Sophie Wilne

Presentation of childhood CNS tumours: a systematic review and meta-analysis

BACKGROUNDnSuspicion of a CNS tumour is classically raised by symptoms of raised intracranial pressure, focal deficits (including seizures), or papilloedema. Development of guidelines is needed for the identification and referral of children who might have a CNS tumour. We did a systematic literature review and meta-analysis to identify the clinical presentation of childhood CNS tumours to provide evidence to support the development of guidelines to assist with the identification and referral for imaging of children who might have a central nervous system tumour.nnnMETHODSnMedline, Embase, and PubMed were searched for cohort studies and case series in children, published between January, 1991, and August, 2005, detailing the symptoms and signs at diagnosis of a CNS tumour.nnnFINDINGSn74 papers (n=4171) met the inclusion criteria. 56 symptoms and signs at diagnosis were identified, ranked by frequency, and clustered according to age, anatomical criteria, and genetic criteria. The most frequent symptoms and signs at diagnosis were: headache (33%), nausea and vomiting (32%), abnormalities of gait and coordination (27%), and papilloedema (13%) for intracranial tumours; macrocephaly (41%), nausea and vomiting (30%), irritability (24%), and lethargy (21%) for children aged under 4 years with intracranial tumours; reduced visual acuity (41%), exophthalmia (16%), and optic atrophy (15%) for children with an intracranial tumour and neurofibromatosis; nausea and vomiting (75%), headache (67%), abnormal gait and coordination (60%), and papilloedema (34%) for posterior fossa tumours; unspecified symptoms and signs of raised intracranial pressure (47%), seizures (38%), and papilloedema (21%) for supratentorial tumours; headache (49%), abnormal eye movements (21%), squint (21%), and nausea and vomiting (19%) for central brain tumours; abnormal gait and coordination (78%), cranial nerve palsies (52%), pyramidal signs (33%), headache (23%), and squint (19%) for brainstem tumours; and back pain (67%), abnormalities of gait and coordination (42%), spinal deformity (39%), focal weakness (21%), and sphincter disturbance (20%) for spinal-cord tumours. Other features noted were weight loss, growth failure, and precocious puberty. Symptoms of raised intracranial pressure were absent in more than half of children with brain tumours. Other neurological features were heterogeneous and related to tumour location.nnnINTERPRETATIONnApart from raised intracranial pressure, motor and visual system abnormalities, weight loss, macrocephaly, growth failure, and precocious puberty also suggest presence of an intracranial tumour. Children with signs and symptoms that could result from a CNS tumour need a thorough visual and motor system examination and an assessment of growth and pubertal status. Occurrence of multiple symptoms and signs should alert clinicians to possible CNS tumours.

The presenting features of brain tumours: a review of 200 cases

Objective: To determine the presenting features of brain tumours in children. Design: Retrospective case note review. Setting: Paediatric and neurosurgical services at the Wessex Neurology Centre and Southampton General Hospital, UK. Patients: 200 patients presenting with a CNS tumour between 1988 and 2001. Results: The commonest first presenting symptoms were headache (41%), vomiting (12%), unsteadiness (11%), visual difficulties (10%), educational or behavioural problems (10%), and seizures (9%). The commonest symptoms occurring at any time were headache (56%), vomiting (51%), educational or behavioural problems (44%), unsteadiness (40%), and visual difficulties (38%). Neurological signs were present at diagnosis in 88%: 38% had papilloedema, 49% cranial nerve abnormalities, 48% cerebellar signs, 27% long tract signs, 11% somatosensory abnormalities, and 12% a reduced level of consciousness. The median symptom interval was 2.5 months (range 1 day to 120 months). A short symptom interval was significantly associated with high grade tumours and patient age of 3 years or younger. Conclusions: The well known predominance of headache in children with CNS tumours is confirmed. Visual, behavioural, and educational symptoms were also prominent. With the exception of seizures, every initial symptom was accompanied by other symptoms or signs by the time of diagnosis. Questions about visual symptoms and educational or behavioural difficulties, as well as the more widely recognised symptoms of raised intracranial pressure and motor dysfunction, are important in the diagnosis of brain tumours, as are vision assessment and the appropriate plotting of growth and head size.

