Articles

Treatment of medulloblastoma with postoperative

chemotherapy alone: an SFOP prospective trial in
young children
Jacques Grill, Christian Sainte-Rose, Anne Jouvet, Jean-Claude Gentet, Odile Lejars, Didier Frappaz, Franois Doz, Xavier Rialland, Fabienne Pichon,
Anne-Isabelle Bertozzi, Pascal Chastagner, Dominique Couanet, Jean-Louis Habrand, Marie-Anne Raquin, Marie-Ccile Le Deley, Chantal Kalifa,
on behalf of the French Society of Paediatric Oncology (SFOP)

Summary
Background Morbidity and mortality are high in young children with medulloblastoma who receive craniospinal
radiotherapy. We aimed to assess whether adjuvant treatment with protracted chemotherapy alone could replace
radiotherapy.
Methods We enrolled 79 children aged younger than 5 years who had had surgical resection of medulloblastoma
onto a multicentre trial. Patients were treated with combination chemotherapy, which did not include methotrexate,
for more than 16 months irrespective of the extent of disease. Early postoperative imaging dened three groups:
R0M0 (no residual disease, no metastasis), R1M0 (radiological residual disease alone), and RXM (presence of
metastases). Patients who did not relapse did not receive radiotherapy. Patients who relapsed or had disease
progression received salvage treatment, which consisted of high-dose chemotherapy and stem-cell transplantation
followed by local or craniospinal radiotherapy. For children classied as R0M0, the primary endpoint was 5-year
overall survival and the secondary endpoint was 5-year progression-free survival. For children classied as R1M0 or
RXM, the primary endpoint was best radiological response and the secondary endpoints were 5-year overall
survival and 5-year progression-free survival. Analyses were done by intention to treat.
Findings Two of 15 patients classied as RXM and four of 17 patients classied as R1M0 had a complete
radiological response. 5-year progression-free survival was 29% (95% CI 1844) in the R0M0 group, 6% (127) in the
R1M0 group, and 13% (438) in the RXM group. 5-year overall survival was 73% (5984) in the R0M0 group, 41%
(2264) in the R1M0 group, and 13% (438) in the RXM group. In the R0M0 group, 5-year progression-free
survival was 41% (2658) for the 34 patients who underwent gross total resection compared with 0% for the
13 patients who had subtotal resection (relative risk 27 [1356], p=00065).
Interpretation Conventional chemotherapy alone can be used to cure children with non-metastatic medulloblastoma
who have gross total resection conrmed by early radiological assessment, but is not sufcient for treatment of those
with metastatic or incompletely resected medulloblastoma. Salvage treatment followed by posterior-fossa
radiotherapy can effectively treat local relapses or progression.

Introduction
Medulloblastoma accounts for 20% of brain tumours
during childhood, and about 50% of these tumours arise
in children younger than 5 years of age.1 Young children
do not generally survive as long as older children,2 and
neurotoxic effects are common after radiotherapy.3,4
Identication of the most effective adjuvant therapy that
has fewest treatment-related toxic effects is a difcult
challenge in this tumour type and within this age-group.
Standard treatment of medulloblastoma consists of
surgery followed by craniospinal radiotherapy with or
without chemotherapy. Since the early 1990s,
chemotherapy has been used in the management of
brain tumours in young children to defer radiotherapy
and thus improve intellectual outcome.57 In 1990, the
French Society of Paediatric Oncology (SFOP) started a
prospective trial of postoperative chemotherapy without
radiotherapy in children younger than 3 years of age
with malignant brain tumours, irrespective of tumour
http://oncology.thelancet.com Vol 6 August 2005

histology; after 1996, children aged 35 years could also

be entered in the study. Because the outcomes differ
substantially with histological diagnosis, we focus on
medulloblastoma and dene the circumstances under
which these children can be cured without craniospinal
radiotherapy.

Methods
Participants
Children younger than 5 years of age (or younger than
age 3 years before 1996) with newly diagnosed and
histologically conrmed medulloblastoma were eligible
for the study, irrespective of tumour subtype and extent.
Informed consent was obtained from the parents or
guardians of every child in accordance with guidelines of
the participating institutions. The trial was reviewed and
approved, including ethics approval, by the board of the
brain-tumour subcommittee of SFOP and by every
participating centre.

