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Oncology and haematology

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G129 EARLY COGNITIVE OUTCOME IN CHILDREN TREATED FOR BRAIN TUMOURS IN COMPARISON WITH MATCHED NORMAL CONTROLS

R. Shortman1, R. J. McCarter1, A. Penn2, S. Lowis2, M. Stevens2, A. Curran1, P. M. Sharples2.1Frenchay Hospital, Bristol, UK; 2Bristol Royal Hospital for Children, Bristol, UK

Introduction: Brain tumours are the second most common childhood malignancy. There is evidence that cognitive function is reduced in long term brain tumour survivors but few data exist concerning early outcome. The relative contributions of tumour, surgery, and radiotherapy/chemotherapy to cognitive outcome remain to be defined.

Aims: To measure cognitive outcome in children with brain tumours one month after diagnosis.

Design Methods: Longitudinal prospective study of children with brain tumours admitted to the Regional Neuroscience Centre compared with normal children matched for age, sex, and socioeconomic status. Intellectual outcome was assessed using the Wechsler Intelligence Scale for Children (WISC III UK), the Wechsler Primary and Preschool Scale of Intelligence – Revised. Attention was assessed using the Test of Everyday Attention (TEACh). Memory was assessed using the Children’s Memory Scales (CMS). Academic status was assessed using the Wechsler Quicktest.

Results: Twenty two tumour patients and 22 matched controls have been studied to date. The mean age was 10.7 years, range 3.8–16.73; 12 were boys, 10 girls. There were significant differences between tumour patients and controls with respect to Processing Speed Index of WISC (p 0.002), selective attention (Sky Search, p 0.019), the general memory scale of the CMS (p 0.046), and the Wechsler Quicktest Composite score (p 0.025). There were no significant differences between tumour patients and controls with regard to verbal IQ (VIQ) (p 0.063), performance IQ (PIQ) (p 0.132), or other aspects of cognitive function.

Conclusion: Children newly diagnosed with brain tumours have significant impairments in cognitive function that could negatively impact on their performance in the school setting and appear to be due to the tumour and surgery. Follow up of these patients will permit the contribution of radiotherapy/chemotherapy to long term cognitive outcome to be defined.

G130 SECOND MALIGNANT NEOPLASMS AFTER CHILDHOOD HODGKIN’S DISEASE DIAGNOSED IN THE UK BETWEEN 1951 AND 1997

S. J. Passmore1, P. A. Brownbill1, A. Bayne1, M. M. Hawkins2, C. A. Stiller1.1Childhood Cancer Research Group, Oxford, UK; 2Centre for Childhood Cancer Survivor Studies, Birmingham, UK

Aims: To describe the range of second malignant neoplasms occurring after treatment for childhood Hodgkin’s disease and to estimate the risk of their occurrence and survival thereafter.

Methods: The National Registry of Childhood Tumours (NRCT) was searched for cases of Hodgkin’s disease diagnosed in Great Britain at age <15 years between 1951 and 1997. Sources for the diagnosis of a second tumour were: cancer registries, death certificates, UK Children’s Cancer Study Group, and British Childhood Cancer Survivor Study. Survivors were followed up for second cancer to the end of 2001. Diagnoses were verified from histology reports and by pathology review where material was available. Non-malignant intracranial and intraspinal tumours were counted as second cancers but non-melanoma skin cancer was excluded. Standardised incidence ratios (SIRs) were calculated as the ratio of observed numbers of second malignancies to expected numbers based on national registration data assuming the same age sex and calendar period.

