Seminar article
Considerations on implementing diagnostic markers into clinical decision making in bladder cancer☆

https://doi.org/10.1016/j.urolonc.2009.11.004Get rights and content

Abstract

Bladder cancer is a common disease that is often detected late and has a high rate of recurrence and progression. Cystoscopy is the main tool in detection and surveillance of bladder cancer but is invasive and can miss some cancers. Cytology is frequently utilized but suffers from a poor sensitivity. There are several commercially available urine-based tumor markers currently available but their use is not recommended by guideline panels. Markers such as the Urovysion FISH assay and the NMP22 BladderChek test are approved for surveillance and detection in patients with hematuria. The added benefit of these markers and other commercially available markers (e.g. Ucyt+, BTA stat) has not been well investigated though it appears these markers are insufficiently sensitive to replace cystoscopy. Additional studies are needed to determine the clinical scenarios where bladder markers are best utilized (screening, surveillance, early detection, evaluating cytologic atypia) and what impact they should have on clinical decision making. Furthermore, a variety of issues and barriers can affect the movement of clinical tests from research to clinical practice. This article addresses some of the challenges facing research and medical communities in the delivery and integration of markers for bladder cancer diagnosis. Moreover, we attempt to outline criteria for the clinical utility of new bladder cancer diagnostic markers.

Introduction

Bladder cancer is a major public health problem in the developed countries. The explosion of knowledge about the basic biological processes and the genetics of cancer has led to increasing optimism that this knowledge can be put to practical clinical use in the near future. Indeed, important examples of translational approaches can already be found in the areas of drug discovery and development, disease diagnosis and classification, selection of therapeutic regimens for individual patients, and designing clinical trials. These are important developments but, as with any new approach, there is a danger of unwarranted enthusiasm and premature clinical application of laboratory results based on insufficient evidence. To carry out the translation of knowledge into practice with maximal efficiency and effectiveness, it is essential to conduct studies with appropriate designs and analyses based on sound statistical principles. In bladder cancer, laboratory and clinical investigations have identified several potential urine markers for its diagnosis. Many of them exhibit a higher sensitivity to standard urine cytology, and some of them are used at some centers [1]. However, despite approval by the FDA, none of them has achieved uniform acceptance or inclusion in clinical guidelines [2]. A PubMed Search on “bladder cancer” and (“biomarker” OR “biomarkers” or “molecular marker” or “molecular markers”) yielded 3,813 hits (date of search: 10/15/08). Nevertheless, only urine cytology is widely used in the diagnosis of bladder cancer. This provokes the question, “Why have markers not lived up to their promise”?

A variety of issues and barriers can affect the movement of clinical tests from research to clinical practice [2]. This article addresses some of the challenges facing research and medical communities in the delivery and integration of markers for bladder cancer diagnosis. Moreover, we attempt to outline criteria for the clinical utility of new bladder cancer diagnostic markers.

Section snippets

Why did we fail in the past?

Although noninvasive tests were designed to diagnose bladder cancer, it remains unclear how they can effectively be integrated into clinical decision making. Several authors have argued that this is a result of poor study design; typical marker studies have involved convenience samples from poorly defined populations, non-standardized assays, and small numbers of patients subject to missing data. Marker research has actually been largely guided by intuition and experience [3].

It seems obvious

Potential indications for marker use

The following putative indications for the use of diagnostic bladder cancer markers can be delineated (Table 1).

  • •

    Screening

  • •

    Voiding symptoms

  • •

    Assessment of patients with hematuria (gross/microhematuria)

  • •

    Follow-up of patients with bladder cancer

Requirements for markers in these situations

In order to select an appropriate assay, the purpose of a test needs to be considered. It is evident that the test requirements differ significantly between screening a low risk population and surveillance of patients with high risk bladder cancer. In both scenarios, a test with high sensitivity and specificity is desirable. However, while specificity is extremely important in screening, maximizing sensitivity is usually sought for surveillance.

Importantly, there are additional obstacles that

Cost calculations

One area that cannot be avoided is the issue of cost. Any addition of tests to a clinical evaluation will add cost and thus needs to be balanced by a benefit to be cost-effective. Markers vary in cost dramatically from point of care tests such as the NMP22 BladderChek test (around $20–$30/test) to tests such as Ucyt and Urovysion that require specialized labs and cost more than $200/test [27]. The issue of cost must be considered in light of small differences in sensitivity and specificity

Potential trial designs

The goal of future marker research should be validation of clinical utility. Current and future markers should focus on “added value.” Too late in the life of other markers such as prostate specific antigen (PSA) are studies being performed to evaluate the benefit [36], [37].

Other markers are unlikely to be widely accepted prior to evidence-based trials that establish their utility. Such trials will need to address how the marker performs in the setting of detection and surveillance and how it

Possible clinical trial designs for prospective validation of markers

For a marker to be of value in routine clinical practice, it must favorably affect clinical outcomes, such as decreasing toxicity, increasing overall and/or disease-free interval, provide prognostic information, or improve quality of life. Once the methods for assessment of the marker have been established and initial results show promise, the marker needs to be tested in a clinical trial (Fig. 1). Typical designs for bladder cancer urine marker clinical trials include the sequential testing,

Conclusions

Markers have the potential to improve screening for, diagnosis, or monitoring of bladder cancer. However, discovery experiments have often overemphasized the significance of novel candidates, and efforts to further credential such candidates have been rare. This has been due in large part to a lack of effective and efficient strategies to determine which marker candidates justify the great investment of time and money required for assay development, optimization, and demonstration of analytical

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