Lancet Oncol 2005; 6: 57380

See Reection and Reaction
page 541
Published online July 14, 2005
DOI:10.1016/S1470-2045(05)
70252-7
Department of Paediatric and
Adolescent Oncology
(J Grill PhD, M-A Raquin MD,
C Kalifa MD), Department of
Diagnostic Radiology
(D Couanet MD), Department of
Radiotherapy
(Prof J-L Halbrand MD), and
Department of Biostatistics
(M-C Le Deley PhD), Institute
Gustave Roussy, Villejuif,
France; Department of
Neurosurgery, Necker Hospital
for Sick Children, Paris, France
(Prof C Sainte-Rose MD);
Department of Pathology,
Wertheimer Hospital, Lyon,
France (A Jouvet MD);
Department of Paediatric
Oncology, University Hospital
Centre, Marseille, France
(J-C Gentet MD); Department of
Paediatric Haematology/
Oncology, University Hospital
Centre, Tours, France
(O Lejars MD); Department of
Paediatric Oncology, Centre
Lon Brard, Lyon, France
(D Frappaz MD); Department of
Paediatric Oncology, Curie
Institute, Paris, France
(Prof F Doz MD); Department of
Paediatric Haematology/
Oncology, University Hospital
Centre, Angers, France
(X Rialland MD); Department of
Paediatric Oncology, Centre
Oscar Lambret, Lille, France
(F Pichon MD); Department of
Paediatric Haematology/
Oncology, University Hospital
Centre, Toulouse, France
(A-I Bertozzi MD); and
Department of Paediatric
Haematology/Oncology,
University Hospital Centre,
Nancy, France
(Prof P Chastager PhD)

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Correspondence to:
Dr Jacques Grill, Department of
Paediatric and Adolescent
Oncology, Institut Gustave
Roussy, 39 rue Camille
Desmoulins, 94805 Villejuif,
France
grill@igr.fr

574

Treatment
Patients were enrolled only if they had had maximum
surgical resection unless the anatomical location of the
tumour and the patients clinical status contraindicated
extensive resection.
Chemotherapy was to begin within 1 month of surgery
and consisted of three courses given in seven cycles. In
the rst course, patients received 15 mg/kg (450 mg/m2)
carboplatin (Paraplatin, Bristol-Meyers-Squibb, France)
infused over 1 h on day 1, and 4 mg/kg (120 mg/m2)
procarbazine (Natulan, Sigma Tau, France) given orally
on days 17. In the second course given on days 22
and 23, patients received an infusion of 5 mg/kg
(150 mg/m2) etoposide (Etoposide Teva, Teva Pharma,
France) infused over 1 h on both days, and 1 mg/kg
(30 mg/m2) cisplatin (Cisplatine Merck, Merck, Merck
Gnriques, France) a day infused over 3 h with 6 mL/kg
mannitol 10% (Mannitol Aguettant, Aguettant, France)
and saline on both days. The third course, given on
day 43, consisted of 005 mg/kg (15 mg/m2) vincristine
(Vincristine Teva, Teva Pharma), given as intravenous
bolus and 50 mg/kg (1500 mg/m2) cyclophosphamide
(Endoxan, Baxter Oncology, France) infused over 1 h
with uromitexan (120% of cyclophosphamide dose;
Mesna, Baxter Oncology). Doses were calculated in
mg/kg for children aged 03 years and in mg/m2 for
children aged 35 years. Chemotherapy was
discontinued if disease progressed or unacceptable toxic
effects developed. No radiotherapy was planned after the
end of chemotherapy.
Salvage therapy (including radiotherapy) was indicated
only for disease progression or relapse during or after
the end of chemotherapy. Local relapse or progression
was to be treated with high-dose chemotherapy with
375 mg/m2 busulfan (Myleran, GlaxoSmithKline,
France) four times a day for 4 days and 300 mg/m2
thiotepa (Thiotepa, Genopharm, France) a day infused
over 2 h for 3 days, a second operation if indicated, and
involved-eld radiotherapy (two opposed lateral beams
encompassing the whole posterior fossa) at a dose of
50 Gy (one fraction of 18 Gy a day).8 Children with
metastatic relapse were treated mainly within two
consecutive pilot studies. In one study, treatment
consisted of two courses of 100 mg/m2 melphalan9
(Alkeran, GlaxoSmithKline) followed by 600 mg/m2
busulfan and 900 mg/m2 thiotepa,10 and stem-cell
transplantation after every course. This treatment was
completed with posterior-fossa radiotherapy. Treatment
in the other pilot study consisted of 100 mg/m2
melphalan, followed by 100 mg/m2 cisplatin (Cisplatine
Dakota Pharm, Dakota Pharm, France or Cisplatine
Merck, Merck Gnriques), then 100 mg/m2
melphalan, then 100 mg/m2 cisplatin, then 720 mg/m2
thiotepa, with stem-cell support after every course of
chemotherapy, followed by reduced-dose craniospinal
radiotherapy (18 Gy in children aged younger than
3 years and 24 Gy in those aged 35 years, given as one

