paediatrics Brussels 17

Articles

Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study Richard G Grundy, Sophie AWilne, Claire LWeston, Kath Robinson, Linda S Lashford, James Ironside, Tim Cox, W Kling Chong, Richard H A Campbell, Cliff C Bailey, Rao Gattamaneni, Sue Picton, Nicky Thorpe, Conor Mallucci, MartinW English, Jonathan A G Punt, David AWalker, DavidW Ellison, David Machin, for the Children’s Cancer and Leukaemia Group (formerly UKCCSG) Brain Tumour Committee Summary Background Over half of childhood intracranial ependymomas occur in children younger than 5 years. As an adjuvant treatment, radiotherapy can be effective, but has the potential to damage the child’s developing nervous system at a crucial time—with a resultant reduction in IQ and cognitive impairment, endocrinopathy, and risk of second malignancy. We aimed to assess the role of a primary chemotherapy strategy in avoiding or delaying radiotherapy in children younger than 3 years with intracranial ependymoma. Methods BetweenDecember, 1992, and April, 2003, we enrolled 89 childrenwith ependymoma whowere aged 3 years or younger at diagnosis, of whom nine had metastatic disease on pre-operative imaging. After maximal surgical resection, children received alternating blocks of myelosuppressive and non-myelosuppressive chemotherapy every 14 days for an intended duration of 1 year. Radiotherapy was withheld unless local imaging (ie, from the child’s treatment centre) showed progressive disease. Findings 50 of the 80 patients with non-metastatic disease progressed, 34 of whom were irradiated for progression. The 5-year cumulative incidence of freedom from radiotherapy for the 80 non-metastatic patients was 42% (95% CI 32–53). With a median follow-up of 6 years (range 1·5–11·3), overall survival for the non-metastatic patients at 3 years was 79·3% (95% CI 68·5–86·8) and at 5 years 63·4% (51·2–73·4). The corresponding values for event-free survival were 47·6% (36·2–58·1) and 41·8% (30·7–52·6). There was no significant difference in event-free or overall survival between complete and incomplete surgical resection, nor did survival differ according to histological grade, age at diagnosis, or site of disease. In 47 of 59 (80%) patients who progressed, relapse resulted from local control only. The median time to progression for the 59 patients who progressed was 1·6 years (range 0·1–10·2 years). The median age at irradiation of the whole group was 3·6 years (range 1·5–11·9). For the 80 non-metastatic patients, the 23 who achieved the highest relative dose intensity of chemotherapy had the highest post-chemotherapy 5-year overall survival of 76% (95% CI 46·6–91·2), compared with 52% (33·3–68·1) for the 32 patients who achieved the lowest relative dose intensity of chemotherapy. Interpretation This protocol avoided or delayed radiotherapy in a substantial proportion of children younger than 3 years without compromising survival. These results suggest, therefore, that primary chemotherapy strategies have an important role in the treatment of very young children with intracranial ependymoma. Introduction

Lancet Oncol 2007; 8: 696–705 Published Online July 20, 2007 DOI:10.1016/S1470- 2045(07)70208-5 See Reflection and Reaction page 665 Children’s BrainTumour Research Centre, University of Nottingham, Queen’s Medical

Centre, Nottingham, UK (Prof R G Grundy MBChB,

S AWilne MBBS, J A G Punt MBBS,

Prof D AWalker MBBS) ; Children’s Cancer and

Leukaemia Group, Data Centre, Leicester, UK (C LWeston MSc, K Robinson BA, L S Lashford MBBS, R H A Campbell MBChB, Prof C C Bailey MBBS, R Gattamaneni MBChB, Prof D Machin PhD) ;Western General Hospital NHSTrust, Edinburgh, UK (Prof J Ironside MBChB) ; Great Ormond Street Hospital for Children NHSTrust, London, UK (T Cox MBChB, W K Chong MBChB) ; St James Hospital NHSTrust, Leeds, UK (S Picton MBChB) ; Alder Hey Children’s Hospital, Liverpool, UK (NThorpe MBChB, C Mallucci MBChB) ; Birmingham Children’s Hospital, Birmingham, UK (MW English MBChB) ; Newcastle General Infirmary NHSTrust, Newcastle upon Tyne, UK

immature CNS to radiation damage. Although the degree of functional impairment depends on field size, radiation dose, and age at treatment, most long-term survivors have multiple problems including a global reduction in IQ and more specific cognitive defects such as short-term memory loss. 8–11 Preliminary studies suggest that conformal radiotherapy to the posterior fossa in children older than 12 months might not result in severe neurocognitive damage, at least in the short term. 4 However, there are other serious delayed effects from radiotherapy, such as neuroendocrine sequelae and second cancers which could adversely affect the child’s quality of life. 12–14 The perception of unacceptable side-effects of cranial radiotherapy in young children led a number of institutions and national groups to adopt chemotherapy-based strategies designed to avoid or delay irradiation. 2,3,5,6,15

Over half of childhood intracranial ependymomas occur in children under 5 years of age, and the effective treatment of these patients remains one of the more difficult tasks in paediatric oncology. 1 The success of any treatment strategy in this age group has to be measured not only in terms of event-free or overall survival, but also in terms of the potential for serious or irreversible damage to the developing brain. Most childhood ependymomas arise in the posterior fossa, are large, and are difficult to resect. There is general acceptance that adjuvant therapy is required even when complete resection is achieved. 2–7 Choices over adjuvant therapy are difficult, and to an extent, have depended on the underlying philosophies of national groups and institutions. Radiotherapy is effective, but its delivery is complicated by the vulnerability of an

(Prof DW Ellison MBChir) ; National Cancer Centre, Singapore (D Machin) Correspondence to:

Prof Richard Grundy, Children’s BrainTumour Research Centre, University of Nottingham,The Medical School, Queen’s Medical Centre, Nottingham NG7 2UH, UK richard.grundy@nottingham. ac.uk

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http://oncology.thelancet.com Vol 8 August 2007