The diagnosis of brain tumours in children: a guideline to assist healthcare professionals in the assessment of children who may have a brain tumour

Background Brain tumours are the commonest solid tumour in children. Children with brain tumours are frequently unwell for months prior to diagnosis. A prolonged period between symptom onset and diagnosis is associated with increased morbidity. Objective To develop an evidence-based clinical guideline to support healthcare professionals in the identification, assessment and investigation of children presenting with symptoms and signs that could be due to a brain tumour. Methods A systematic literature review with a meta-analysis and cohort study provided the guideline evidence base. A multi-disciplinary workshop and Delphi consensus voting were used to translate the evidence into a clinical guideline. The results of the literature review and cohort study have been previously published. Results 20 healthcare professionals and parents participated in the workshop. 77 statements were generated detailing the presenting features of childhood brain tumours, factors that could be used to discriminate brain tumours from other less serious conditions and possible referral pathways for children with brain tumours. 156 healthcare professionals agreed to participate in the Delphi process; 112 completed the first round and 88 completed all three rounds (attrition rate 21%). 64 statements reached consensus. The final guideline comprises 76 recommendations advising on the symptomatology of childhood brain tumours, assessment of children who may have a brain tumour and recommendations for selection for and timing of central nervous system imaging. Conclusion Implementation of this guideline may support clinicians in the identification and timely imaging of children with brain tumours. This may reduce the morbidity currently experienced by many children with brain tumours.

Primary postoperative chemotherapy without radiotherapy for treatment of brain tumours other than ependymoma in children under 3 years: results of the first UKCCSG/SIOP CNS 9204 trial.

BACKGROUNDnRadiotherapy is an effective adjuvant treatment for brain tumours arising in very young children, but it has the potential to damage the childs developing nervous system at a crucial time - with a resultant reduction in IQ leading to cognitive impairment, associated 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 malignant brain tumours other than ependymoma, the results of which have already been published.nnnMETHODSnNinety-seven children were enrolled between March 1993 and July 2003 and, following diagnostic review, comprised: medulloblastoma (n=31), astrocytoma (26), choroid plexus carcinoma [CPC] (15), CNS PNET (11), atypical teratoid/rhabdoid tumours [AT/RT] (6) and ineligible (6). Following maximal surgical resection, chemotherapy was delivered every 14 d for 1 year or until disease progression. Radiotherapy was withheld in the absence of progression.nnnFINDINGSnOver all diagnostic groups the cumulative progression rate was 80.9% at 5 years while the corresponding need-for-radiotherapy rate for progression was 54.6%, but both rates varied by tumour type. There was no clear relationship between chemotherapy dose intensity and outcome. Patients with medulloblastoma presented as a high-risk group, 83.9% having residual disease and/or metastases at diagnosis. For these patients, outcome was related to histology. The 5-year OS for desmoplastic/nodular medulloblastoma was 52.9% (95% confidence interval (CI): 27.6-73.0) and for classic medulloblastoma 33.3% (CI: 4.6-67.6); the 5-year EFS were 35.3% (CI: 14.5-57.0) and 33.3% (CI: 4.6-67.6), respectively. All children with large cell or anaplastic variants of medulloblastoma died within 2 years of diagnosis. The 5-year EFS for non-brainstem high-grade gliomas [HGGs] was 13.0% (CI: 2.2-33.4) and the OS was 30.9% (CI: 11.5-52.8). For CPC the 5-year OS was 26.67% (CI: 8.3-49.6) without RT. This treatment strategy was less effective for AT/RT with 3-year OS of 16.7% (CI: 0.8-51.7) and CNS PNET with 1-year OS of 9.1% (CI: 0.5-33.3).nnnINTERPRETATIONnThe outcome for very young children with brain tumours is dictated by degree of surgical resection and histological tumour type and underlying biology as an indicator of treatment sensitivity. Overall, the median age at radiotherapy was 3 years and radiotherapy was avoided in 45% of patients. Desmoplastic/nodular sub-type of medulloblastoma has a better prognosis than classic histology, despite traditional adverse clinical features of metastatic disease and incomplete surgical resection. A subgroup with HGG and CPC are long-term survivors without RT. This study highlights the differing therapeutic challenges presented by the malignant brain tumours of early childhood, the importance of surgical approaches and the need to explore individualised brain sparing approaches to the range of malignant brain tumours that present in early childhood.