fraction of 18 Gy a day). However, in some centres,

patients with metastatic relapse received conventional
chemotherapy (various protocols at the discretion of the
physician) and craniospinal radiotherapy at a standard
dose of 35 Gy given as one fraction of 18 Gy a day, with
a further boost of 20 Gy to the posterior fossa given as
one fraction of 18 Gy a day.

Assessment
At recruitment, four neuropathologists did histological
analyses of biopsy samples from all patients for
classication in accordance with WHO criteria. Only
patients with centrally reviewed and conrmed
medulloblastoma were included in the analysis.
All operative reports were reviewed centrally by CS-R
and JG and classied for extent of resection in
accordance with guidelines from the International
Society of Pediatric Oncology (SIOP).11 Resection was
deemed gross total if the neurosurgeon recorded no
residual tumour at the end of the operation in the
operative report. If the neurosurgeon mentioned
tumour adhesions or unresectable residual disease,
resection was classied as less than gross totaldespite
the absence of visible tumour on postoperative imaging.
The extent of disease at diagnosis was assessed by use
of spinal MRI before or after the operation and by
cytological analysis of cerebrospinal uid obtained from
spinal taps done after the operation. CT or MRI lms
were reviewed centrally by a skilled paediatric radiologist
(DC). The extent of resection was assessed by early
imaging within 3 days of surgery, and patients were
classied into three risk groups in accordance with SIOP
guidelines:11 patients with no radiological residue and no
metastasis (R0M0, standard risk); patients with
radiological residual disease but no metastasis (R1M0,
high risk of local recurrence); patients with metastatic
tumours irrespective of the presence of radiological
residual disease (RXM, metastatic high risk of
metastatic relapse).
Neuroradiological follow-up consisted of cranial MRI
every 3 months until the third year after diagnosis, then
every 6 months. The level of response was dened as
best response at any time after the start of
chemotherapy. Disease progression was dened in
accordance with SIOP guidelines11 as more than 25%
radiological progression of the tumour surface, with or
without clinical signs. Complete response was dened
as radiological decrease of 100% of the original tumour
surface at study entry; partial response was dened as
radiological decrease of at least 50% of the original
tumour surface at study entry. Complete remission was
dened as no radiological evidence of disease.
Audiographs and renal-function tests were done before
courses containing cisplatin and every 2 years after the
end of chemotherapy.
Neurodevelopmentie, psychomotor and intellectual
development, and school attendance when applicable
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Articles

was assessed by the clinician after recovery from acute

postoperative neurological decits, and then during and
after treatment. Children were also required to
complete neuropsychological assessments with the
Brunet-Lezine or Wechsler scales, which were adapted
to the age of the child.
Overall survival was estimated from the rst day of
chemotherapy until death or until the date of last followup visit for patients last seen alive. Progression-free
survival was estimated from the rst day of
chemotherapy to the time of documented progression or
relapse, or to the date of last follow-up visit for those
remaining in rst complete remission.

