Non-muscle-invasive Bladder Cancer

8. FOLLOW UP

As a result of the risk of recurrence and progression, patients with NMIBC need surveillance following therapy. However, the frequency and duration of cystoscopy and imaging follow-up should reflect the individual patient’s degree of risk. Using the EAU NMIBC prognostic factor risk groups (see Section 6.3, Tables 6.1 and 6.2) or further prognostic models for specific patient populations (see Chapter 6), the short- and long-term risks of recurrence and progression in individual patients may be predicted and the follow-up schedule adapted accordingly (see Section 8.1) [222,224]. However, recommendations for follow-up are mainly based on retrospective data and there is a lack of RCTs investigating the possibility of safely reducing the frequency of follow-up cystoscopy.

When planning the follow-up schedule and methods, the following aspects should be considered:

• The prompt detection of muscle-invasive and HG/G3 non-muscle-invasive recurrence is crucial and the percentage of tumours missed should be as low as possible because a delay in diagnosis and therapy can be life-threatening. Therefore, the best surveillance strategy for these patients will continue to include frequent cystoscopy and cytology.
• Tumour recurrence in the low-risk group is nearly always low stage and LG/G1. Small, Ta LG/G1 papillary recurrence does not present an immediate danger to the patient and early detection is not essential for successful therapy [250,409] (LE: 2b). Fulguration of small papillary recurrences on an outpatient basis could be safe [410] and comparable to conventional TURB (LE: 1b). Multiple authors have suggested active surveillance in selected cases [411-413] (LE: 3/2a). However, repeated TURBs before entry, as well as presence of more than one lesion at entry, were significantly associated with AS failure [256].
• The first cystoscopy after TURB at 3 months is an important prognostic indicator for recurrence and progression [230,235,248,251,414] (LE: 1a). Therefore, the first cystoscopy should always be performed 3 months after TURB in all patients with TaT1 tumours and CIS.
• In tumours at low risk, the risk of recurrence after 5 recurrence-free years is low [251] (LE: 3). Therefore, in low-risk tumours, after 5 years of follow-up, discontinuation of cystoscopy or its replacement with less invasive methods can be considered [414].
• In tumours originally intermediate-, high risk, or very high risk treated conservatively, recurrences after ten years tumour-free are not unusual [415] (LE: 3). Therefore, life-long follow-up is recommended [414].
• The follow-up strategy must reflect the risk of extravesical recurrence (prostatic urethra in men and UUT in both genders).
• The risk of UUT recurrence increases in patients with multiple- and high-risk tumours [96] (LE: 3).
• There may be a role for newer methods of tumour visualisation in follow-up cystoscopy. In two prospective studies of blue light flexible cystoscopy (BLFC) for surveillance of NMIBC, BLFC allowed identification of 4 to 5.7 % of recurrences that would have been missed in case of WL cystoscopy alone [416,417]. On the other hand, a prospective study of NBI for NMIBC surveillance failed to show any benefit for NBI over WL cystoscopy alone [418].
• The current status of urine cytology and urinary molecular marker tests is discussed in detail in Sections 5.5, 5.6 and 5.7. Non-muscle-invasive BC follow-up strategies include urine cytology and urinary molecular marker tests as adjunct (or companion) tests to improve detection at the time of flexible cystoscopy or as replacement tests to reduce the number of flexible cystoscopies.
• The role of urinary cytology or urinary molecular markers as an adjunct to cystoscopy (companion test) in the follow-up of NMIBC has been investigated [118,119,131,132,142]. One prospective RCT found that knowledge of positive test results (microsatellite analysis) can improve the quality of follow-up cystoscopy [143] (LE: 1b), supporting the adjunctive role of a non-invasive urine test performed prior to follow-up cystoscopy [143] (see Section 5.7.3).

In order to reduce or replace cystoscopy altogether, urinary markers should be able to detect recurrence in all risk groups. However the previously reported low sensitivity for LG recurrences limits their utility in this group [113,118] (LE: 1b) although more recent studies have shown reasonable sensitivity in low grade recurrences (sensitivity of 40–65% [136,419] and only a 5.8% risk of missed recurrences using repeated molecular testing in a cohort of patients undergoing active surveillance for low-grade NMIBC [420].

• In patients initially diagnosed with Ta LG/G1–2 BC, US of the bladder or a urinary marker may be a mode of surveillance in case cystoscopy is not possible or refused by the patient [139,142,421].
• According to current knowledge, no urinary marker can replace cystoscopy during follow-up or lower cystoscopy frequency in a routine fashion. Nonetheless, some urinary markers have shown fairly high sensitivities to detect tumour recurrence, particularly in HG disease, along with very high NPVs to make the premises for their future implementation in follow-up [135,419,420,422] (Table 8.1).

Table 8.1: Urinary markers in the surveillance setting*

*Data extracted from a pooled analyses of systematic review 8.
HG = high grade; NMIBC = non-muscle-invasive bladder cancer; PPV = positive predictive value; NPV = negative predictive value; n = number.

8.1. Summary of evidence and guidelines for follow-up of patients after transurethral resection of the bladder for non-muscle-invasive bladder cancer