Progression from first symptom to diagnosis in childhood brain tumours

This study was undertaken to investigate the evolution of clinical features between onset of symptoms and diagnosis in children with brain tumours and to identify ways of shortening the time to diagnosis. One hundred and thirty-nine children with a brain tumour were recruited from four UK paediatric neuro-oncology centres. Children had a median of one symptom or sign at symptom onset and six by diagnosis. The symptoms and/or signs experienced at symptom onset and at diagnosis were as follows: headache in 55 and 81 children, nausea and vomiting in 39 and 88 children, motor system abnormalities in 31 and 93 children, cranial nerve palsies in 24 and 75 children, visual system abnormalities in 23 and 96 children, endocrine or growth abnormalities in 10 and 35 children and behavioural change in 4 and 55 children. The median time between symptom onset and diagnosis (symptom interval) was 3.3xa0months. A longer symptom interval was associated with head tilt, cranial nerve palsies, endocrine and growth abnormalities and reduced visual acuity. More than half of children with brain tumours developed problems with vision and more than a third developed motor problems, cranial nerve palsies, behavioural change, or nausea and vomiting between symptom onset and diagnosis.

Identifying brain tumours in children and young adults

#### Summary pointsnnHealthcare professionals caring for children need to promptly identify the child or young person with a serious underlying condition from the majority who present with minor self limiting illness. Recognising when a child might have cancer can be particularly difficult. Despite the perception that cancer is rare in children, an average general practice will see a child or young person with a new cancer every six years, and a quarter of the tumours will be brain tumours (personal communication, Patricia O’Hare, 2013).1 Early diagnosis can be crucial—evidence from cohort studies shows that it can improve short term and long term outcomes.2 3 4 5 This review summarises current evidence on the presentation and recognition of brain tumours in children and young adults and provides an overview of the treatment and long term care strategies for this population.nn#### Sources and selection criteriannWe searched Medline, Embase, and the Cochrane Library for review articles. Key words were brain tumour(s), brain tumor(s), and diagnosis. Articles were restricted to …

A new clinical guideline from the Royal College of Paediatrics and Child Health with a national awareness campaign accelerates brain tumor diagnosis in UK children—“HeadSmart: Be Brain Tumour Aware”

BACKGROUNDnA national survey in 2006 identified that UK referral practice for pediatric CNS tumors ranked poorly in international comparisons, which led to new National Health Service (NHS) Evidence accredited referral guidelines published in 2008 by the Royal College of Paediatrics and Child Health and a campaign to raise awareness of early features of CNS tumors and the need for timely imaging.nnnMETHODSnThe HeadSmart: Be Brain Tumour Aware campaign was launched in June 2011 across the UK as a quality improvement strategy directed at reducing the total diagnostic interval (TDI) from a pre-campaign (2006) median of 14 (mean, 35.4) weeks to a target of 5 weeks in order to equal the best reported internationally. Professional and public awareness was measured by questionnaire surveys. TDI was collected by clinical champions in 18 regional childrens cancer centers and the public campaign was coordinated by a national charity, working with a network of community champions.nnnRESULTSnThe guidelines and campaign raised awareness among pediatricians and were associated with reduction in TDI to a median of 6.7 (mean, 21.3) weeks by May 2013. This change in referral practice was most pronounced in the time from first medical contact to CNS imaging, for which the median was reduced from 3.3 to 1.4 weeks between January 2011 and May 2013 (P = .009).nnnCONCLUSIONnThis strategy to accelerate brain tumor diagnosis by the NHS using a public and professional awareness campaign is a world first in pediatric cancer and is being emulated internationally and acknowledged by a series of NHS and charity awards for excellence.

Guidelines for the Prophylaxis of Pneumocystis jirovecii Pneumonia (PJP) in Children With Solid Tumors.

Although it is well-established that children undergoing allogeneic stem cell transplants and treatment for leukemia should be offered prophylaxis against Pneumocystis jirovecii pneumonia, the risk for children with solid malignancies is less certain. This guideline has been developed with the aim of standardizing practice and optimizing the benefit versus risk of prophylactic medication in this group of patients. P. jirovecii pneumonia has a high mortality rate even with prompt antimicrobial treatment. Since prophylaxis with co-trimoxazole is safe, effective, and inexpensive, we suggest that all children with malignancies undergoing immunosuppressive therapy are offered prophylaxis unless there are clear contraindications.