Study design and statistical analysis

Our study was designed as a phase II trial for patients
with evaluable disease at diagnosis, assessing RXM
and R1M0 groups separately. The primary endpoint for
these patients was the best radiological response (ie,
complete or partial) that had been recorded at any time
during chemotherapy conrmed by central review. We
estimated that this chemotherapy regimen would be
effective if 50% or more patients had a response and

ineffective if 30% or fewer had a response. Patients were

accrued by use of a Fleming two-stage phase II design.
In each group (ie, RXM and R1M0), enrolment of
15 patients was needed during the rst stage of the
study. If fewer than ve responses were recorded, no
further patients would be accrued and the treatment
would be classied as inefcient. If more than nine
responses were noted, the treatment would be classied
as effective. If the number of responses was between ve
and nine, 20 further patients were to be included. On the
basis of 35 patients, chemotherapy would be regarded as
ineffective if fewer than 16 responses were recorded and
effective if 16 responses or more were seen.12 In these
high-risk patients, secondary endpoints were 5-year
overall survival and 5-year progression-free survival.
For patients without radiological residual disease or
metastasis (ie, R0M0), the primary endpoint was 5-year
overall survival and the secondary endpoint was 5-year
progression-free survival. The study aimed to improve
overall survival compared with historical controls. The
trial was designed to show a 20% improvement in
survival with chemotherapyfrom 50% in those who do
not improve (ie, historical controls)3 to 70% in those who

93 recruited
14 excluded after histological analysis
6 diagnosed with ependymoma
8 diagnosed with teratoid
and rhabdoid tumour
79 analysed

17 R1M0

47 R0M0

14 had protocol treatment

1 had high-dose chemotherapy
and posterior-fossa radiotherapy

17 had protocol treatment

46 had protocol treatment

1 had craniospinal irradiation

4 had complete
response

14 alive in first complete

remission
13 had no radiotherapy
1 had craniospinal irradiation

15 RXM

33 relapsed and had

salvage treatment

3 relapsed

2 had complete
response

16 relapsed or progressed and

had salvage treatment

13 did not respond

13 progressed and had

salvage treatment

13 died

10 died

12 died

21 alive
18 in second complete
remission
3 alive with disease
17 had posterior-fossa
radiotherapy
4 had craniospinal irradiation

13 did not respond

1 alive in first complete

remission (did not have
radiotherapy)

6 alive in second complete

remission
6 had posterior-fossa
radiotherapy

2 alive in first complete

remission
1 did not have radiotherapy
1 had posterior-fossa
radiotherapy

0 alive

Figure 1: Participant ow

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575

Articles

Jan 1, 2005. Statistical differences in overall survival and

progression-free survival were tested by the two-tailed
log-rank test. Relative risks (RR) and 95% CI were
estimated with a Cox model.
A prognostic-factor analysis of progression-free
survival was done for all patients in the R0M0 group.
Risk factors analysed were tumour location (cerebellar
hemisphere vs vermis), residual tumour mentioned on
the operative report, and histological subtype (nondesmoplastic vs desmoplastic tumours).

100%

Overall survival (%)

80%

R0M0

60%

p00001
R1M0

40%

20%

Role of the funding source

RXM

The sponsors of the study had no role in the trial design;

in the analysis and interpretation of the data; or in the
writing of the report. The corresponding author had full
access to the data in the study and had nal
responsibility for the decision to submit for publication.

0%
0

10

Time (years)
Numbers at risk
R0M0

47

45

42

38

31

24

20

15

15

11

R1M0

17

15

10

RXM

15

Results

Figure 2: Overall survival in 79 patients allocated to treatment by risk group

do. The number of patients needed was estimated with a

one-group 2 test: 47 patients were needed for a twosided signicance level of 5% and power of 80%.
Analyses of all risk groups were by intention to treat.
Treatment results are expressed as proportion of
patients with 95% CI, estimated by use of binomial
distribution for small sample sizes.
Overall survival and progression-free survival were
estimated with the Kaplan-Meier method and
Rothmans CI. Median follow-up was estimated with the
Schemper method. The cut-off date for follow-up was
100

Overall survival (%)

80
Local relapse
or progression
60
Metastatic
relapse

40

20

0
0

3
4
5
Time from relapse (years)

