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A Systematic Review of Molecular and Biological Tumor Markers in Neuroblastoma

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A Systematic Review of Molecular and Biological Tumor Markers in Neuroblastoma 4 Vol. 10, 4–12, January 1, 2004 Clinical Cancer Research Review A Systematic Review of Molecular and Biological Tumor Markers in Neuroblastoma Richard D. Riley,1 David Heney,2 reviews in the future. In particular, collaboration of cancer David R. Jones,1 Alex J. Sutton,1 research groups is needed to enable bigger sample sizes, Paul C. Lambert,1 Keith R. Abrams,1 standardize methods of analysis and reporting, and facilitate the pooling of individual patient data. Bridget Young,3 Alan J. Wailoo,4 and Susan A. Burchill5 Introduction Departments of 1Health Sciences, 2Medical Education, University of Leicester, Leicester; 3Department of Psychology, University of Hull, Neuroblastoma is a neuroblastic tumor of the primordial Hull; 4School of Health and Related Research, University of neural crest and is the most common extracranial solid tumor of Sheffield, Sheffield; and 5Cancer Research United Kingdom Clinical childhood, comprising between 8 and 10% of all childhood Centre, St. James’s University Hospital, Leeds, United Kingdom cancers. It is an enigmatic tumor demonstrating diverse clinical and biological characteristics and behavior (1). Tumors may regress spontaneously, reflecting induction of apoptosis or dif- Abstract ferentiation, or they may exhibit extremely malignant behavior Purpose: The aim of this study was to conduct a sys- with very low cure rates. The spectrum of clinical behavior tematic review, and where possible meta-analyses, of molec- suggests that genetic, biological, and morphological features ular and biological tumor markers described in neuroblas- may be useful markers to stratify children with this disease for toma, and to establish an evidence-based perspective on the most appropriate management. Knowledge of prognostic their clinical value for the screening, diagnosis, prognosis, markers may also help understand the genesis of this disease. and monitoring of patients. Neuroblastoma is predominantly a disease of the first dec- Experimental Design: A well-defined, reproducible ade with ϳ80% of children presenting at Ͻ4 years old; median search strategy was used to identify the relevant literature age is 22 months. The incidence in the United Kingdom and the from 1966 to February 2000. United States is ϳ1 in 7000 live births, and there is slight sex Results: A total of 428 papers studying the use of 195 predominance in most series with a male-to-female ratio of different tumor markers in neuroblastoma were identified. 1.2:1. The disease accounts for 15% of all childhood cancer Small sample sizes, poor statistical reporting, large hetero- deaths, indicating the poor prognosis of many of the tumors geneity across studies (e.g., in cutoff levels), and publication (2–4). Children with stage 1, 2, or 4 s disease, or presenting in bias limited meta-analysis to the area of prognosis only; the first year of life have a good prognosis. In contrast, children MYCN, chromosome 1p, DNA index, vanillylmandelic acid: (Ն1 year of age) with stage 3 and 4 disease have 3-year survival homovanillic acid ratio, CD44, Trk-A, neuron-specific eno- rates of 50% and 15%, respectively. Most children present over lase, lactate dehydrogenase, ferritin, and multidrug resist- the age of 1 year with metastatic (stage 4) disease; this group has ance were all identified as potentially important prognostic an overall survival of 10–20% (3, 4). tools. A number of genetic and biological features have been Conclusions: This systematic review forms a knowledge investigated in recent years in an effort to improve the under- base of the tumor markers studied thus far in neuroblas- standing of the behavior of neuroblastoma and to identify tumor toma, and has identified some of the most important prog- markers that would improve cure rates by facilitating the screen- nostic markers, which should be considered in future re- ing, diagnosis, prognosis, or monitoring of patients. In particu- search and treatment strategies. Importantly, the review has lar, many prognostic studies have identified many tumor mark- also highlighted some general problems across primary tu- ers associated with overall or disease-free survival, including mor marker studies, in particular poor and heterogeneous MYCN copy number, ploidy, and deletion or loss of heterozy- reporting. These need to be addressed to allow better clinical gosity of chromosome 1p and gain of chromosome 17q. How- interpretation and enable more appropriate evidence-based ever, it has proved difficult to identify which prognostic markers are the most useful, reflecting the complex nature of the tumor and the lack of large prospective clinical outcome studies. The