Research Article: Prognostic Role of Survivin in Bladder Cancer: A Systematic Review and Meta-Analysis

Date Published: October 18, 2013

Publisher: Public Library of Science

Author(s): Chanhoo Jeon, Myong Kim, Cheol Kwak, Hyeon Hoe Kim, Ja Hyeon Ku, Antonia Vlahou.


The objective of the present study was to conduct a systematic review and meta-analysis of published literature investigating the survivin expression and its effects on bladder cancer prognosis.

We carefully searched online Pubmed, Cochrane Library and SCOPUS database from August 1997 to May 2013.

A total of 14 articles met the eligibility criteria for this systematic review. The eligible studies included a total of 2,165 patients with a median number of 155 patients per study (range: 17–726). Of the 14 studies, nine evaluated immunohistochemistry in formalin-fixed paraffin-embedded tissue blocks. In non-muscle invasive bladder tumor, the pooled hazard ratio (HR) was statistically significant for recurrence-free survival (pooled HR, 1.81; 95% confidence interval [CI], 1.30–2.52), progression-free survival (pooled HR, 2.12; 95% CI, 1.60–2.82), cancer-specific survival (pooled HR, 2.01; 95% CI, 1.32–3.06), and overall survival (pooled HR, 1.53; 95% CI, 1.02–2.29). The overall HRs by survivin status were robust across advanced stages. When only adjusted survival data were included, statistically significant differences were identified for all survival subgroup analyses. There was no between-study heterogeneity in the effect of survivin status on the majority of meta-analyses. There was no clear evidence of publication bias in this meta-analysis.

Survivin expression indicates worse prognosis in patients with bladder cancer but the results should be interpreted with caution. It is necessary that better-designed studies with standardized assays need to provide a better conclusion about the relationship between survivin expression and the outcome of patients with bladder cancer.

Partial Text

Bladder cancer is the second most common cancer arising in the genitourinary tract [1], and is characterized by its variable prognosis. In about 70% of patients with non-muscle invasive bladder cancer, tumors recur and some of these patients will eventually show progression towards muscle invasive cancer. Tumors that are muscle invasive have a high risk of progression, despite radical cystectomy and other treatments. One of important focuses in bladder cancer research is the prediction of tumor recurrence and tumor progression. Conventional prognostic factors, like tumor stage and grade, do not accurately predict the clinical outcome of many patients with bladder cancer, because of the inherent heterogeneity of tumor biology and patient characteristics. Additional effective biomarkers are required for explaining variability of outcome in patients with bladder cancer.

Our search strategy identified 463 articles. Following deduplication, two reviewers independently screened the identified titles and abstracts. They subsequently agreed that 44 articles should be retrieved for detailed review; for these manuscripts, full texts were obtained. On careful review of study methodologies, 31 were excluded for the following reasons: 20 studies had no formal investigation of outcomes [23]–[42]. Instead, these studies assessed only the predictive ability and included the detection validity in the diagnosis of bladder cancer or based their results on association tests; seven studies provided incomplete information for HRs and 95% CIs [43]–[49]; and three studies were excluded because it contained duplicate data [9], [50], [51]. Thus, a total of 14 articles met the eligibility criteria for this systematic review [10], [11], [52]–[63]. A flow diagram of the study selection process is presented in Fig. 1.

Currently, expression of survivin is being used as a novel prognostic factor in several human neoplasms. The rationale for investigating survivin as a prognostic marker in bladder cancer is based on its ability to inhibit apoptosis, promote proliferation and enhance angiogenesis, as well as its predominantly tumor-specific expression in adult tissues. In spite of suggested pivotal role of survivin as a prognostic marker, there are relatively few studies available exploring the role of survivin in bladder cancer, and some of them are controversial. In addition, the power of most individual studies was limited, due to low sample size. To date, no meta-analysis had been undertaken for any studies evaluating survivin as a prognostic marker in bladder cancer.

In conclusion, our meta-analysis has yielded significant association between survivin expression and bladder cancer recurrence, progression, and mortality, although these findings need to be interpreted with caution. It is difficult to draw any reliable conclusion for the current meta-analysis of survivin for overall survival in bladder cancer, due to the limited number of evaluable studies. Survivin determination might help identify patients with bladder cancer at high risk of disease recurrence, progression and poor prognosis, who might benefit from closer follow-up or more aggressive therapy. However, simplified, quantitative and reproducible assays need to be developed and validated for the detection of survivin. In addition, it is rather necessary that better designed studies need to be enrolled into such kind of analysis in the future, to provide a better conclusion about the relationship between survivin expression and the outcome of patients with bladder cancer. The value of survivin for molecular staging of bladder cancer also needs to be confirmed in controlled trials involving larger number of patients with longer follow-up, before any definitive conclusions can be made.