Local relapse 34
or progression

25

20

18

16

15

12

14

12

11

Numbers at risk

Metastatic
relapse

Figure 3: Overall survival in patients without metastatic disease at diagnosis (ie, R0M0 and R1M0) who
relapsed after rst treatment

576

From January, 1990, to December, 2002, 93 patients

were treated according to the BBSFOP (Baby Brain
French Society of Paediatric Oncology) protocol with an
initial diagnosis of medulloblastoma in 18 centres in
France, one centre in Belgium, and one centre in the UK
(gure 1). Recruitment was stopped early for patients
classied as RXM (in 1995) and R1M0 (in 1996)
because of insufcient response.
After central review of all histological diagnoses by the
panel of neuropathologists, 14 children were excluded
from the present study (gure 1) and thus 50 boys and
29 girls with proven medulloblastoma were included in
the analysis. Of 75 medulloblastomas in which the
histological subtype could be assigned, 25 were
desmoplastic and 50 were non-desmoplastic.
The median age at diagnosis was 25 months (range
459). The median follow-up was 68 years (28135).
15 patients had metastases at diagnosis, six were stage
M1, one stage M2, and eight stage M3. In the 64 children
with non-metastatic disease, 47 patients were classied
as R0M0 (34 had gross total resection and 13 had
subtotal or partial resection), and 17 as R1M0 (ve had
gross total resection and 12 had subtotal or partial
resection). 18 children with non-metastatic disease had a
discrepancy between the operative report and the results
of early postoperative imaging: in ve patients the
neurosurgeon regarded the operation as gross total
resection, but residual disease was detected on the
radiological lms (ie, the patients were R1M0), and in
13 patients no residual disease was found on early CT
scan or MRI (ie, the patients were R0M0), whereas the
neurosurgeon had reported macroscopic residue.
In the 32 children with evaluable disease at enrolment
(ie, R1M0 and RXM), six had a complete radiological
response to the conventional-chemotherapy protocol;
there were no partial responses (gure 1). Two of 15
(13% [95% CI 240]) patients with metastases achieved a
complete response and are alive in rst complete
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Progression-free survival (%)

100

80

60
Gross total resection
40

Subtotal resection

20

p=00065

0
0

5
6
Time (years)

Gross total
resection

34

21

16

15

13

11

Subtotal
resection

13

10

10

Numbers at risk

Figure 4: Progression-free survival in R0M0 patients by extent of surgery as stated on operative report

tandem melphalan plus busulfan and thiotepa; and two

were given busulfan and thiotepa. Four children then
had posterior-fossa radiotherapy (three died and one is
alive with disease), seven had reduced-dose craniospinal
radiotherapy (four are alive and in second complete
remission), and one died before radiotherapy (toxic
death). One child received craniospinal radiotherapy
only (and died), and two had rapid progression and did
not receive any salvage chemotherapy nor radiotherapy.
3-year overall survival after metastatic relapse was 47%
(2570, gure 3). In patients with metastases (ie,
RXM) at diagnosis, none of the 13 patients who had
disease progression responded to salvage treatment.
In the 64 patients without metastases at diagnosis,
Radiotherapy-free survival at 3 years was 23% (1535)
and at 5 years was 22% (1333). Craniospinalradiotherapy-free survival at 3-years was 63% (4972)
and at 5 years was 57% (4569).
140
120
100
IQ score

