Reviewed by Morgan Rouprêt (Pitié-Salpêtrière Hospital – AP-HP Sorbonne University, Paris, France)
Prof. Fred Witjes (Radboud UMC, Nijmegen, The Netherlands) recently discussed the opportunity to use urinary markers to reduce the number of cystoscopies in low-grade non-muscle invasive bladder cancer (NMIBC) at the European Association of Urology Virtual Congress (EAU20V) – July 17-26, 2020 .
Are we ready to stop cystoscopies?
According to Prof. Witjes, cystoscopies are required in primary diagnosis of NMIBC. Even if abnormalities are detected with imaging technologies, such as a CT scans or ultrasound, cystoscopies are still useful to visualize the tumour and get additional information about it (size, multiplicity, location and prediction of grade and stage) and to plan the surgical endoscopic procedure (i.e., TURBT).
However, Prof. Witjes argues that the story is different for monitoring tumour recurrence in low-grade NMIBC patients. The current follow-up schedules for NMIBC surveillance are not standardised (NICE versus EAU guidelines) and are based on weak evidence and experts’ opinion only. Hence, there is a strong need for uniform follow-up procedures to monitor tumour recurrence.
Why consider giving up cystoscopies?
Several disadvantages are related to the current follow-up procedures in low-grade NMIBC:
- Overuse of cystoscopies in 75% of low-risk patients 
- 8% of all cost in NMIBC is due to detection of low risk recurrence 
- Cystoscopies are burdensome for the patient. Nevertheless, patients are willing to undergo cystoscopies because they are afraid to miss a tumour. Only with urinary biomarkers that are very sensitive, or are as sensitive as cystoscopy are patients willing to replace a cystoscopy by a biomarker [4-6]
- Both low-grade and the progression to high-grade, including CIS, lesions may be missed. In fact, up to 30% of patients with CIS lesions may be missed with white light cystoscopy (integrated results from PDD studies). Urine cytology also misses tumours due to a sensitivity of less than 50% 
Stopping cystoscopies completely, and shifting to active surveillance is tricky, as we have no histological information about the grade of the tumour. This is where urinary markers can be of help.
Prof. Witjes stated in his presentation:
“In low-grade NMIBC, I think we do too much, it is of low quality and with low level of evidence… Maybe urinary markers are a realistic plan B.”
Some older urinary markers (FISH, NMP22) never found their way into clinical practice because of low sensitivity and specificity or technical difficulty. Moreover, benign conditions such as urinary tract infections or previous BCG instillations lead to false positive results.
The EAU 2020 guidelines do not currently recommend using markers in routine practice, but they acknowledge the fact the research has been carried out, and it is recognized by leading Key Opinion Leaders that a reliable classification by markers may help reduce cystoscopies.
The “origin” of newly developed urinary markers is epigenetics, which are factors that are able to switch genes “on” and “off” and affect how cells read genes without altering the underlying DNA sequence. These include aberrant DNA methylation, histone modification and non-coding RNA.
Epigenetic changes are frequently observed in cancers, including bladder cancer, both in tissue and in urine. So, they might be useful in diagnosis, prognosis, and even as potential therapy targets for NMIBC. Several urinary marker tests based on epigenetics have been developed, such as Xpert Bladder Cancer Monitor, Bladder EpiCheck®, Cxbladder Monitor, ADXBLADDER, …
For example, the Bladder EpiCheck® has a negative predictive value (NPV) of 99.3% for non-low-grade Ta recurrence and 95.1% overall. Moreover, the results of the Bladder EpiCheck® are not influenced by urinary tract infections or instillation therapy .
In an extension of this study, 657 patients obtained consistent outstanding results with a NPV of 98.8% for non-low-grade tumours .
Prof. Witjes concluded that alternating cystoscopy and cytology with one of the new tests demonstrating NPV of 99% for non-LG recurrences, could reduce the current diagnostic burden. He stated: “I have been doing that now in my current practice*, and patients are really very happy with this strategy, and so am I. So, I hope you will all look at this as the new future.”
*Prof. Witjes is referring to the pilot currently running in Radboud University Hospital of alternating between cystoscopy and Bladder EpiCheck® in NMIBC monitoring.
Watch Prof. Witjes’ presentation here.
(Logging-in with MyEAU credentials is needed to view this content on the EAU20 Resource Centre.)
Read a free-accessible written version of the talk here.
(Written by Hanan Goldberg, MD, MSc., Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA)
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