Background
Most forms of urothelial carcinoma (UC) are cancers of the bladder. Although most cases of non-muscle-invasive UC can be treated, bladder cancer has a high rate of recurrence. Even patients with low-grade or low-risk UC require regular surveillance after treatment [
1]. As a result, bladder cancer carries the highest per-lifetime, per-patient cost of any type of cancer [
2], with 60% of the total cost attributable to surveillance and recurrence [
3].
Major guidelines recommend risk-adjusted surveillance or active surveillance strategies for patients after treatment for UC, cystoscopy, cytology and imaging for diagnosis and monitoring in most cases [
4‐
10]. The first cystoscopy should be at 3–4 months after the completion of treatment [
10]. If this is negative, patients should undergo cystoscopies over longer time periods for low-risk vs intermediate vs high-risk categorizations [
7,
10]. All patients with a recurrence start their evaluation sequence again. Costs rapidly accrue because cystoscopy is an invasive endoscopic procedure requiring local anesthesia, expensive equipment and expertise. Patients often find the procedure disagreeable and time-consuming, keeping them from work and life activities. Reluctance to undergo cystoscopy impacts patient compliance with guideline-recommended surveillance protocols [
11], which may increase disease progression.
There is evidence to suggest that the benefit: risk equation for diagnostic and surveillance procedures does not necessarily favor current practices [
12‐
14]. For example, American Urological Association (AUA) guidelines for the evaluation of hematuria recommend extensive and intensive use of tests and procedures, including CT imaging [
10], impacting significantly on costs, compared with guidelines that recommend less intensive assessment [
12]. Comparatively less intensive approaches miss more low-grade UCs, but with fewer adverse outcomes [
12]. Moreover, studies specifically investigating the surveillance of patients after treatment for UC suggest that low-risk patients often undergo more frequent surveillance cystoscopies than is recommended by AUA guidelines [
13,
14]. Such overuse is associated with increases in surgical procedures and total medical costs, without reducing risk of UC progression or death [
14].
The level of diagnostic performance of the current generation of urinary biomarker tests means that they now successfully reduce the need for invasive and expensive cystoscopy assessments in patients being managed for bladder cancer. Recent real-world evidence has been published investigating a new protocol that combines imaging with Cxbladder Triage™, an algorithm combining urinary biomarker data with patient phenotypic data, for hematuria patients being evaluated for UC [
15]. With the high negative predictive value (NPV) and high sensitivity of Cxbladder Triage, the new protocol provided a rule-out strategy that was able to safely identify patients without disease and avoid the need for cystoscopy in 32% of patients undergoing evaluation of hematuria [
15].
The Cxbladder-Monitor (CxbM) test uses a similar ‘rule-out strategy’ to rule out the presence of UC among patients being evaluated for UC recurrence. CxbM quantifies urine mRNA levels of five cancer biomarkers [
16,
17], and incorporates this information into a mathematical algorithm with clinical variables (primary versus recurrent UC and time since previous tumor resection) to derive a score with a binary outcome [
16] (see Additional file
1). Prospective studies in patients undergoing surveillance for recurrent bladder cancer have reported sensitivity of between 91 to 95% for CxbM, and an NPV of 96 to 97% [
16,
17].
Based on these published data, several of New Zealand’s public healthcare providers (PHP) have integrated CxbM into their routine clinical surveillance of patients for recurrence of bladder cancer. The new clinical practice alternates the use of CxbM and cystoscopy during regular surveillance of low-risk patients.
This real-world audit describes the use and outcomes of cystoscopy at these PHPs over a 35-month period after the inclusion of CxbM into the surveillance protocol, and specifically the clinical utility and rule-out rate of CxbM when used in routine surveillance of patients at low or high risk of recurrent bladder cancer.
Discussion
This audit demonstrated the real-world clinical utility of CxbM as a rule-out test for both low- and high-risk patients undergoing surveillance for recurrent UC. The data showed no advantage to patients being segregated on the basis of risk prior to the use of CxbM.
There were no incidences of pathology-confirmed recurrence at the post CxbM cystoscopy testing ~ 10 months later. Three patients with an equivocal cystoscopy finding were pathology confirmed at a subsequent follow-up ~ 3 months later. Overall, for low-risk and high-risk patients, a CxbM-positive result was associated with a 16.2-fold greater likelihood of confirmed UC on initial cystoscopy compared with CxbM-negative findings. High-grade tumors were seen in only two patients (0.79%) who had been initially categorized as being at high risk for recurrence. One additional low-risk patient progressed to a Cis. All three had a CxbM-positive result.
Previous studies have shown that CxbM has high sensitivity and NPV [
16,
17], and the current audit demonstrates that CxbM provides tangible clinical utility when used as a rule-out test to identify patients at low risk of recurrence who do not need a cystoscopy and identify those at higher risk who would benefit from cystoscopy. The integration of CxbM into local practice guidelines identified a high proportion of patients (77.8%) who were safely managed by only one cystoscopy every 2 years. Reducing by half the number of cystoscopies in this portion of patients treated for UC would decrease the total number of annual cystoscopies needed by 39%, thereby significantly reducing long-term costs of UC surveillance, without compromising detection, and enabling resources to be focused on patients most in need.