aim of this study was to conduct a systematic review, Received 8/23/02; revised 9/15/03; accepted 9/19/03. and where possible meta-analyses, of molecular and biological Grant support: National Health Service Health and Technology As- tumor markers described in neuroblastoma, and to establish an sessment (HTA) Program (Grant 97/15/03). The costs of publication of this article were defrayed in part by the evidence-based perspective on their clinical value for the payment of page charges. This article must therefore be hereby marked screening, diagnosis, prognosis, and monitoring of patients. This advertisement in accordance with 18 U.S.C. Section 1734 solely to should facilitate identification of the most useful tumor markers indicate this fact. for clinical management and the development of future research Requests for reprints: Richard David Riley, Department of Health Sciences, University of Leicester, 22-28 Princess Road West, Leicester, strategies by: (a) establishing the importance of the markers LE1 6TP, United Kingdom. Phone: 44-116-2525427; Fax: 44-116- studied; and (b) identifying the markers that warrant additional 2523272; E-mail: [email protected]. investigation. Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2004 American Association for Cancer Research. Clinical Cancer Research 5 Table 1 Set of keywords used in the neuroblastoma literature search of Medline, Embase, and Cancerlit A. Neuroblastoma Clinical Area Neuroblastoma Patient(s) Prognostic Ganglioneuroblastoma Child Diagnostic Ganglioneuroma Children Pediatric Prognosis Paediatric Diagnosis Screening Monitoring Infant(s) Follow-up B. Tumor marker Tumour marker(s) DOPA Homovanillic acid Tumor marker(s) Neuron-specific enolase HVA Marker(s) NSE Normetanephrine N-MYC Ferritin NM NMYC Lactate dehydrogenase Metanephrine MYCN LDH MN Tyrosine hydroxylase Ganglioside(s) 3-methoxy tyramine TH Monosialganglioside 3-MT Dopa-decarboxylase Disialoganglioside Vanillacetic acid DDC C-neu VPA Phenylethanolamine-N-methyl transferase C-myc Vanillglycol PNMT Neuropeptide(s) VG PGP9.5 Somatostatin receptors Vanillglycol acid Dopamine-␤-hydroxylase Telomerase VGA DBH CD44 Catechol acetic acid Phenylalanine Mitotic index CAA Drug resistance RT-PCR VAA MRP Dopamine Norepinephrine Tyrosine NB84 Vanilalamine 3,4-dihydroxyl phenyl alanine Noradrenaline VA 1p deletion Adrenaline Trk A DNA diploidy Vanillylmandelic acid Trk B 17q VMA Trk C 14q Epinephrine C. Psychosocial Economic Quality of life Cost Cea Anxiety Cost-effectiveness Cba Psychosocial Econ Cua Adjustment Materials and Methods A paper was included if a word from {Neuroblastoma}, a word The systematic review followed the guidelines contained in from {Tumor Marker}, and a word from {Clinical Area} were NHS Centre for Reviews and Dissemination (1996), and its included anywhere in the paper. underlying philosophy was to maintain breadth, synthesize the Three investigators independently performed the assess- evidence qualitatively, and then, only where appropriate, use ment of the papers. All three had previous experience of iden- quantitative methods, making procedures explicit and transpar- tifying relevant tumor marker literature for a systematic review ent throughout (5). and subsequent meta-analysis (6, 7). Furthermore, the second Search Strategy. The three on-line bibliographic data- investigator is a pediatric oncology consultant, with a special bases Medline, Embase, and Cancerlit were chosen as a basis for interest in neuroblastoma, and the third investigator is a trans- identifying the relevant literature from 1966 to February 2000. lational scientific research fellow, with a special interest in small An iterative procedure was used to develop an optimal search round cell cancers of childhood. Both of these investigators held strategy, which culminated in the use of three important sets of regular meetings with the first investigator about the review keywords in the strategy (Table 1). The keywords in {Neuro- process and the assessment of the literature. blastoma} related to the family of this disease, whereas those in The first investigator read the available abstract to classify {Tumor Marker} included the named markers thought a priori each paper into one of three categories: “relevant,”“uncertain,” to be potentially important. The set {Clinical Area} included or “not relevant.” The second and third investigators, who had more specific terms for the clinical use of markers in children. more background clinical knowledge in the research area, Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2004 American Association for Cancer Research. 6 A Systematic Review of Tumor Markers in Neuroblastoma checked all of the abstracts where classification was uncertain, provide an important comparative estimate of the risk of death/ and ϳ10% of the papers in each of the relevant and not relevant
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