Perception of urinary biomarker tests among patients referred with suspected urological malignancy

Abstract Objective To determine the acceptability of a non‐invasive urinary biomarker test in place of conventional flexible cystoscopy for the diagnosis of bladder cancer in patients referred to a Rapid Access Haematuria Clinic (RAHC) with suspected urological malignancy. Patients and methods Patients attending a RAHC were recruited to a prospective observational study evaluating a novel urinary biomarker (URO17™) for the detection of bladder cancer and invited to complete a two‐part structured questionnaire. Questions related to demographics, attitudes towards conventional cystoscopy and the minimal acceptable sensitivity (MAS) at which a urinary biomarker would be considered an alternative to flexible cystoscopy both before and after undergoing the procedure. Results A total of 250 patients completed the survey; the majority of whom were referred with visible haematuria (75.2%). One hundred seventy‐one (68.4%) would be willing to accept a urinary biomarker in place of cystoscopy, with 59 (23.6%) expressing preference for the biomarker with a MAS as low as 85%. Conversely, 74 patients (29.6%) would not be willing to accept a urinary biomarker, regardless of its sensitivity. A significant number of patients reported a change in MAS after undergoing cystoscopy, with 80 (32.0%) and 16 (6.4%) increasing and decreasing the required value respectively (P = 0.001). The greatest increase was seen in the proportion of patients unwilling to accept a urinary biomarker regardless of its sensitivity, rising from 29.6% to 38.4%. Conclusions Although many patients attending a RAHC would be willing to accept a urinary biomarker test in place of conventional flexible cystoscopy for the detection of bladder cancer, effective patient, public and clinician engagement will be necessary at all stages of implementation if it is to become an established component of the diagnostic pathway.


| INTRODUCTION
Bladder cancer is the 10th most common cancer worldwide, accounting for approximately 573,000 new cases and 213,000 deaths in 2020. 1 Approximately 75% of patients have non-muscle invasive bladder cancer (NMIBC) at the time of diagnosis, which is associated with a risk of both recurrence and progression, thereby mandating risk-adapted approaches to intravesical treatment and ongoing surveillance. 2,3 Conversely, those patients found to have muscle invasive bladder cancer (MIBC) or metastases at presentation have a much worse prognosis, with median 5-year survival estimates of 36.3-69.5% and 4.6%, respectively, despite contemporary treatment. 4 Timely presentation and investigation are therefore imperative to identifying disease at an early stage and hence optimising outcomes, with studies indicating that improved survival is seen in those with a shorter time to diagnosis. 5,6 As there is no accepted screening test for bladder cancer, the majority of patients in the United Kingdom (UK) initially present to their General Practitioner in primary care, with subsequent referral to their local urology department for triage, appointment booking and clinical assessment. Visible haematuria is the most common presenting complaint, with a recent large UK multicentre study identifying the prevalence of bladder cancer to be 22.4% in this cohort. 7 This is acknowledged in the suspected cancer recognition and referral guidelines published by the National Institute for Health and Care Excellence (NICE; NG12), in which patients aged 45 years and over with visible haematuria in the absence of urinary tract infection or aged 60 years and over with non-visible haematuria and either dysuria or a raised white cell count are recommended to be seen by the receiving urology department within 2 weeks of referral. 8 Those patients not meeting these criteria are also assessed but within a less prescriptive timeframe in accordance with local urology department protocols.
In most UK institutions patients referred with suspected urological malignancy are assessed in a 'rapid access' or 'one stop' clinic.
Usually, this comprises a clinical assessment together with blood and urine analysis. Upper urinary tract imaging is undertaken with ultrasound and/or computed tomography (CT), and the lower urinary tract is directly visualised using flexible cystoscopy. The personnel responsible varies between centres, but in all cases, the appointment is undertaken by a practitioner (either Urological Surgeon or Specialist Nurse) with sufficient training and expertise in each component so that the patient can be counselled accordingly and either discharged or referred for ongoing investigations and/or treatment as required.
Although flexible cystoscopy has a sensitivity of 98% for the diagnosis of bladder cancer and is the current gold standard test, it is invasive and associated with a reported risk of dysuria (50%), bleeding (19%) and infection (5.5%). 9 Furthermore, cystoscopy is performed as a component of Secondary Care assessment for which there may be delays in referral or appointment allocation or issues with access for those that reside in remote areas or have limitations in mobility.
Urinary biomarkers have been proposed as a non-invasive and cost-effective alternative to cystoscopy for use in both the initial diagnosis and ongoing post-treatment follow-up of patients with bladder cancer. Although urinary cytology has been shown to have a high specificity in the diagnosis of high-grade tumours, it has an overall sensitivity of less than 40%, rendering it unsuitable as a diagnostic tool in isolation. 10 Several novel urinary biomarkers have been described in the literature and are in varying stages of development, with mechanisms of detection based upon alterations in genomic, transcriptomic, epigenetic or proteomic signatures within samples. 11 However, whilst such tests are being developed on the premise that they may present a means of avoiding flexible cystoscopy and its associated risks in those with suspected bladder cancer, it is also paramount to establish the attitudes of patients to the use of such a test in their diagnostic pathway. Until now this has not yet been characterised. This prospective questionnaire-based study therefore sought to establish the attitudes of patients referred to a Rapid Access Haematuria Clinic with suspected urological malignancy to a novel urinary biomarker for the detection of bladder cancer, particularly with respect to the sensitivity required for such a test to become an acceptable alternative to conventional flexible cystoscopy.