remission. Four of 17 (24% [750]) patients with

radiological residual disease and no metastasis achieved
a complete response, three of whom relapsed at 10, 13,
and 14 months from diagnosis, respectively (gure 1).
5-year progression-free survival was 29% (1844) in
the R0M0 group, 6% (127) in the R1M0 group, and
13% (438) in the RXM group. All patients who had
disease progression or relapse did so within 2 years of
diagnosis, except for one patient. Median time to
progression was 17 months (range 251) in the R0M0
group, 8 months (217) in the R1M0 group, and
3 months (017) in the RXM group. Compared with
the R0M0 standard-risk group, patients with local highrisk disease were at increased risk of progression or
relapse (RR 22 [95% CI 1240]), as were those with
metastatic high-risk disease (26 [1450]; log-rank
overall comparison, p=00024).
At the time of the analysis, 17 patients in the three
groups were in rst complete remission (median followup 90 months from diagnosis [range 37163]), 24 were
in second complete remission (median follow-up
66 months from relapse or progression [15153]), and
three were alive with disease (gure 1). In the R0M0
group, 32 patients were in complete remission: 13
without radiotherapy, 15 with posterior-fossa
radiotherapy alone, and four with craniospinal
radiotherapy. Overall, 35 children died, all but two
because of disease progression. The other two children
died from delayed infection complicated by multiorgan
failure after salvage treatment.
5-year overall survival was 73% (95% CI 5984) in the
R0M0 group, 41% (2264) in the R1M0 group, and 13%
(438) in the RXM group (gure 2). Compared with
standard-risk patients, children with local high-risk
disease were at greater risk of death (RR 31 [1372]),
as were those with metastatic high-risk disease (84
[38187]; overall comparison, p00001).
62 patients had disease progression or relapse
151 months after starting chemotherapy. 16 children
(11 in the R0M0 group and ve in the R1M0 group) had
a second operation (either before chemotherapy as rst
treatment [n=9], or before [n=1] or after [n=6] high-dose
chemotherapy) for treatment of relapse; six children had
an operation after high-dose chemotherapy with
busulfan and thiotepa. In patients free of metastasis at
diagnosis (ie, in R0M0 and R1M0), the rst relapse or
progression was local in 34, local and metastatic in 12,
and metastatic alone in three. 25 of the 34 patients with
local relapse were given busulfan and thiotepa plus
stem-cell
rescue
followed
by
posterior-fossa
radiotherapy, ve were given craniospinal radiotherapy,
and four developed early progression. 3-year overall
survival after a local relapse or progression was 61%
(4576, gure 3). Of the 15 patients with metastatic
relapse, 12 were given high-dose chemotherapy: six
children were given melphalan followed by cisplatin,
melphalan, cisplatin, and thiotepa; four were given

80
60
40
20
0

12

23

34

45

56

67

Time after diagnosis (years)

Number
assessed

24

15

13

14

11

Figure 5: Intellectual outcome in patients given conventional chemotherapy

Data are median (range).

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In the R0M0 group, the only risk factor associated with

progression-free survival was the presence of residual
tumour mentioned in the operative report despite the
absence of visible residual disease on imaging
(ie, subtotal resection). 5-year progression-free survival
was 41% (2658) for the 34 patients who underwent
gross total resection compared with 0% for the
13 patients who had subtotal resection (RR 27 [1356],
p=00065; gure 4). 5-year overall survival was 79%
(6289) for patients who had gross total resection and
58% (3081) for those who had subtotal resection
(p=02322). Histological subtype (ie, desmoplastic vs
non-desmoplastic) and tumour location (cerebellar
hemisphere vs vermis) did not affect progression-free
survival (p=04290 and p=02361, respectively).
BBSFOP chemotherapy was never discontinued
because of toxic effects. In particular, no acute ototoxicity
occurred, and cisplatin courses were given to all patients
as per protocol. There were no toxic deaths during
BBSFOP chemotherapy, and the two deaths from toxic
effects occurred after salvage treatment with high-dose
chemotherapy (one early death and one from delayed
multiorgan failure). Neutropenia (05109 cells/L)
occurred in 86 (9%) of 993 courses, mainly after
receiving carboplatin and procarbazine. Six children
developed septicaemia (ve in the absence of
neutropenia). 15 children needed a platelet transfusion,
and 26 children developed anaemia that needed redblood-cell transfusion (mostly during the rst three
cycles). Eight patients had an allergic reaction caused by
procarbazine (skin rash) that led to withdrawal of the
drug, but the protocol was continued with the other
drugs; no allergy to carboplatin was recorded. No child
lost more than 10% bodyweight, and, as at Jan 1, 2005,
no second tumour had developed in this cohort.
At the last follow-up visit neurological examination was
normal in 15 of 43 children; data were missing for one
patient. 19 had cerebellar ataxia, 12 had visual decits, and
eight had oculomotor problems. No patient had hearing
loss that was of clinical importance (ie, hypoacousia).
Neurodevelopment, as reported by the clinician, was
normal in 21 children, suboptimum in 16, and severely
impaired in six of 43 long-term survivors. No radiological
signs of leucoencephalopathy were noted during followup, but transient changes in the posterior fossa were
recorded with MRI in four of 24 children given busulfan
and thiotepa followed by posterior-fossa radiotherapy.
Symptoms related to complications were uncommon, the
most noteworthy being worsening of cerebellar signs.
Overall, 99 complete neuropsychological assessments
including an intelligence-quotient (IQ) score were
available for 33 children during follow-up (mean
assessments per patient=3). Figure 5 shows median IQ
scores after diagnosis. The mean IQ score at last
measurement for every patient (median interval from
diagnosis 54 months [range 8144]) was 77 (SD 19);
14 children had an IQ score of more than 80. At last
578