Results: The series included 2155 patients with Hodgkin’s disease, of whom 2042 were on the population based NRCT data for 1962 onwards and 113 were 3 year survivors diagnosed before 1962. There were 1489 boys and 666 girls; 87 second tumours were identified, 54 in males and 33 in females. The most numerous types of second tumour were: breast (n =  13), CNS (n = 7), leukaemia (n = 10), thyroid (n = 8), soft tissue sarcoma (STS) (n = 9), non-Hodgkin’s lymphoma (NHL) (n = 7), bone tumours (n = 8), malignant melanoma (n = 6), and digestive system tumours (n = 10). The SIRs for these tumour groups are: breast 10.0 (CI 5.3 to 17), CNS 6.0 (CI 2.4 to 12.4.), leukaemia 12.4 (CI 5.9 to 22.8), thyroid 45.1 (CI 19.4 to 88.9), soft tissue sarcoma 39.1 (CI 17.9 to 74.1), non-Hodgkin’s lymphoma 9.4 (CI 3.6 to 18.5), bone 34.8 (CI 15.1 to 69.0), melanoma 8.5 (CI 3.1 to 18.5), and digestive 8.9 (CI 4.3 to 16.4). 73 of the 87 had radiotherapy as part or all of their treatment, 7 definitely had no radiotherapy, and 7 cases treatment type is unclear. 10 year survival after diagnosis of second tumour was 31% (SE 7%) for males and 60% (SE 10%) for females.

Conclusions: All who care for these young people need to be aware of the risks of second tumours, particularly if therapy has included radiation.

G131 HEPATIC FIBROSIS ASSOCIATED WITH 6-THIOGUANINE THERAPY FOR ACUTE LYMPHOBLASTIC LEUKAEMIA

M. J. Murray, G. Noble-Jamieson, D. M. Williams, M. Gattens, J. C. Nicholson.Addenbrooke’s Hospital, Cambridge, UK

Background: The MRC ALL 97 trial for treatment of childhood acute lymphoblastic leukaemia randomised patients to receive either 6-thioguanine (6-TG) or 6-mercaptopurine (6-MP) as their maintenance thiopurine. Reversible veno-occlusive disease secondary to use of 6-TG in this clinical setting has previously been reported. More recently, concern has arisen about the development of chronic hepatotoxicity leading to portal hypertension, also associated with the use of 6-TG.

Methods: We identified two patients during their maintenance 6-TG therapy who had persistent splenomegaly and a degree of thrombocytopenia that was discordant with the severity of neutropenia. To identify other similar patients, we retrospectively analysed the case notes of all children treated on the MRC acute lymphoblastic leukaemia 97 protocol at our centre, prior to the close of thiopurine randomisation on 1 June 2002.

Results: In total we identified four male patients (median age at diagnosis 9.1 years, range 5–14 years) who developed thrombocytopenia, splenomegaly, mild elevation of liver transaminases, and abnormal hepatic parenchymal echogenicity on ultrasound examination. All four patients had received 6-TG as part of their maintenance chemotherapy. In three patients these findings occurred during treatment (10, 12, and 15 months into maintenance) and in one 5 months off treatment. As these features persisted, referral to the hepatology service was arranged where other causes of chronic liver disease were excluded. Two patients have proceeded to liver biopsy at 16 and 32 months after the complication was first recognised. The histology in both showed severe fibrosis consistent with incomplete cirrhosis. One of these patients also underwent endoscopy, which revealed oesophageal and gastric varices, for which he is receiving propranolol therapy. These findings have not previously been reported. Follow up at a median of 30 months (range 26–46 months) in all four patients demonstrate persisting portal hypertension.

Conclusion: We have identified a group of patients who have developed chronic liver disease with portal hypertension following 6-TG therapy for acute lymphoblastic leukaemia. Two of our patients have histologically proven incomplete cirrhosis, one of whom has varices. Paediatricians involved in the follow up of patients treated with 6-TG must be aware of this potential complication of therapy. Patients presenting with unexplained splenomegaly and/or thrombocytopenia should be referred to the hepatology service for further assessment. Close follow up will be essential in these patients to monitor for development of life threatening complications such as oesophageal varices.

G132 FEBRILE NEUTROPENIA MANAGEMENT IN THE UK?

