Elsevier

The Lancet Oncology

Volume 6, Issue 9, September 2005, Pages 678-686
The Lancet Oncology

Articles
P53 as a prognostic marker for bladder cancer: a meta-analysis and review

https://doi.org/10.1016/S1470-2045(05)70315-6Get rights and content

Summary

Background

P53 is the most widely investigated molecular marker in bladder cancer. We aimed to review comprehensively the evidence for use of changes in P53 to predict bladder-cancer recurrence, progression, and mortality.

Methods

We reviewed 168 publications from 117 studies. Estimates of significance were extracted from association tests, and hazard ratios with 95% CI from actuarial curves and Cox regression analyses. A meta-analysis was done on the studies that applied Cox models.

Findings

The methods used to assess significance varied widely between studies. 27% (nine of 34) of studies that assessed the prognostic value of P53 overexpression in recurrence by use of multivariate tests showed a significant association. The corresponding values for progression and mortality were 50% (12 of 24) and 29% (ten of 35), respectively. In the studies that used Cox models, the overall risk of recurrence was 1·6 (95% CI 1·2–2·1), of progression was 3·1 (1·9–4·9), and of mortality was 1·4 (1·2–1·7). These findings could be overestimates because of publication and reporting bias.

Interpretation

After 10 years of research, evidence is not sufficient to conclude whether changes in P53 act as markers of outcome in patients with bladder cancer.

Introduction

A hallmark of bladder cancer is its variable prognosis. About 70% of superficial (Ta and T1) tumours recur, and 10–20% become invasive.1, 2, 3, 4, 5 Tumours that are invasive have a high risk of progression despite radical cystectomy and other treatments.6 Conventional prognostic factors, such as tumour stage, grade, size, and multifocality, do not accurately predict the clinical outcome of many patients with bladder cancer,1, 2, 3, 4, 5 and widespread efforts have been made to identify markers that predict recurrence and progression of the disease, response to treatment, and survival. P53 is the most frequently involved gene in cancer in human beings; its product, P53, has a fundamental role in the control of cell proliferation, apoptosis, and genetic stability.7, 8 Overexpression of P53 in the nucleus, detected by use of immunohistochemical techniques (figure 1), is commonly regarded as a surrogate marker for P53 mutation, and has been the most widely investigated molecular marker in bladder cancer in the past decade.4, 9, 10 The first important report11 which showed that P53 changes were predictive of outcome in patients with bladder cancer undergoing cystectomy was published by Esrig and colleagues in 1994.

We have done a systematic review of papers published in the past decade on changes in P53 and their effects on bladder-cancer prognosis. We aimed to: assess the quality of published studies; summarise the accuracy of changes in P53 in prediction of recurrence, progression, and mortality in patients with bladder cancer; identify factors that could affect the assessment of the prognostic role of changes in P53; and do a meta-analysis of available estimates.

Unlike previous reviews,10, 12, 13, 14, 15 we have included all identified published reports, have assessed potential sources of heterogeneity contributing to conflicting results, and applied quantitative methods to summarise data.

Section snippets

Search strategy and selection criteria

We did a systematic review of original articles published between January, 1993, and July, 2003, in English, Spanish, German, French, Italian, and Portuguese that analysed the prognostic role of P53 overexpression or P53 mutation in patients with bladder cancer. We identified 698 articles from a search of MEDLINE, CancerLit, and EMBASE databases using the keywords “P53” and “bladder neoplasms-in-human”. The number of studies was reduced to 430 by limiting the search with the keywords

Results

Of 168 studies identified, 22 were excluded because they contained duplicate data. 29 articles investigated the same cohort as analysed in an earlier report but assessed different endpoints, focused on different subgroups, or used different P53 antibodies or cut-off points, and were thus included in the review and used for specific analyses only. Webreference lists and webtables 1–6 give further information about these studies.

In all studies reporting a significant result, changes in P53 were

Discussion

Our results showed that estimates of the significance of P53 changes vary substantially between studies. Overall, meta-analysis showed that changes in P53 are weakly predictive of recurrence, progression, and mortality in bladder cancer. However, these findings should be interpreted with caution since only a few studies were eligible for inclusion in the meta-analysis.

P53 has a central role in the cellular response to many types of stress and in the maintenance of genomic stability. This

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