The effectiveness and safety of proton beam radiation therapy in children with malignant central nervous system (CNS) tumours: protocol for a systematic review

BackgroundThe aim of this study is to use a systematic review framework to identify and synthesise the evidence on the use of proton beam therapy (PBT) for the treatment of children with CNS tumours and where possible compare this to the use of photon radiotherapy (RT).MethodsStandard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. Twelve electronic databases have been searched, and further citation, hand searching and reference checking will be employed. Studies assessing the effects of PBT used either alone or as part of a multimodality treatment regimen in children with CNS tumours will be included. Relevant economic evaluations will also be identified. The outcomes are survival (overall, progression-free, event-free, disease-free), local and regional control rates, short- and long-term adverse events, functional status measures and quality of survival. Two reviewers will independently screen and select studies for inclusion in the review. All interventional study designs will be eligible for inclusion in the review. However, initial scoping searches indicate the evidence base is likely to be limited to case series studies, with no studies of a higher quality being identified. Quality assessment will be undertaken using pre-specified criteria and tailored to study design if applicable. Studies will be combined using a narrative synthesis, with differences in results between studies highlighted and discussed in relation to the patient population, intervention and study quality. Where appropriate, if no studies of a comparative design are identified, outcomes will be compared against a range of estimates from the literature for similar populations and treatment regimens from the best available evidence from studies that include the use of advanced conventional photon therapy.DiscussionThe evidence base for the use of PBT in children with CNS tumours is likely to be relatively sparse, highly heterogeneous and potentially of a low quality with small sample sizes. Furthermore, selection and publication biases may limit the internal and external validity of studies. However, any tentative results from the review on potential treatment effects can be used to plan better quality research studies that are of a design appropriate for outcome comparison with conventional therapy.Systematic review registrationPROSPERO CRD42015029583

G239 Validation of two risk stratification guidelines in a one year cohort of febrile admissions in paediatric oncology patients in a UK centre

Background Febrile illnesses complicate chemotherapy for cancers; selecting cases at the least risk of complications to avoid unnecessary admissions safely, is a desirable objective for the children, their families and hospital services. Aims To validate SPOG 2003 and Alexander guidelines for febrile children (one fever spike >38.5°C or two >38°C) on cancer chemotherapy in an audit dataset of febrile patients (n = 202), presenting to a primary treatment centre, recording outcome criteria including “one hour door to antibiotics time”, non-severe events (NSE) and severe events (SE) and duration of hospital stay. Results 202 children with leukaemia, solid tumours and brain tumours had febrile admissions, 60% presenting to the out of hours team. 55 of 96 (57%) neutropaenic patients (<.05 ×u2002109/L) breached the one hour door to antibiotic time, the majority (47, 85%) whilst awaiting blood results. In the neutropaenic group there were 43 (45%) NSEs and 2 (2%) SEs. In the non-neutropaenic group there were 36 (34%) NSEs and 2 (2%) SEs. The median length of stay of neutropaenic and non-neutropaenic groups were 5 (mean 3.3; range 0–28 days) and 2 days (mean 3.6; 0–16 days), respectively. In applying the Alexander and SPOG 2003 risk stratification criteria, an analysis of duration of stay was not performed, as the rules were not in use. The Alexander criteria identified three groups; low risk at admission and at 48 h (LR-LR), low risk at admission and standard risk at 48 h (LR-SR), or standard risk from presentation (SR). The SPOG 2003 rule identified low and standard risk patients between 8–24 h of admission. The results are presented (Table 1). Abstract G239 Table 1 Conclusion Neutropaenia alone is a poor discriminator for risk stratification of febrile events in this patient group. The Alexander and SPOG 2003 risk criteria for LR predicted patients without SEs. The SPOG system’s single assessment makes it applicable to the time of emergency assessment. The Alexander system lends itself to ongoing assessment of patients for early discharge. These systems would support the out of hours team in making complex judgement in this vulnerable patient group.