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http://oncology.thelancet.comVol 8 August 2007
Radiotherapy was withheld unless there was progressive
disease defined on local imaging—age did not determine
whether radiotherapy was given. For localised, non-
metastatic tumours, 50 Gy in 25 daily fractions of 2 Gy
per fraction, 5 days per week, was prescribed for the
radiologically defined macroscopic tumour plus a margin
of 2 cm. Whole neuroaxis radiotherapy was recommended
for metastatic disease: for children aged 3 years and older,
35 Gy in 21 daily fractions of 1·67 Gy per fraction was
prescribed to the whole neuroaxis. This was followed by a
boost to the primary tumour of 20 Gy in 12 daily fractions
of 1·67 Gy per fraction given to the initial tumour volume,
plus a margin of 2 cm. For infants younger than 3 years,
the whole neuroaxis dose was reduced to 25 Gy in 20 daily
fractions of 1·25 Gy per fraction. The boost dose to the
primary tumour was 20 Gy in 12 daily fractions of 1·67 Gy
per fraction (ie, as for the older children).
Assessment
Patients were staged by full neuraxis imaging,
postoperative scans (within 48 h) were recommended,
but for various reasons this was achieved in most but
not all cases. All patients underwent primary surgery
with the aim of achieving maximal surgical resection.
A complete resection was recorded when there was no
visible tumour documented by the surgeon at the end of
operation, a subtotal resection when visible tumour
remained, and a biopsy when only sufficient tumour for
diagnosis was removed. The operative notes and
postoperative scans were reviewed centrally (JAGP,
CM). Central radiological review of the extent of the
surgical resection on postoperative scans was done
according to SIOP criteria (CM, TC, WKC, RG).
17
Routine scans were requested at day 112, 224, and the
end of the chemotherapy schedule. 6-monthly post-
treatment scans were recommended. MRI scans of
children on long-term follow-up of more than 4 years
post-surgery were reviewed centrally for evidence of
leucoencephalopathy as determined by white matter
changes acting as a surrogate marker for methotrexate
neurotoxicity. Minimum criteria for this review included
T1-weighted and T2-weighted MRI scans with
gadolinium enhancement. Cerebrospinal fluid samp-
ling before chemotherapy was recommended.
Histological slides from all patients were reviewed by
DE and JI. Tumours were classified as grade II or III
according to WHO criteria.
18
Ependymoblastomas, which
are now classified with other primitive neuroectodermal
tumours, were excluded.
18
Toxicity was assessed by the
treating physician and coded in the CCLG data centre.
The UKCCSG shortened listing of National Cancer
Institute common toxicity criteria version 2.0 were
used.
Statistical analysis
Standardised
received
dose
of
chemotherapy
(SRDChemo) was calculated for each patient as the
Children weighing up to
10 kg (dose by weight)
Children weighing more than
10 kg (dose by surface area)
Course 1 (day 0)
Vincristine (IV bolus)
0·05 mg/kg
1·5 mg/m²
Carboplatin (IV over 4 h)
20 mg/kg
550 mg/m²
Course 2 (day 14)
Vincristine (IV bolus)
0·05 mg/kg
1·5 mg/m²
Methotrexate
250 mg/kg
8000 mg/m²
Folinic acid
15 mg fixed dose
15 mg fixed dose
Course 3 (day 28)
Vincristine (IV bolus)
0·05 mg/kg
1·5 mg/m²
Cyclophosphamide
50 mg/kg
1500 mg/m²
Mesna
60 mg/kg
1800 mg/m²
Course 4 (day 42)
Cisplatin (continuous infusion for
48 h)
1·3 mg/kg×2 days
80 mg/m² in two divided doses
IV=intravenous.There were seven cycles in total, each cycle was delivered over 56 days.
Table 1
: Chemotherapy schedule
Metastases at diagnosis*
No
Yes
Study population
80
9
Male sex
54
4
Younger than <1 year at diagnosis
11
3
Median age (range) in years
1·93
(0·05–3·16)
1·36
(0·24–2·25)
Infratentorial ependymoma
69
7
Supratentorial ependymoma
11
2
Central review histology as classic (II) 54
5
WHO classified as anaplastic (III)
26
4
*Based on preoperative MRI.
Table 2
: Patient characteristics at diagnosis
Number of patients (n=89)
Haematological
Grade 3
6
Grade 4
83
Renal
Grade 3
3
Grade 4
0
Audiological
Grade 3
3
Grade 4
2
Gastrointestinal
Grade 3
23
Grade 4
3
Other
Grade 3
27
Grade 4
3
Table 3
: Cumulative toxicity