measurement, the mean IQ of children given BBSFOP

chemotherapy alone was 91 (13) at a mean of 23 months
after diagnosis, compared with 72 (19) at a mean of
62 months after diagnosis in those who received highdose chemotherapy and radiotherapy after relapse. Of
17 children who had more than one assessment, 15 of
whom had had a relapse, IQ scores had increased in two,
remained stable in six, and decreased in nine between
the rst and last assessment.

Discussion
We have shown that craniospinal radiotherapy can be
omitted in rst-line treatment of young children with
localised medulloblastoma, but not in those with
metastases. Cure was possible with conventional
chemotherapy alone in children with non-metastatic
medulloblastoma who underwent gross total resection
conrmed by early radiological assessment. After local
relapse or progression, a salvage strategy based on highdose chemotherapy followed by posterior-fossa
radiotherapy was benecial, resulting in a good overall
survival.
Restriction of the role of radiotherapy in the
management of brain tumours, especially in young
children, has been the main aim of contemporary
protocols in this age-group. The potential to cure
medulloblastoma without craniospinal radiotherapy was
suggested in a pilot study,7 and two large US prospective
trials5,6 reported on selected patients who were cured by
chemotherapy without the craniospinal radiotherapy
planned by the protocol. Furthermore, ndings from the
German HIT-SKK protocol based on methotrexate
chemotherapy without radiotherapy have raised some
challenging questions.13
In the BBSFOP protocol, children who had no
postoperative radiological residual disease and no
metastasis (ie, R0M0) had a 73% 5-year survival, and
most children did not receive craniospinal radiotherapy.
These ndings are consistent with those of the HIT-SKK
study.13 Furthermore, an update of the Baby Paediatric
Oncology (POG) Group I study14 reported a 69% 5-year
overall survival in the same group of patients, although
most patients received craniospinal radiotherapy (but at
a reduced dose of 24 Gy). In the Childrens Cancer
Group (CCG) study,6 30% of the R0M0 group were alive
and disease-free at a median follow-up of 72 months.
Progression-free survival for patients with R0M0
disease is much the same as that achieved with the POG,
CCG, and BBSFOP regimens, but our study introduced
an effective salvage regimen based on high-dose
chemotherapy and posterior-fossa radiotherapy at the
time of local relapse.8 The intensive chemotherapy used
by the German group13 resulted in increased progressionfree survival compared with other studies; however, the
toxic effects of high-dose intravenous and intrathecal
methotrexate have caused concern because 19 of 23
evaluable patients had signs of leucoencephalopathy.13
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Articles