S. Humphrey, S. Parke, P. McMaster.University Hospital North Staffordshire, Staffordshire, UK

Aims: We reviewed the management of febrile neutropenia across the 22 UKCCSG (UK Childhood Cancer Services Group) centres to see how comparable practice was.

Methods: A telephone survey was carried out and a member of staff on the oncology unit, who knew about their local policy, was asked questions following a set pro forma. Information was collected regarding the unit’s definition of febrile neutropenia, which first and second line antibiotics they used, the time at which they were introduced, the use of antifungals, and what their discharge criteria were.

Results: There was wide variation among the UKCCSG centres: not only in what antibiotics they used, but also in how they defined febrile neutropenia. Sixteen centres defined neutropenia as a neutrophil count less than 1.0×109/l with the remaining six using a count of less than 0.5×109/l. Many centres used two separate definitions depending on the magnitude of the temperature and the number of times recorded. A wide variety of first line antibiotics were used, with the majority of the centres using two first line antibiotics as opposed to monotherapy. Fifteen centres used an aminogylocoside in combination with a broad spectrum antibiotic. Six centres used teicoplanin first line if there was suspicion of CVL infection or a previously documented coagulase negative staphylococcal (CoNS) infection. There was variation in the timing of the introduction or substitution of second line antibiotics. Fourteen centres added in teicoplanin. The change happened at around 48 hours in the majority of centres. Teicoplanin was the preferred option for treating proven or potential CVL infections.

Conclusion: It is time to produce an optimal national, standardised approach to paediatric oncology supportive management of febrile neutropenia.

G133 AUDIT OF KNOWLEDGE OF ASPECTS OF TRANSFUSION AMONG PAEDIATRIC ONCOLOGY HEALTHCARE PROVIDERS

A. R. Rama, N. M. Rao, R. Phillips, S. Picton.St James University Hospital, Leeds, UK

Aims: The commonest errors reported in the serious hazard of transfusion in 2003–04 were the failure to request irradiated blood appropriately. To assess the knowledge of healthcare staff (doctors and nurses) who look after children and young adults with malignant or haematological disease with regard to their knowledge of local guidelines relating to transfusion. In view of the risk of transfusion associated graft v host disease, the need for irradiated blood products in certain groups of patients was specifically addressed.

Methods: Questionnaire survey of nurses and doctors working in, or covering while on-call, the paediatric oncology and haematology departments.

Results: Fifty three people responded to the survey (16 doctors and 37 nurses). Overall knowledge of indications for blood product transfusion, volumes to be transfused, and indications for irradiated and/or CMV negative products were good. Specific areas of concern were: 40% of people were not aware that patients’ with Hodgkin’s disease should receive irradiated blood products, and 15% did not recognise fludarabine (in FLAG) as a further indication for irradiated products. Nurses scored better than doctors in questions related to indications for platelet transfusion and volumes of platelets required in each age group.

Conclusion: The need to provide a first class service with maximum safety at minimum distance from the patient’s home recommended in the draft NICE guidance on paediatric cancer care. Adding this to the potentially decreasing pool of blood products with the advent of further vCJD precautions means we should be striving to use all products correctly and sparingly. Most people’s knowledge is good, but to avoid serious complications and maximise the use of rare products we need to continue to improve the education of our healthcare staff. The recommendation is that prescription and ordering of blood products can be developed as an extended nursing care.

G134 INFANT EPENDYMOMA: THE UKCCSG EXPERIENCE

R. G. Grundy, C. Weston, K. Robinson, S. Wilne, J. Ironsides, D. Ellison, K. Chung, T. Cox, R. H. A. Campbell, R. Gattamaneni, J. Punt, C. C. Bailey, D. Walker, L. S. Lashford.UKCCSG, Leicester, UK

Introduction: The unacceptable late effects of cranial radiotherapy in young children led to the adoption of chemotherapy based strategies designed to avoid/delay irradiation. The UKCCSG “baby brain” protocol commenced in 1992 and was open to all histological types of brain tumour occurring in children under 3 years of age at diagnosis. The chemotherapy strategy involved alternating blocks of myelo- and non-myelosuppressive chemotherapy given every 14 days for an intended duration of 378 weeks.

