe type ofrecurrence(among45patientswithreportedsites)

Numberof Patients Chemotherapy Surgery Radiotherapy HDC Response(%)a

patients treated

Local 10 10 9 4 1 1 6(60)

Distant 10 8 8 1 2 4 3(37)

Local+distant 25 23 19 2 5 4 13(56)

Combined 23 20 18 1 4 4 7 (35)

Isolated 22 21 18 6 4 5 15(71)

HDC, high-dose chemotherapy. aPercentage according to the number of treated patients.

-0

e-

cc$

100 90 80 70 60 50 40 30 20 10

7 14 21 28

Timefrom relapse(months) Figure 1 Overall survival in months from time of relapse (n

Overall,among 41 patientstreated attime ofreli patients achievedasecondcompleteremission,

eigl

partial remission, and four had a transient

resp

progression-free survivalwas 11 monthsforrespoi Threepatients hadstabledisease,and 16

progressed

ment. One responding patient died of toxicity a chemotherapy.

Outcome

Forty-fourpatients died.The mediansurvival time 5 months(Figure1).Two patients remainalive,onl)

free. Thirteen patients survived over 1 year after tumour recur- rence.Among these 13patients, ten had isolated relapses: six(out of eight) with supratentorial relapse, three (out of four) with isolated CSF relapse, and one (out of ten) with local relapse.

Among theprognostic factors analysed, age, sex, initial staging and location ofrelapse (local, distant, local + distant) were not significant (Tables3 and4).The 23patientsrelapsing beyond315 daysafterdiagnosishad alongersurvival than the 23patientswith early relapses. Patients with relapses detected by surveillance scanning had a longer survival than patients with symptomatic relapse(Figure 2). Patientswithisolatedrelapsehad asignificantly 35 42 longer survival thanpatientswithcombinedrelapse(Figure 3).The

35 42

mediansurvival time for the 12patientswith either isolated CSF orisolatedsupratentorialfailures was 17.8 monthsvs4.7 months

= 46patients) for the 34 other patients (P = 0.00004). Patients with isolated relapseswere morelikelytorespondtosalvage therapy(response rate: 71% vs 35%, P = 0.03). Patients responding to salvage apse, 11(27%) therapy had a significantly better survival than non-responders.

ithad asecond Survivaltime did not differbetweencarboplatin andnon-carbo-

ionse.

Median platin-containing regimens (P=0.42).Patientstreated withhigh- nding patients. dose chemotherapy had a median survival of 14.7 months, which ddespitetreat- did not significantly differ from patients responding to conven- fter high-dose tionaltherapy(P=0.78).

Weanalysedtheeffects of clinicalparametersandtreatmentina multivariateanalysis ofthefivemostsignificant factors (i.e.time to relapse, circumstances ofrelapse, extentof

relapse,

radiation therapy and response to treatment). The extent of

relapse

and fromrelapseis response to salvage therapy were the only independent factors for (oneis disease the

prediction

ofthe

length

of survival.

Table 3 Univariate and multivariate analysis of survival according to clinical variables and treatment modalities

Univariate multivariate

analysis analysis

Variable P p

Age (<6/>6) 0.59 NS

Sex 0.30 NS

Initial staging(localized/metastatic) 0.28 NS

Timetorelapse(<315days/>315 days) 0.004 NS

Surveillancerelapse/clinical relapse 0.0008 NS

Local/distant/local+distantrelapse 0.41 NS

Isolated/combined relapse 0.003 0.0027

Treatment modality

Radiotherapy 0.02 NS

Surgery 0.08 NS

BMT 0.19 NS

Response totreatment 0.000001 <0.0001

BMT, bone marrow transplantation.

..

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Table 4 Median survival time bysubgroup

Variable Patient Median Variable Patient Median

number survival number survival

<315 days 23 10.5 >315days 23 4.5

Subclinical 17 13.7 Symptomatic 29 4.3

Isolated 22 11.6 Combined 24 4.4

RTa 8 16.5 No RTa 33 5.7

BMTb 9 14.7 Response/noBMTb 14 10.5

Respondersa 23 11.5 NR/stablea 19 4.3

t.,

1 e;

I';

0.

aOnly41patientstreated;bamong23respondingpatients.RT,radiotherapy;BMT,bonemarrowtransplantation.NR,non-responders.

.30 201

L~~~~~~~~~~~~~~~~~A

r tZ^

L. W ^ R~~~~~~~~~1

Figure2 Survival accordingtocircumstances of relapse (-) symptomatic, 29patients;(----)surveillance relapse,17patients

DISCUSSION

Several studies haveanalysed thepatternsofrelapse in medullo- blastoma (Silverman and Simpson, 1982; Wara et al, 1994).

However,littleis known about theoutcomeandthe factors influ- encing survival of relapsing patients, and most published data relate to selectedcases orpilot studies ofsalvage therapies. Our study analyses anunselectedpopulation from time ofrecurrence.

Its weakness is to analyse retrospectively patients treated in a

heterogenousway.However,nopatient withrecurrenttumourwas

excluded fromanalysis. The 6yearsfollow-upfrom last registra- tionallowssomeconclusionstobedrawn.

Themediantimefrom initialdiagnosistoprogressiondoesnot differfrom previous reportsand approaches 1 year(Evans etal, 1990; Waraet al, 1994; Bailey et al, 1995; Gentet et al, 1995).