In our study, some children with local residual disease

were also cured without craniospinal radiotherapy, but at
the cost of having high-dose chemotherapy followed by
posterior-fossa radiotherapy after progression under
conventional chemotherapy. The 5-year overall survival
in our study was 41% for these children, compared with
32% in the Baby POG I study and 56% in the HIT-SKK
study. Therefore, children with metastatic disease cannot
be cured with the strategy described here, and should
probably be treated with more aggressive regimens.13,15,16
The ndings from our study enabled us to introduce a
new risk stratication that was based not only on
radiological assessment but also on the surgeons report.
Indeed, in the standard-risk group (ie, R0M0), children
who remained progression-free on BBSFOP chemotherapy alone and without radiotherapy all had no visible
residual disease mentioned in the operative report. Half
the children with a gross total resection and no
metastasis remained progression-free at 2 years. Our
study thus lends support to having a standardised
operative questionnaire, especially for strategies that try
to avoid craniospinal radiotherapy.
The neuropsychological outcome of the survivors
seems favourable compared with outcome results
achieved with standard radiotherapy in this young age
group reported in previous studies.1719 Indeed, severe
cognitive impairment has been noted in these patients,
and mean IQ scores frequently below 70 points have
been reported.3 Our results cannot be compared with
those of the HIT-SKK study in terms of cognitive
outcome because of differences in the tests used.
However, a relapse and subsequent salvage treatment
seem to have a negative effect on intellectual outcome in
our study, as shown previously.17
Whether reduced craniospinal radiotherapy at diagnosis
can improve cognitive outcomes in this age-group is
being tested in trials. In view of the known side-effects of
combination high-dose chemotherapy and radiotherapy
of the whole posterior fossa20 and the role of cerebellar
damage on cognitive outcome,21 less toxic alternatives
should be sought, including conformal radiotherapy of
the tumour bed, lowered radiotherapy doses, or both.
Changing the drugs used in high-dose chemotherapy
might not prove to be feasible, since similar radiochemotherapeutic interactions have been shown with
carboplatin and thiotepa,22 cyclophosphamide alone,23 and
thiotepa alone.24 Furthermore, adjuvant treatment is not
the only cause of impairment of neuropsychological
function, and the effect of tumour-associated and surgeryrelated damage is an important outcome measure that
should also be taken into account.21
In conclusion, this multicentre study conrms the
results of a previous German study,13 showing that
craniospinal radiotherapy might no longer be needed in
standard treatment for medulloblastoma. In selected
patients with local disease, cure can be obtained with
protracted conventional chemotherapy alone, or with
http://oncology.thelancet.com Vol 6 August 2005

high-dose chemotherapy and local radiotherapy in

patients who have relapsed disease. The cognitive
outcome associated with the strategies presented here
seems preserved in this very young population. Until
biological risk factors can be conrmed prospectively,
the neurosurgeons report is of high importance for
selection of patients who will benet from conventional
chemotherapy alone.
Contributors
J Grill reviewed the operative reports, analysed data and wrote the article;
C Sainte-Rose reviewed the operative reports; A Jouvet was in charge of
the central review panel (Arielle Lellouch Tubiana,
Marie-Madeleine Ruchoux, and Dominique Figarella-Branger);
J-C Gentet, O Lejars, D Frappaz, F Doz, X Rialland, F Pichon,
A I Bertozzi, and P Chastagner were members of the brain-tumour
subcommittee of the main SFOP referral centres and reviewed the paper;
D Couanet reviewed radiological les on behalf of the central-review
panel (Serge Braccard, Philippe Thiesse, and Sylviane Neuenschwander);
J-L Habrand designed the radiotherapy protocol for treatment of
relapses; M-A Raquin was the data manager and also did data analysis;
M-C Le Deley was the statistician; and C Kalifa designed the study.
Conict of interest
We declare no conicts of interest.
Acknowledgments
Thanks to Lorna Saint Ange for editing the article; Virginie Kieffer for
neuropsychological assessment of most patients; SFOP participating
centres not represented in the list of authors, Grard Couillaud (Dijon),
Claire Berger (Saint Etienne), Catherine Behar (Reims),
Vronique Laithier (Besanon), Jean-Paul Vannier (Rouen), Yves Perel
(Bordeaux), Christine Edan (Rennes), Franoise Mchinaud (Nantes),
Patrick Lutz (Strasbourg), Nicolas Sirvent (Nice), Franois Demeocq
(Clermont-Ferrand), Christophe Piguet (Limoges), Frdric Millot
(Poitiers), Genevive Marguerite (Montpellier), Heather MacDowell
(Liverpool), and Eric Sariban (Brussels); and Guillame De La
Bourdonnaye for statistical analysis. The study was not funded directly
but was made possible with the help of the Clinical Research Assistants
of the SFOP. Neuropsychological assessments were done with the help
from a grant of the Child Health Fund of the Johnson & Johnson
Company (Brussels, Belgium).
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