CxbM incorporates risk factors in its validated algorithm, providing an objective, repeatable measure. The audit showed that use of CxbM as a rule-out test in all recurrence patients obviates the need for risk stratification because CxbM identifies those at high risk of recurrence, irrespective of their guideline-defined risk stratification.
Other noninvasive biomarker assays have been approved in the US for the diagnosis or monitoring of bladder cancer including an Enzyme-Linked Immunosorbent Assay (ELISA) test for Nuclear Matrix Protein 22 (NMP22) (BladderChek®; Matritech Inc., Newton, MA, USA [
18,
19]), a multiprobe fluorescence in situ hybridization (FISH) test (UroVysion®; Abbott Molecular, Des Plaines, IL) and an immunocytologic fluorescent assay (ImmunoCyt™/uCyt™ Diagnocure; Quebec City, Quebec, Canada). However, it has been previously observed they provide low overall sensitivity [
20]. A previous study compared CxbM with NMP22 ELISA assays and UroVysion FISH in patients previously diagnosed with UC undergoing monitoring for recurrence [
17]. CxbM provided significantly better sensitivity and NPV than BladderCheck (91% vs. 11% and 96% vs. 86%, respectively), and in a smaller patient sample, showed a similar advantage over UroVysion FISH (sensitivity 33%, NPV 92%) [
17]. These data suggest that the NMP22 point-of-care test is likely to miss a substantial number of patients with recurrence, whereas CxbM does not.
Currently, there are limited data on the clinical value of introducing urinary biomarkers into the surveillance protocol for recurrent UC, and most studies have used the early generation, single biomarker tests with low performance [
21,
22]. To our knowledge, this study is the first to have investigated the impact of incorporating a multi-biomarker urine test into a routine clinical surveillance protocol in a real-world setting. Further longer-term studies should be conducted to confirm our findings.
Collection of a urine sample carries a significantly lower burden for patients compared with cystoscopy in terms of time away from work, anxiety, pain and discomfort during the procedure, and painful micturition afterwards and is likely to lead to an increase in patient compliance with physician recommendation [
11]. The results of in-office cystoscopy may be available sooner than the results of some out-sourced biomarker tests, which may limit patient anxiety compared with waiting for a result [
23,
24]. However, not all cystoscopies provide a clear result, and patients may need to undergo further testing if cystoscopy is equivocal or cytology atypical [
25].
Adding urine biomarker testing to a standard regimen of cystoscopy may not be cost effective when added to the standard tests and procedures for each scheduled assessment [
26,
27]; however reducing the frequency of cystoscopy would significantly reduce the cost of post-treatment UC surveillance in low-risk patients [
28]. The more sensitive and accurate the urine biomarker test is, the more cost-effective it is in the surveillance of recurrent UC [
26], and the more acceptable it becomes to patients as an alternative to routine cystoscopy [
29].
Our data have clinical implications for the surveillance of UC patients after treatment. First, because of the high sensitivity (91–95%) and NPV (96–97%) of the CxbM test, a voided urine sample can be used to rule out a substantial number of both high- and low-risk patients who are very unlikely to have recurrent UC and can safely miss one of the recommended cystoscopies, saving money and sparing patients the discomfort and anxiety. Our study also showed that CxbM effectively identified patients at higher risk of recurrence regardless of the time since the original UC diagnosis, and therefore can be implemented at any time during the post-treatment course of the disease. All three centers included in this audit now use the CxbM test in their clinical protocols to rule-out low risk patients and prioritize UC patients for follow-up cystoscopy.
This audit is not without limitations. Because this was a real-world analysis of clinical practice, a complete dataset was not available for each patient, no data were available of treatments received, and some patients were lost to follow-up through real-world events such as moving, change of contact details, or death from co-morbidities. Some patients had both CxbM and cystoscopy simultaneously, reflecting patient-specific variation in the implementation of the new standard protocols. Variability in the timing of the first post-CxbM cystoscopies and differences in data availability existed between the low- and high-risk groups (e.g. 391 urine samples vs. 52 urine samples, respectively), and some low-risk patients had more than one cystoscopy and recurrence, which impacted on the comparison of recurrence rates between the CxbM-positive and -negative patient groups over time. The difference in the number of urine samples between the low-risk and high-risk patients was partly an artefact of the new surveillance protocol, where high-risk patients underwent frequent surveillance by cystoscopy, rather than by CxbM, whereas low-risk patients had an alternating surveillance regimen (CxbM then cystoscopy, then CxbM and so on). Finally, low-risk CxbM-negative patients did not undergo any conventional follow-up until the 12-month cystoscopy, so we are unable to confirm whether the 12-month equivocal cystoscopy events were developed after CxbM testing. Any comparison between CxbM and cystoscopy results in the low-risk patient group is similarly limited by missing data, as a consequence of adopting this alternating CxbM to cystoscopy protocol.
Strengths of this study are that we included a large sample of patient data collected over a 35-month audit period, during real-world clinical practice, in which clinical decisions were made based on the results of the CxbM molecular test.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.