Non-muscle-invasive Bladder Cancer

8. FOLLOW UP

Due to the risk of recurrence and progression, patients with NMIBC need follow-up after treatment. The first cystoscopy after TURB at three months is an important prognostic indicator for recurrence and progression [238,243,265,268,443]. Therefore, the first cystoscopy should always be performed three months after TURB in all patients with TaT1 tumours and CIS. The subsequent frequency and duration of cystoscopy and imaging follow-up should reflect the individual patient’s degree of risk. This can be defined by using the EAU NMIBC prognostic factor risk groups (Section 6.3, Tables 6.1 and 6.2) or further prognostic models for specific patient populations (Section 6) which predict, the short- and long- term risks of recurrence and progression in individual patients (Section 8.1) [229,231]. 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.

8.1. Intravesical surveillance during follow-up

8.1.1. Follow-up of low-risk NMIBC

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 [267,444]. In addition, recurrence after five recurrence-free years is low [268]. Therefore, in low-risk tumours, after five years of follow-up, discontinuation of cystoscopy or its replacement with less invasive methods should be considered [443,445]. A recent study found that a negative dipstick test for haematuria has a high negative predictive value in two cohorts with low-risk tumours at follow-up (0.89 and 0.94, respectively), suggesting its possible use as a surveillance strategy with limited costs [446].

8.1.2. Follow-up of intermediate-risk NMIBC

Patients in the intermediate-risk group carry a risk of progression somewhere in between the low- and high-riskcategories [235]; therefore, the intensity of any follow-up scheme could be adapted in line with this. Based on the safety of a reduced intensity follow-up scheme compared to high-risk NMIBC, in a small RCT on multiple and/or recurrent grade 1 and 2 tumours [447], these patients can be safely followed-up with a cystoscopy at three months and, if negative, with six monthly cystoscopies for two years followed by yearly cystoscopies up to ten years. This surveillance scheme for this disease category has already been adopted by the Scottish Access Collaborative Workstream [448]. Due to lack of data supporting the safety of a reduced scheme in the subgroup of high-grade intermediate-risk NMIBC the Panel recommend this group be followed-up in the same way of high-risk NMIBC.

8.1.3. Follow-up of high- and very high-risk NMIBC

In tumours originally, high-risk, or very high-risk treated conservatively, 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 voided urine cytology. Recurrences after ten years tumour-free are not unusual [449]. Therefore, the optimal surveillance strategy for these patients includes initial frequent cystoscopy and voided urine cytology and life-long follow-up [443].

8.1.4. Follow-up of extravesical sites urothelium

The follow-up strategy must reflect the risk of extravesical recurrence (prostatic urethra in men and UUT in both genders). This risk becomes significant for both sites in high-risk tumours [100], with ten-year tumour rates in UUT varying between 2.8% in CIS [450] and 25% in patients with multiple and recurrent high-risk NMIBC [451]. Voided urine cytology, cystoscopy and CT urography are key investigations for early detection of extravesical recurrence.

8.1.5. Aids for tumour detection during follow-up

8.1.5.1. Enhanced visualisation

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 [452,453]. On the other hand, a prospective study of NBI for NMIBC surveillance failed to show any benefit for NBI over WL cystoscopy alone [454].

8.1.5.2. Ultrasound

In patients initially diagnosed with Ta LG/G1–2 BC, US of the bladder and/or a urinary marker may be a mode of surveillance in case cystoscopy is not possible or refused by the patient [134,455,456].

8.1.5.3. Urine cytology

Non-invasive follow-up strategies include urine cytology as an adjunct (or companion) test to improve detection of HG disease at the time of flexible cystoscopy. With the implementation of the Paris system when reporting urinary tract cytology with the emphasis on improving the detection of HG tumours and recognising the limitation of cytology in diagnosing LG disease, urine cytology is not recommended for follow-up in the low-risk group and intermediate-risk group (with the exception of HG/G3 tumours). However, the Paris system has improved the clinical utility in HG disease as demonstrated in a systematic review where the average proportion HG malignancy for the three categories Atypical urothelial cells (Atypia), suspicious for HG UC (Suspicious), and high-grade/G3 UC (Malignant) were 40%, 81%, and 91%, respectively [457].

8.1.5.4. Urinary molecular markers

Non-invasive follow-up strategies include urinary cytology and urinary molecular marker tests as an adjunct test to improve detection of HG disease at the time of flexible cystoscopy or as replacement tests to reduce the number of flexible cystoscopies (marker guided use). In order to reduce or replace cystoscopy altogether, urinary markers should be able to detect recurrence in all risk groups. However, the reported low sensitivity for LG recurrences limits their utility in this group [131,458] although more recent studies have shown reasonable sensitivity of 40–65% in detecting low grade recurrences [459,460].

For clinical implementation of urinary molecular markers for NMIBC surveillance some key issues are relevant [133]:

• Inflated NPVs: Prevalence of recurrence influences both NPV and PPV at a given sensitivity and specificity, i.e. a low proportion of recurring patients in a cohort automatically renders a higher NPV. For example, a urinary marker missing all recurrences in a cohort where 15% recur will display a NPV of 0.85 despite not being clinically useful
• Clinical context: In a patient with high- or very high-risk NMIBC the consequence if a urinary marker test misses recurrent disease is more severe than in a patient with either low- or intermediate-risk NMIBC. In these lower risk categories, the clinical utility of a urinary marker would be to postpone or even replace a cystoscopy (marker guided use). Furthermore, in a high-risk NMIBC scenario a marker enforced application would be simultaneously relevant to improve detection of a HG recurrence.
• Patient preferences: Patients prefer certainty over the burden of cystoscopic surveillance [461].
• Cost-effectiveness: Needs to be shown prior to implementation, i.e. to calculate quality-adjusted life-years (QALY), total costs, and incremental cost effectiveness ratios (ICER) for different follow-up scenarios.

In the current absence of randomised trials investigating marker guided use of urinary molecular markers with non-inferiority design in predefined NMIBC risk groups, high-level evidence for clinical implementation is currently lacking. Consequently, no urinary marker can replace cystoscopy during follow-up or lower cystoscopy frequency in a routine fashion. Nonetheless, some urinary markers, chiefly those detecting multiple genetic alterations in the urine (so-called “multiplex” urine 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 [460,462-464] (Table 8.1). Table 8.2 summarises the current recommended follow-up scheme for NMIBC according to the disease risk category.

Table 8.1: Performance of multiplex urine markers in the surveillance setting

HG = high grade; n = number
* Ranges refer to the lowest and the highest value respectively reported from available individual studies or systematic reviews.

Table 8.2: Proposed follow-up schedule based on patient’s risk category

*Intermediate-risk HG/G3 subgroup should be followed-up as high-risk
** At the same intervals as cystoscopy

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