Health Technology Assessment 2003; Vol. 7: No. 5
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1 Department of Epidemiology and Public Health, University of Leicester, UK
2 ICRF Cancer Medicine Research Unit, St James’s University Hospital, UK
3 Department of Medical Education, University of Leicester, UK
4 School of Health and Related Research, University of Sheffield, UK
5 Department of Paediatric Oncology, St James’s University Hospital, UK
* Corresponding author
The databases MEDLINE, EMBASE and CANCERLIT were searched iteratively to identify the relevant literature from 1966 to February 2000. Sets of keywords relating to tumour markers, ESFT or neuroblastoma, and clinical use were developed; papers were identified if they contained a word from each of these sets.
To be included, papers had to provide a quantitative result or tabulated individual patient data (IPD) evaluating the use of a tumour marker in ESFT or neuroblastomas, based on primary research data from humans relevant to screening, diagnosis, prognosis or monitoring. Review articles and those reporting only laboratory work, methodologies for identifying new markers, or results from animal studies were thus excluded. Histological characteristics of tumours were not included in the markers reviewed.
From papers classified as ‘relevant’, information was extracted on the tumour marker used, the clinical area of application, the age range of patients, stage of disease, whether the outcome was overall survival (OS) or disease-free survival (DFS), and the cut-off level of the marker.
Meta-analysis was performed, where possible, for those tumour markers on which three or more papers provided data. For the meta-analysis of prognostic data, estimates of the natural log of the hazard ratio (loge(HR)) and its variance were sought. Where direct estimates were not reported, indirect estimation or IPD were used to obtain an unadjusted, or if necessary, an adjusted estimate.
The ‘relevant’ papers were also screened for any results from economic or psychosocial evaluations of the clinical use of tumour markers in ESFT or neuroblastomas.
Eighty-four ‘relevant’ papers were identified which studied 70 different markers. Eighty-four papers related to diagnosis, 45 to prognosis and five to monitoring, but none to screening. Meta-analysis of the data from the diagnosis or monitoring papers was not possible because of the poor quality and reporting of data.
Meta-analysis of prognostic papers was possible but hindered by the extremely poor presentation of survival analyses. Of 132 attempts to obtain estimates of loge(HR) and its variance, only 83 proved successful. Only six of these 83 HRs were provided directly in a paper, ten had to be calculated indirectly and the remaining 67 were calculated using the IPD available.
High levels of serum lactate dehydrogenase and lack of S-100 protein expression in the tumour were significantly associated with a worse prog-nosis and an increased risk of death or disease recurrence/death. Expression of the EWSFLI type 1 fusion transcript in tumours from patients with localised disease was associated with a more favourable outcome and reduced risk of disease recurrence/death, compared with expression of other EWSETS fusion transcripts. However, these results must be treated with caution given the poor reporting problems identified.
No studies reported an economic or psychosocial evaluation, which perhaps reflects the lack of certainty about which markers show enough clinical effectiveness and importance to warrant subsequent economic/psychosocial studies.
Four hundred and twenty-eight ‘relevant’ papers were identified, which studied 195 different markers. The screening results demonstrated uncertainty as to whether population-based screening for neuroblastomas is clinically effective and cost-effective, and, if so, what is the optimal age at which to screen, and also the optimal screening strategy, that is, single stage or multistage. No meta-analysis of the data from the diagnosis or monitoring papers was performed because of the large degree of heterogeneity and inadequacy in reporting.
Thirteen tumour markers were studied in depth for their prognostic value. Of 575 occasions where levels of one of these markers were related to survival by summary statistics or IPD, only 204 successful estimates of loge(HR) and its variance were obtained because of inadequate, incomplete and inconsistent reporting. IPD were used to obtain 41 of these estimates.
Development of clinically meaningful results was difficult because of heterogeneity in the stage of disease, age of patients, marker cut-off level, outcome observed (OS or DFS), type of estimate (unadjusted or adjusted), and adjustment factors. Publication bias was also observed. Despite these problems, the following were found to be significantly associated with patients experiencing a worse outcome: amplification of the MYC-N gene; expression of diploid cells (a DNA index of 1) in the tumour; high expression of neurone-specific enolase in the tumour at diagnosis; high serum levels of lactate dehydrogenase and/or ferritin; high multidrug resistance gene-product expression in the tumour; deletion of chromosome 1p; low tumour expression of CD44 and/or TrkA; and a low urinary VMA:HVA ratio. Studies published since the start of our review indicate that chromosome 17q is an important prognostic marker, and so in retrospect we also reviewed the prognostic literature for this marker; gain of chromosome 17q was found to be associated with a worse OS and DFS.
No papers reported a psychosocial or an economic evaluation; two papers reported cost data in relation to screening but the information was of limited value. Once a tumour marker has been identified as clinically effective, the decision to use the marker in practice (e.g. for screening or monitoring) also involves the cost of its implementation and the psychological impact it has on patients; hence, it was disappointing to identify such large gaps in the literature, but this perhaps reflects the uncertainty as to which markers are indeed clinically effective.
Riley RD, Burchill SA, Abrams KR, Heney D, Lambert PC, Jones DR, et al. A systematic review and evaluation of the use of tumour markers in paediatric oncology: Ewing’s sarcoma and neuroblastoma. Health Technol Assess 2003;7(5).
The NHS R&D Health Technology Assessment (HTA) Programme was set up in 1993 to ensure that high-quality research information on the costs, effectiveness and broader impact of health technologies is produced in the most efficient way for those who use, manage and provide care in the NHS.
Initially, six HTA panels (pharmaceuticals, acute sector, primary and community care, diagnostics and imaging, population screening, methodology) helped to set the research priorities for the HTA Programme. However, during the past few years there have been a number of changes in and around NHS R&D, such as the establishment of the National Institute for Clinical Excellence (NICE) and the creation of three new research programmes: Service Delivery and Organisation (SDO); New and Emerging Applications of Technology (NEAT); and the Methodology Programme.
This has meant that the HTA panels can now focus more explicitly on health technologies (‘health technologies’ are broadly defined to include all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care) rather than settings of care. Therefore the panel structure has been redefined and replaced by three new panels: Pharmaceuticals; Therapeutic Procedures (including devices and operations); and Diagnostic Technologies and Screening.
The HTA Programme continues to commission both primary and secondary research. The HTA Commissioning Board, supported by the National Coordinating Centre for Health Technology Assessment (NCCHTA), will consider and advise the Programme Director on the best research projects to pursue in order to address the research priorities identified by the three HTA panels.
The research reported in this monograph was funded as project number 97/15/03.
The views expressed in this publication are those of the authors and not necessarily those of the HTA Programme or the Department of Health. The editors wish to emphasize that funding and publication of this research by the NHS should not be taken as implicit support for any recommendations made by the authors.
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