| Patient cohort
Patients attending a RAHC in a single large tertiary referral centre between 28 September 2021 and 8 August 2022 were invited to participate in a prospective observational study exploring the sensitivity and specificity of a urinary biomarker test based on the positivity of cells for keratin 17 when stained with immunohistochemistry, URO17™, as described previously. 12,13 Those patients who provided informed consent to participate were also invited to complete a structured questionnaire to establish their attitudes towards conventional cystoscopy and a novel urinary biomarker for the detection of bladder cancer, as outlined below.

| Questionnaire
A two-part structured questionnaire was based on a previously published tool used to determine attitudes towards a urinary biomarker for the follow-up of patients with previously confirmed NMIBC. 14 Public and patient involvement formed an integral part of the development of patient information and question design to ensure all were appropriately worded, understandable and relevant. The first part was completed by respondents prior to undergoing flexible cystoscopy and comprised questions relating to demographics, attitudes towards cystoscopy and the minimum sensitivity at which a urinary biomarker would be considered an acceptable alternative to flexible cystoscopy [termed minimal acceptable sensitivity (MAS)], as determined using the standard gamble method. 15 Cystoscopy was defined as having a sensitivity of 98% for the detection of bladder cancer, as previously reported, and MAS was defined as the sensitivity at which patients either expressed a preference for the urinary biomarker or were neutral about accepting either the biomarker or conventional cystoscopy. 9,14 The second part was completed following flexible cystoscopy and comprised questions relating to the experience of the procedure, as well as whether this resulted in a change in MAS of a urinary biomarker test. Questions relating to patient experience, such as those pertaining to levels of anxiety, discomfort and embarrassment were evaluated using the established method of a five-point Likert scale. 16 A full version of the questionnaire is provided in Appendix 1 .

| Statistical analysis
All data analysis was performed using SPSS statistical software version 27 (IBM Corporation, Armonk, New York, USA). Continuous age data were confirmed to be normally distributed and represented as mean [standard deviation (SD)], with statistical comparisons between groups conducted using the one-way analysis of variance (ANOVA). Categorical data were represented as values and/or percentages, and differences between groups were assessed using the chi-squared test. The McNemar-Bowker test was used to assess for a significant change in pre-and post-cystoscopy MAS between individual respondents. A value of p ≤ 0.05 was used to determine statistical significance.

| Pre-procedural perceptions and experience of flexible cystoscopy
Most respondents reported some level of anxiety regarding flexible cystoscopy prior to undergoing the procedure, with 74.0% being somewhat anxious to very anxious, as shown in Figure 1. The greatest perceived downside to flexible cystoscopy was reported to be anticipated discomfort (54.8% of respondents), followed by anticipated embarrassment and risk of infection (11.2% of respondents each). of respondents reported some or more discomfort, 20.4% did not experience any discomfort at all, with 53.2% stating that the procedure was less uncomfortable than expected. Similarly, 49.6% of respondents did not report any embarrassment associated with procedure, with 60.4% expressing that it was less embarrassing than expected.  Conversely, 74 patients (29.6%) were not willing to accept a urinary biomarker over conventional cystoscopy, regardless of its sensitivity. decreasing the sensitivity value required for a urinary biomarker to be sufficient to replace cystoscopy respectively (P = 0.001). As shown in Figure 3, the greatest increase was seen in the proportion of patients who would be unwilling to accept a urinary biomarker over conventional cystoscopy regardless of its sensitivity, which rose from 29.6%

| Minimum Acceptable Sensitivity before and after cystoscopy
to 38.4% of the overall cohort.

| DISCUSSION
This is the first study to explore the perceptions of a non-invasive urinary biomarker as a potential replacement for flexible cystoscopy in the detection of bladder cancer among patients presenting to a rapid access haematuria clinic with suspected urological malignancy.  18 In both studies, male sex was associated with a lower MAS. 17,18 Despite methodological differences again limiting direct T A B L E 2 Differences in minimal acceptable sensitivity for a urinary biomarker to replace conventional flexible cystoscopy for the diagnosis of bladder cancer as reported prior to undergoing the procedure, stratified by patient demographics.