Mostof therelapses (76%) occurred during the first 2yearsafter diagnosis. In thepresentstudy,the overall 7-yearprogression-free survival inthesethree consecutive protocols is 60%. Thismeans

that, in ourexperience, the 5-year survival of patients who are

alive recurrence-free at2years is 90%. Three relapses occurred after4 years. Similarlate recurrences have been reported previ- ously andaccountfor2-10% oftreatmentfailuresinmedulloblas- toma(Latchawetal, 1985; Lefkowitzetal, 1988). Regardless of the circumstances of detection, the disease-free time correlated positively with survival time afterrecurrence. Such aresult isin accordancewith other paediatric and adult malignancies(Elsonet

al, 1988; Grundyetal, 1989; Leivonen and Kalima, 1991).

Inourstudy, 17 (37%) of the patients had subclinical relapses detectedonsurveillance imagingorby lumbarpunctureperformed during the follow-up. This incidencerangesbetweenTorresetal

Figure 3 Survival according to the extent of the disease at time ofrelapse (-) single site of relapse, 22 patients;(----) multiplesites, 23patients

(1994) (17%) and Mendeletal(1996) (76%). This might be dueto

somedifferences in thetimingofsurveillance scanning, and the

useofdifferent procedures of surveillance suchas CTscan,MRI

scan orrepeatedlumbarpunctures. There has beensomecontro-

versyaboutthe role of surveillance scanning and guidelines for surveillance remain controversial in medulloblastoma. A gain in survival inpatients with subclinical detection has been reportedby

some authors (Friedman and Kun, 1995; Mendel et al, 1996).

However, other authorsarguethat theoutcomeisuniformlypoor

regardless of the circumstances of detection (Torres etal, 1994;

Steinbok et al, 1996). Such differences in clinical presentation have also been described in newly diagnosed medulloblastoma patients, larger tumours and seeding being associated with a

shorteronset ofsymptoms (Halperin andFriedman, 1996). This suggeststhatthe biology of thetumourmight influence theclinical presentation of relapse and its detection. In our experience, univariate analysis points outalonger survival time forpatients with subclinical relapse. However, the multivariate analysis weakens this significance andhighlights both the importance of thetypeofrelapse and theresponsetosalvagetreatment.Itisstill

not certain that surveillance scanning may benefit patients with medulloblastomaand for thesamereasons the role offollow-up CSF sampling remains debatable.

The pattern of relapse influences the outcome. Classically, relapsesaredescribedaslocal, distant and local+distantrelapses.

No difference in outcome is observed in this study using this classification. Our proposal to divide failures into isolated vs

combinedrelapses provides additional information. This is partic- ularly clear in patients with isolated CSF and supratentorial BritishJournal of Cancer (1998)77(8), 1321-1326

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.e_-

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relapses. The former all had subclinical recurrences possibly related to biological features of slowly growing tumours. The latter had relapses that might be amenable to chemotherapy, surgery oradditional radiation therapy. Thissubgroup of patients has a longer survival time and is likely to respond to salvage therapy.

Medulloblastoma has proven to bechemosensitive (Finlayand Goins, 1987).However,despiteahighresponserate, responses at time ofrelapseareoften transient. Thishas led to the assessment ofhigh-dose therapyforresponding patients using various regi- mens(Kalifaetal, 1992;Finlayetal, 1996;Mahoneyetal, 1996).

The mostpromising results concern high-dose chemotherapy in relapsing infants previously non-irradiated (Dupuis-Girod et al, 1996). Encouraging preliminary survival data have beenreported by Finlay (1996) with the use of high-dose chemotherapy in patientswith recurrentmedulloblastoma.Inthisexperience,chil- drenwith minimaltumourburden are the ones whobenefitfrom myeloablative strategies.The present series does not support the useofhigh-dose chemotherapy in the small number ofpatients treatedbythismodality. However, thisstudywas notdesignedto address this question. Survival time, although there may be a trend, does not significantly differ between patients treated with conventional therapyand high-dosechemotherapy. Moreover, in this series, candidates for high-dose chemotherapy have been selected amongresponding patients.High-dosechemotherapy still remains an experimental procedure that has yet to be shown to have any benefit over conventional chemotherapy in relapsing patients. Schedulingthat exposes tumour to moresustainedlevels ofchemotherapy mightbe ofbenefit(Ashleyetal, 1996).

Median survival time inrelapsingmedulloblastoma isshort,and only25-30% of thepatients survivemorethan 1 year. There may behopewith newapproachessuch astargetedtherapy (Kemshead etal, 1992),orgenetherapy(RaffelandCulver,1994)orsequen- tialhigh-dosechemotherapy. Ourfindingsarein agreement with Torres et al (1994), who did not find any benefit in intensive surveillance scanning. Patterns ofrelapse strongly influence the length of survival, and therole of intensive salvage therapy in prolongingsurvivalremainsdebatable. Thisquestionsthe urgency to treat patients with recurrent medulloblastoma in cooperative protocols (rather thanpilot studies forselectedpatients)inorderto clarify those patients who may benefit from aggressive salvage strategies and those for whom decent palliative care is a more valuablealternative.

ACKNOWLEDGEMENT

We areindebtedtoProfessorRossPinkerton for assistanceinthe preparation of the manuscript.

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BritishJournalofCancer(1998) 77(8), 1321-1326 0 Cancer Research

Campaign

1998

References

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