What does Prof. Marek Babjuk think? 
According to the EAU guidelines, the
urinary markers Bladder EpiCheck, Cxbladder Monitor, ADXBLADDER, Xpert Bladder Cancer Monitor might be used t
o replace and/or postpone cystoscopy during surveillance as they may identify rare high-grade recurrences in both
low- and intermediate-risk NMIBC [1]. Moreover, it is recommended to use urinary markers in patients initially diagnosed with Ta low-grade/grade 1-2 bladder cancer during surveillance in case cystoscopy is not possible or refused by the patient (weak recommendation).
This statement was newly added in the EAU guidelines of 2022, and may raise some questions to you. Therefore, I will address the most important questions below to clarify the benefits of urinary markers for NMIBC surveillance.
Why do we need to think of alternatives for cystoscopy?
There are 2 important reasons for this:
1. Cystoscopic surveillance poses a significant burden
Cystoscopy, the current standard in the follow-up of NMIBC, is invasive and may cause significant anxiety and discomfort to patients that negatively impact their quality of life, especially in those patients with frequent follow-up visits (e.g. intermiediate-risk patients with follow-up visits every 3 to 6 months).
In addition to patient burden, they also pose a significant burden on the healthcare system as the cystoscopic examinations need to be performed in hospitals or outpatient clinics. Prolonged waiting times due to the extensive workload in hospitals and clinics, and shortage of staff have further worsened with the COVID-19 pandemic [2]. Urinary markers could alleviate this burden by reducing or replacing cystoscopies during surveillance. These tests are non-invasive and substantially reduce professionals’ time spent in the hospital. The urine sample can simply be collected from the patient’s home or a community location nearby and shipped to a laboratory for analysis.
2. Cystoscopy is not 100% accurate to detect disease recurrence
The sensitivity for detecting papillary tumours ranges from 75 to 84% and is even lower (61-62%) for detecting carcinoma in situ (CIS), meaning high-grade lesions are often missed [3,4].
Why Bladder EpiCheck, Cxbladder Monitor, ADXBLADDER and Xpert Bladder Cancer Monitor?
These 4 promising and commercially available urine biomarkers, although not tested in randomised controlled trials, have such high sensitivities and negative predictive values (NPVs) for high-grade disease that they may approach the sensitivity of cystoscopy [1].
This statement in the EAU guidelines was confirmed for certain urine biomarkers by a recent systematic review and network meta-analysis that reported on the pooled diagnostic values of urinary biomarkers based on individual validation studies [5,6].
Pooled sensitivity, specificity and NPV for NMIBC recurrence of the guideline recommened markers: Bladder EpiCheck, Cxbladder Monitor, ADXBLADDER, Xpert Bladder Cancer Monitor [5,6]
Pooled diagnostic estimates were calculated from univariate statistics for 1,000 patients based on the pooled recurrence rate.
This meta-analysis also demonstrated that urinary markers are efficient in reducing the number of invasive cystoscopies [5,6]. The low number of false positives ensures that only a limited number of patients will have unnecessary downstream cystoscopies.
Estimated number of cystoscopies avoided and unnecessary cystoscopies in clinical practice based on a pooled recurrence rate of 18 [5,6]
Why in low- and intermediate-risk NMIBC?1. High-grade disease
Because of their high sensitivities and high NPVs for detecting high-grade disease [5,6], certain urinary markers can reduce patient burden without compromising early detection of high-grade recurrences. Therefore, these makers are of interest to replace and/or postpone cystoscopy during surveillance of high-grade, intermediate-risk NMIBC.
2. Low-grade disease
For patients with low-grade NMIBC, although the majority of recurrences would be low grade, there is still a small risk for high-grade recurrence. A delayed detection of low-grade recurrences does not present an immediate threat to the patient, but frequent routine follow-up is still needed to ensure early detection of high-grade recurrences. Reducing the frequency of follow-up cystoscopies by using urinary marker tests in between would ensure early detection of high-grade recurrences while lowering the burden of routine surveillance.
References
- Babjuk M, Burger M, Compérat E, et al. European Association of Urology (EAU) guidelines on non-muscle-invasive bladder cancer (TaT1 and CIS). Update March 2022. Available at: https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/
- Teoh JY, Ong WLK, Gonzalez-Padilla D, et al. Eur Urol 2020:78:265-75. PubMed
- Daneshmand S, Patel S, Lotan Y, et al. J Urol 2018;199:1158-65. PubMed
- Burger M, Grossman HB, Droller M, et al. Eur Urol 2013;64:846-54. PubMed
- Laukhtina E, Shim SR, Mori K, et al. Eur Urol Oncol 2021;4:927-42. PubMed
- Laukhtina E, Shim SR, Mori K, et al. Eur Urol Oncol 2022;5:480-1. PubMed