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The lack of CSF cytology to determine M1 status in our study, although a deficiency, is probably of lesser importance than the detection of leptomeningeal deposits on MRI scanning in terms of patient outcome. This study was mainly devised to investigate whether chemotherapy can avoid or delay radiation in young children with malignant brain tumours. Assessing tumour response to chemotherapy was not a principal component of the study. It is now accepted that assessing chemotherapy response in ependymoma is a considerable challenge. Several factors can confound radiological review, for example, changes in the contrast uptake by the tumour, the use of surgicell as an adjunct to stopping tumour-bed haemorrhage, the timing of the scan, and residual anatomical abnormality after surgery. The role of more sophisticated imaging methods such as PET or magnetic resonance spectroscopy now need to be investigated. 36 The selection of drugs in this study was determined by a combination of factors predictive of tumour sensitivity and myelotoxicity to create a time-intensive schedule. Methotrexate was selected because of the high-level folate receptor expression in ependymoma cells, thereby providing a mechanism to maximise drug accumulation into the tumour. 37 The Children’s Cancer and Leukaemia Group have just initiated a phase II study investigating the single-agent activity of high-dose methotrexate in children with incompletely resected ependymoma. The group continues to use this chemotherapy protocol for children with completely resected disease, but now recommend conformal radiotherapy using multiple fields and a dose of 59·4 Gy to the tumour bed. Cisplatin doses in this study were higher than those in the SFOP protocol and vincristine was used in three of four courses of each cycle. Cisplatin ototoxicity is well recognised, but the incidence of grade IV ototoxicity in this study was reassuringly low. Future strategies to improve outcome could include the use of granulocyte-colony stimulating factor to maintain dose intensity and etoposide in combination with either cisplatin or carboplatin. Scheduling and sequencing of chemotherapy drugs could also be important, since the 14-day schedule might have acted through antiangiogenic mechanisms and the predicted cytotoxic effects. We delayed radiotherapy to avoid damaging the developing CNS at a crucial point in its maturation. This protocol began in an era in which the longitudinal follow-up of patients was not considered as crucial as it now is, and neuropsychological assessment was not an intrinsic part of this study as this cohort was recruited as part of a study seeking to establish the role of chemotherapy for children younger than 3 years with a variety of brain tumours. However, data on neuro- psychological outcome of nine children, none of whom had been irradiated, from a single UK centre treated on this protocol have recently been reported. 38 At a mean age at diagnosis of 22 months and a mean time from diagnosis of 75 months, all children had full-scale IQ

precludes strong conclusions, although immaturity and tumour biology are likely to affect outcome. Comparison of event-free survival in cohorts receiving primary radiotherapy with overall survival in those receivingprimary chemotherapy anddelayed radiotherapy when necessary can be justified since radiotherapy is used in both, but delayed or avoided in some depending on the efficacy of the primary surgery and chemotherapy. 2,23 The 3-year overall survival of 79·3% of this UK study was higher than the St Jude study (3-year progression-free survival 69·5%) 4 and higher than other primary radiotherapy studies. 24 Critical to the interpretation of this data is the proportion receiving radiotherapy and the number of patients who were not irradiated despite progression, through parental or physician choice. The approach used here for calculating cumulative incidence of radiotherapy, using the competing risks methodology, reflects more accurately the need for radiotherapy, justifying our conclusion that 42% of patients studied are true radiotherapy-free survivors. Comparisons between these relatively small studies highlight inconsistencies in methods of reporting, and the effect of tumour and patient factors such as age, histological grading, and surgical resection upon primary outcomes, making direct comparison problematic. The current international effort using meta-analysis to arrive at a clinical and scientific consensus on the optimum stratification of patients for the next era of clinical trials in this diagnostic group is therefore justified as the most important next step for testing of the next generation of treatments. 25 Consistent application of histological grading of malignant ependymomas using the WHO 2000 classification, 18 identifies classic ependymoma (grade II) and anaplastic ependymoma (grade III). Differentiation between these categories requires the recognition and interpretation of a spectrum of pathological features. In this cohort, 59 (66%) of 89 had WHO grade II histology, whilst the SFOP reported 60 (88%) of 68 as grade III. 2 Some reports, including ours, did not identify histological grade as prognostic, 3,26–30 whilst others did. 2,4,31–33 An international consensus on the interpretationof histological grade and its true value as a prognostic factor is required. Nine (10%) of 89 children in this cohort had metastatic disease, and all nine progressed. Metastatic disease has been reported in 7–12%of patientswith ependymoma. 22,26,27 Although two studies found no effect of metastatic disease on outcome, 22,27 four studies (including ours) did detect an effect. 5,26,34 Compliance with CSF cytological examination in this study was relatively poor, with results in just over 40% of cases. However, recent evidence suggests that this investigation was not helpful in predicting those patients who would subsequently have a relapse in the spinal cord. 35 The use of CSF cytology in determining outcome in ependymoma seems therefore to be limited, although a larger multicentre assessment is needed to clarify this.

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