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704 Vol 8 August 2007
(103), verbal (105) IQ, and performance (non-verbal) (99)
IQ within the normal range.
There is a clear association between methotrexate and
acute and late neurotoxicity, the severity and nature of
which are dependent on the dose and mode of
administration of the drug, folinic acid rescue, and the
concomitant use of radiotherapy.39–41 Evidence of late CNS
damage by high-dose methotrexate comes from the
presence of leucoencephalopathy. Only two of our long-
term survivors had subtle white-matter changes on MRI.
Similar low incidence rates of this abnormality have been
reported by Kellie and co-workers.42 The risk factors for
leucoencephalopathy due to methotrexate include highest
doses (>10000 mg/m²) and frequent administration
(7–10 day intervals).40,41 The methotrexate dose
(8000 mg/m²) and interval (8 weeks) in our study were
less than this. The report describing the use of
intraventricular and intravenous methotrexate in children
younger than 3 years with medulloblastoma is also
reassuring as although leucoencephalopathy was detected,
its presence did not predict for worse neurocognitive
outcomes within the treatment cohort, except when
cranial radiotherapy was also used. The cognitive outcomes
were, however, worse than a normal comparative group.43
The risk of neurocognitive late effects from high-dose
methotrexate in children with brain tumours would
therefore seem to be acceptable,40,42,44 but requires
monitoring prospectively in future studies with
neuropsychological assessment. We conclude that the risk
of neurotoxicity from this protocol is acceptable given the
serious nature of the presenting clinical problem and the
multimodal therapy required for successful outcomes.
The extent of surgical resection is the most consistently
reported prognostic factor affecting both progression-
free and overall survival both in single centre,4,27,30,45 and
multi-centre studies.2,3,5 A few single-centre retrospective
studies have found no survival advantage to complete
resection.29,46,47 However, the proportion of cases in which
a complete surgical resection is obtained varies from
around 50% in most studies,2,3,27,34 to 85%.4 We have shown
that the neurosurgical assessment of the extent of surgery
more closely reflected outcome than did radiology review.
Our study showed that whilst there was an indication of a
better event-free survival for children who had a complete
resection compared with those with less complete
resection, this did not translate into an improved overall
survival. The lack of evidence for surgical resection
predicting outcome could be due to the confounding
effect of surgical toxicity compromising delivery of
effective chemotherapy, or effective chemotherapy and
stratified radiotherapy diluting out the effect of enhanced
surgical resection. There is no doubt that optimised
uncomplicated primary resection is an excellent start for
the management of childhood ependymoma.1 Whether
centralised specialist surgical centres or vigorous training
and multicentre audits can best deliver low surgical
toxicity rates in health systems is yet to be established.
The original aim of avoiding or delaying radiotherapy
in these children without compromising outcome has
been achieved. Our results confirm a role for primary
chemotherapy in young children with intracranial
ependymoma. The results reported here will contribute
further to the impetus for collaborative studies in Europe
and the US in this very young age group. The
establishment of a clinical scientific consensus on risk
stratification factors is the first, and most important, next
step. Despite these advances, the long-term outlook for
children with ependymoma remains unacceptably poor
and further therapeutic advances will only come through
a better understanding of the underlying tumour
biology.
Contributors
RGG, SW, and MWE were responsible for data analysis and data
interpretation. CW and DM undertook the statistical analysis and
interpretation. KR was the trial coordinator, and was responsible for data
management. JI and DWE undertook the central neuropathology review.
TC and WKC did the central radiological review. JP and CM did the
neurosurgical review and assessment. RG, RHAC, DAW, JP, CCB, and
LSL designed the trial. NT did the trial radiotherapy review. RG and LSL
wrote the report. SP, MWE, DAW, and LSL reviewed the report. LSL also
contributed to data assessment.
Participating centres
Coordinating centre : CCLG Data Centre, University of Leicester, UK.
Clinical centres:
Denmark: University Hospital, Copenhagen.
Eire: Our Lady’s Hospital for Sick Children, Dublin.
England: Addenbrooke’s Hospital, Cambridge; Birmingham Children’s
Hospital; Bristol Children’s Hospital; St James’ University Hospital,
Leeds; Great Ormond Street Hospital for Children, London; The Royal
Manchester Children’s Hospital; Queen’s Medical Centre, Nottingham;
Royal Victoria Infirmary, Newcastle upon Tyne; John Radcliffe Hospital,
Oxford; Sheffield Children’s Hospital; Southampton General Hospital;
Royal Marsden Hospital, Sutton.
Northern Ireland: The Royal Hospital for Sick Children, Belfast.
Scotland: Royal Hospital for Sick Children; Edinburgh.
Sweden: Queen Silvia’s Hospital for Children, Gothenburg.
The Netherlands: Emma Kinderziekenhuis, Amsterdam.
Wales: The Children’s Hospital for Wales, Cardiff.
Conflicts of interest
The authors declared no conflicts of interest.
Acknowledgments
We thank Tai Bee Choo for help with the competing risks analysis,
Charles Stiller for critical reading of the manuscript and helpful
suggestions, and Diane Gumley for data on neurocognitive outcome.
The Children’s Cancer and Leukaemia Group (CCLG) is supported by
Cancer Research-UK and this study was also funded by the Samantha
Dickson Brain Tumour Trust.
References
1 Bouffet E, Perilongo G, Canete A, Massimino M. Intracranial
ependymomas in children: a critical review of prognostic factors
and a plea for cooperation. Med Pediatr Oncol 1998; 30: 319–29.
2 Grill J, Le Deley MC, Gambarelli D, et al. Postoperative
chemotherapy without irradiation for ependymoma in children
under 5 years of age: a multicenter trial of the French Society of
Pediatric Oncology. J Clin Oncol 2001; 19: 1288–96.
3 Duffner PK, Horowitz ME, Krischer JP, et al. Postoperative
chemotherapy and delayed radiation in children less than three
years of age with malignant brain tumors. N Engl J Med 1993;
328: 1725–31.
4 Merchant TE, Mulhern RK, Krasin MJ, et al. Preliminary results
from a phase II trial of conformal radiation therapy and evaluation
of radiation-related CNS effects for pediatric patients with localized
ependymoma. J Clin Oncol 2004; 22: 3156–62.