Elsevier

European Urology

Volume 64, Issue 1, July 2013, Pages 41-47
European Urology

Platinum Priority – Bladder Cancer
Editorial by Brant A. Inman and Michael R. Abern on pp. 48–50 of this issue
Outcomes of a Bladder Cancer Screening Program Using Home Hematuria Testing and Molecular Markers

https://doi.org/10.1016/j.eururo.2013.02.036Get rights and content

Abstract

Background

We previously reported the preliminary findings from a feasibility study of bladder cancer (BCa) screening with urinary molecular markers (Bladder Cancer Urine Marker Project [BLU-P]) that has now been terminated.

Objective

To report the final results from BLU-P to determine whether mass screening for BCa is feasible and useful.

Design, setting, and participants

BLU-P was a Dutch population-based study initiated in 2008 to evaluate BCa screening. A total of 6500 men were invited to participate in the study, 1984 (30.5%) agreed, and 1747 (88.1%) men completed the protocol and were followed for 2 yr.

Intervention

The screening protocol included home hematuria testing followed by molecular markers—nuclear matrix protein 22 (NMP22), microsatellite analysis (MA), fibroblast growth factor receptor 3 (FGFR3) mutation snapshot assay, and a custom methylation-specific (MLPA) test—to determine the need for cystoscopy.

Outcome measurements and statistical analysis

Outcomes included the number of cystoscopies and the cancer detection rate within and outside the protocol, as determined by linkage to national registries.

Results and limitations

Overall, 409 men (23.4%) tested positive for hematuria and underwent molecular testing. Current smokers (n = 295 [17%]) and past smokers (n = 998 [58%]) were significantly more likely to test positive for hematuria than nonsmokers. Seventy-one of 75 men (94.6%) with positive molecular markers underwent the recommended cystoscopy. Four BCas and one kidney tumor were detected through this sequential protocol, whereas one BCa and one kidney tumor were missed through the screening program. Limitations include the possibility of healthy subject bias.

Conclusions

For BCa screening, use of a sequential protocol with home hematuria testing followed by molecular markers substantially reduced the number of cystoscopy recommendations compared with dipstick testing alone. A sequential screening approach may help minimize unnecessary invasive follow-up testing, with very few missed cancers. Nevertheless, this mass screening program had a very low diagnostic yield in an unselected asymptomatic European male population.

Introduction

In 2012 bladder cancer (BCa) accounted for 7% of new cancer diagnoses and 3% of cancer deaths in US men [1]. Due to the high costs of monitoring and treatment, it was among the most expensive cancers in the United States and accounted for approximately $3.7 billion in 2001 [2]. BCa is also a major problem worldwide. According to data from GLOBOCAN 2008, there were 133 696 new BCa cases and 51 056 deaths in Europe [3].

Approximately one-fourth of BCas are muscle invasive at the time of diagnosis, with high rates of treatment-related morbidity as well as metastatic progression. Accordingly, there has been investigation into BCa screening, with the goal of identifying the disease at an earlier stage.

Initial studies of home dipstick testing for microhematuria found lower cancer-specific mortality among screen-detected cases compared to registry data [4], [5]. However, the positive predictive value (PPV) of home microhematuria testing as a trigger for further evaluation was 8% for urothelial carcinoma and 12.3% for any genitourinary malignancy. Traditional screening tools (eg, cystoscopy) are not adequate for population-based screening because they are invasive and are not cost-efficient [2]. In addition, the procedure may be associated with some pain or discomfort in a third of cases [6]. To reduce the number of unnecessary cystoscopies required to diagnose a single cancer, the authors suggested future studies to evaluate a sequential screening approach with dipstick testing and molecular markers [7].

Such a study, called the Bladder Cancer Urine Marker Project [BLU-P], was initiated in the Netherlands [8]. This study analyzed the feasibility and performance characteristics of BCa screening with newly developed molecular tools in an asymptomatic Dutch population. The purpose of this report is to present the final results of the BLU-P study, which has been completed.

Section snippets

Subjects, recruitment, and underlying risk factors

BLU-P was designed as a feasibility study to assess the feasibility of population-based screening for BCa on the basis of consecutive (14-d) home-based hematuria testing.

In addition, we aimed to assess the performance characteristics and feasibility of applying four urine-based molecular tests with the goal of reducing unnecessary cystoscopies; Messing et al. [4] found that up to 92% were unnecessary if positive hematuria was the only indication for cystoscopy.

At the beginning in February 2008,

Outcomes of the screening program

From a total of 6500 men invited to the study up to December 2009, 1984 (30.5%) responded that they would participate in the study and 536 responded that they would not participate. An additional 23 invitations were returned because the addressee had moved away from the area and 19 had died. An additional 50 responded that they were ineligible to participate due to a prior history of BCa (n = 40) or because they were too old (n = 10).

Of the 1984 men who agreed to participate, 1747 (88.1%) actually

Discussion

BCa screening has been studied as a possible way to decrease the frequency, morbidity, and mortality of advanced disease. Our results from the BLU-P screening study suggest that sequential screening for BCa using home dipstick testing and molecular markers is feasible but has a low diagnostic yield in an asymptomatic European population. Although the use of molecular markers reduced the number of cystoscopies performed for microhematuria evaluation, very few urothelial tumors were diagnosed in

Conclusions

A sequential BCa screening protocol of home dipstick testing followed by molecular markers substantially reduced the number of cystoscopy recommendations compared with dipstick testing alone and had very few missed cancers. However, this mass screening program was not useful in an unselected asymptomatic European male population. This finding might be explained in part by a lower frequency of risk factors in our population. Additional study is warranted to evaluate the performance of a two-tier

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