Surveillance of High-grade Non-muscle Invasive Bladder Tumours Using the Xpert Bladder Cancer Monitor
Surveillance of High-grade Non-muscle Invasive Bladder Tumours Using the Xpert Bladder Cancer Monitor
The study aims to evaluate the potential clinical impact of a highly sensitive urinary
 marker, the Xpert Bladder Cancer Monitor, regarding possible reduction in number of flexible
 cystoscopies in an outpatient setting without decreasing recurrence-free survival or
 increasing risk of progression.
Epidemiology and treatment Bladder cancer is the 12th most diagnosed cancer worldwide with an
 incidence of approximately 550 000 new cases each year.1 A majority of the tumors are
 characterized as non-muscle invasive bladder cancer (NMIBC), meaning stage T1 according to
 the 2016 TNM-classification.2 Treatment of primary NMIBC is transurethral resection of the
 bladder (TUR-B) and treatment of recurring NMIBC is repeated TUR-B and often adjuvant
 instillation therapy with either Mitomycin C or Bacillus Calmette-Geerin (BCG) according to
 the histology of the tumor. NMIBC-tumors are graded into high grade (HG) and low grade (LG)
 according to the histological characteristics of their TUR-B specimen. Generally,
 intravesical Mitomycin C is recommended to treat LG tumors and intravesical BCG is
 recommended for treating HG tumors.3,4.

 Follow-up schedules based on risk of recurrence. The histological grade, number of tumors,
 tumor size, T-stage, recurrence-rate and presence of carcinoma in situ (CIS) is used to
 estimate risk of recurrence according to the EORTC-scoring system. Based on the risk
 stratification, different follow-up schedules after initial TUR-B are planned. High risk
 tumors are followed-up with flexible cystoscopy and urinary cytology every four months until
 two recurrence-free years, whereas low and intermediate risk tumors are followed utilizing
 the 4-8-12 model where intervals between follow up are increased for patients without
 recurrence until 5 disease-free years.3 The evidence behind these follow-up schedules is not
 based on high level evidence and research but rather on tradition and 'clinical experience'.

 Clinical challenge of current follow-up schedules The majority of patients with HG tumors
 will have recurrence despite treatment, especially within the two first years after
 diagnosis. Moreover, many patients will receive lifelong follow-up cystoscopy and urinary
 cytology tests. Follow-up schedules are costly due to many visits at the hospital for
 flexible cystoscopy, urinary cytology, and treatment. A micro-costing analysis performed by
 the Urological Research Unit at Aarhus University Hospital prior to initiation of the current
 study, has shown that the total expense in relation to flexible cystoscopy in the outpatient
 clinic is approximately 315 EUR per examination (Appendix 1). Equally important to frequency
 and cost of follow-up, every follow-up visit is associated with patient discomfort, pain,
 risk of infections, and strictures of the urethra.6 Each cystoscopy carries a 15% risk of
 complications. Nearly 1,500 cystoscopies are carried out in HG patients in Central Denmark
 Region each year, resulting in approximately 240 complications each year, with cystitis being
 the most common complication. Furthermore, flexible cystoscopy is not always reliable in
 terms of diagnosing recurrences and CIS.7-9

 Urinary biomarkers A proposed alternative to flexible cystoscopy in the detection of
 recurrent NMBIC is non-invasive molecular urinary markers that detect mRNA, protein or DNA
 from selected genes relevant for bladder cancer in urine samples. Several studies have been
 prospectively validated and shown high sensitivity and specificity for urinary markers.10,11
 Recently, the Xpert Bladder Cancer Monitor test was shown by Valenberg et al.12 to have a
 sensitivity of 83% and specificity of 76% for HG disease and similarly D'Elia et al.13 showed
 a specificity of 77% and sensitivity of 46% for a cohort of mainly LG patients. However,
 studies have until now focused mainly on detection of NMIBC in patients with incident tumors,
 which are most often larger and more easily diagnosed with urinary biomarkers than
 recurrences.14 To our knowledge, no studies have so far substituted cystoscopies for urinary
 biomarkers in a randomized controlled setting. Thus, the need for high level evidence
 regarding the use of urinary biomarkers for surveillance of NMIBC is still there.
Inclusion Criteria:

 -  Age ≥18 years of age at the time of signing the Informed Consent Form

 -  Ability to understand the Participant Information sheet orally and in writing

 -  Signed Informed Consent Form

 -  Is, according to the investigator's judgement, able to comply with the trial protocol

 -  Previously diagnosed with high grade NMIBC Recurrence free at the time of inclusion
 detected by flexible cystoscopy

 Exclusion Criteria:

 -  History of any upper urinary tract tumor regardless of grade and stage within the last
 5 years prior to randomization

 -  T1 tumor where re-resection has not been performed

 -  CIS or invasive tumor within 3 months before randomization