Aims: To examine the outcome of infants with ependymoma treated on this protocol.

Patients and Methods: Eighty eight children with a histological diagnosis of ependymoma were treated. Median age at diagnosis was 1.85 years (range 0.24–3.16). 75 tumours were infratentorial, 50% of patients had residual disease before starting chemotherapy, and 11% had metastatic disease. 53% of children completed 1 year of chemotherapy; 14 progressed on therapy, 2 of whom underwent biopsy alone. 50% had imageable residual disease at completion of therapy; four were electively irradiated.

Results: With a median follow up of 68 months (range 1–34), overall survival at 5 years was 59.1% (95% CI 47.7 to 70.5) and 5 year event free survival was 36.9% (26.3 to 47.6). Relapse predominantly resulted from failure of local control. Complete resection conferred a survival advantage for event free survival (p 0.0319) with 5 year event free survival of 48.3% (95% CI 33.0 to 63.6) compared with event free survival of 25.3% (95% CI 11.2 to 39.3) for incomplete resection. There was a difference in overall survival according to resection with overall survival of 65.2% (95% CI 49.4 to 81.0) for complete resection and 52.5% (95% CI 36.2 to 68.8) for incomplete resection, but this was not formally statistically significant (p 0.1274).

Conclusion: The 5 year radiotherapy free survival was 39.7% (95% CI 28.9 to 50.5). 41% of the cohort remains alive without radiotherapy. Furthermore, the relatively low rate (16%) of progression on chemotherapy and a high overall event free survival of 60% at 2 years (95% CI 49.8 to 70.3) suggests that this protocol has particular merit for ependymoma and represents the best results published for a chemotherapy based strategy in this disease. This may relate to the dose intensity of platinum agents and/or the use of high dose methotrexate. However, children with post surgical residual disease fare badly, forming a high risk group for which new strategies based on international collaboration are now required.

G135 RESEARCH INTO RARE DISEASES: THE NIKOLAS SYMPOSIUM MODEL

J. Pritchard, R. Arceci, R. M. Egeler, P. C. L. Beverley, P. Kontoyannis.Royal Hospital for Sick Children, Edinburgh, UK

Aims: A better understanding of rare diseases, variously defined as a prevalence of 1–7.5 new cases per 10 000 children per annum, often provides insights into pathogenesis and relevant normal physiology, but research funding is a scarce commodity. We have devised an effective way of investigating rare disorders and promoting research, at a modest cost.

Method: The Nikolas symposium, named after an infant patient with Langerhans’ cell histiocytosis (LCH), was set up in 1989. These “think tank” meetings are held annually. A core scientific committee is charged with determining the topic for each symposium and identifying 10–12 scientific leaders in that field. Six to eight clinicians also attend and a clinical session, attended by the families of difficult cases, is especially motivating to the participating basic scientists.

Results: Some conclusions from work initiated at the symposium include: (a) identification of LCH as a proliferative’ disease of abnormal Langerhans cells (LCH cells); (b) demonstration that LCH cells in lesional tissue are monoclonal (cancer-like); (c) confirmation that a cytokine storm, particularly involving GM-CSF, IL-2, and TNFα, is responsible for the inflammatory component of lesions and the scarring (fibrosis and gliosis) is seen in 50% of long term survivors; (d) that anti-CD1a antibodies successfully target disease and have potential for therapy; (e) the need for epidemiological research, such as the current BPSU LCH study; and (f) the probability that there are one or more LCH genes. The cost of the symposium is around £27 000 per annum and is provided by Nikolas’ family. Much research is devised, outsourced, and completed, so in business terms the symposium is an extremely cost effective vehicle.

Conclusions: The Nikolas symposium model provides an effective and economic way to investigate orphan diseases. Basic scientists often get hooked into studying conditions that they might otherwise never even have heard of.

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