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 3 months is an important prognostic indicator for recurrence and progression [230,235,250,253,423]. Therefore, the first cystoscopy should always be performed 3 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) [221,223]. 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 [252,424]. In addition, recurrence after 5 recurrence-free years is low [253] (LE: 3). Therefore, in low-risk tumours, after 5 years of follow-up, discontinuation of cystoscopy or its replacement with less invasive methods should be considered [423].
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 risk categories [227]; 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 low grade tumours [425], low-grade intermediate-risk NMIBC can be safely followed-up with a cystoscopy at 3 months and, if negative, with 6 monthly cystoscopies for 2 years followed by yearly cystoscopies up to 10 years. This surveillance scheme for this disease category has already been adopted by the Scottish Access Collaborative Workstream [426]. 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 cytology. Recurrences after ten years tumour-free are not unusual [427]. Therefore, the optimal surveillance strategy for these patients includes initial frequent cystoscopy and cytology and life-long follow-up [423].
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 [94], with 10 year tumour rates in UUT varing between 2.8% in CIS [428] and 25% in patients with multiple and recurrent high risk NMIBC [429]. 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 [430,431]. On the other hand, a prospective study of NBI for NMIBC surveillance failed to show any benefit for NBI over WL cystoscopy alone [432].
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 [133,433,434].
8.1.5.3. Urinary molecular markers and urine cytology
Non-invasive 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. Research has been carried out into the usefulness of urinary cytology vs. urinary molecular markers in the follow-up of NMIBC [112,115,120,130,433,435]. 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 [130,436] although more recent studies have shown reasonable sensitivity in low grade recurrences sensitivity of 40–65% [118,437]. 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 [117,437-439] (Table 8.1).
Table 8.1: Urinary markers in the surveillance setting*
Marker | Sensitivity overall | HG | Specificity overall | HG | PPV overall | HG | NPV overall | HG | N studies/patients |
XPERT BC® MONITOR | 0.72 | 0.88 | 0.76 | 0.75 | 0.43 | 0.18 | 0.92 | 0.99 | 10/> 2000 |
EpiCheckTM | 0.74 | 0.91 | 0.84 | 0.81 | 0.48 | 0.43 | 0.94 | 0.98 | 5/1600 |
ADX BladderTM | 0.57 | 0.71 | 0.62 | 0.76 | 0.29 | 0.37 | 0.82 | 0.93 | 3/1600 |
CX BLADDER | 0.91 | - | 0.61 | - | 0.16 | - | 0.98 | - | 2/1000 |
FDFGR3+TERT | 0.93 | - | 0.79 | - | 0.67 | - | 0.96 | - | 2/250 |
*Data extracted from a pooled analyses of systematic review [435].
HG = high grade; NMIBC = non-muscle-invasive bladder cancer; PPV = positive predictive value;NPV = negative predictive value; n = number.
Table 8.2: Proposed follow-up schedule based on patient’s risk category
Risk group | Cytology* | Cystoscopy | Imaging | Duration of follow-up |
Low | No | At 3 and 12 months Then annually | Not systematic | 5 years |
Intermediate (not including HG/G3 subgroup)* | No | At 3 months Then every 6 months for 2 years Then annually | Not systematic | 10 years |
High and Very High | Yes** | Every 3 months for 2 years Then every 6 months up to 5 years Then annually | CT annually up to 5 years Then CT every 2 years up to 10 years | Life long |
*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
Summary of evidence | LE |
The first cystoscopy after transurethral resection of the bladder at 3 months is an important prognostic indicator for recurrence and progression. | 1a |
The risk of upper urinary tract recurrence increases in patients with multiple- and high-risk tumours. | 3 |
Recommendations | Strength rating |
Base follow-up of TaT1 tumours and carcinoma in situ (CIS) on regular cystoscopy. | Strong |
Patients with low-risk Ta tumours should undergo cystoscopy at three months. If negative, subsequent cystoscopy is advised nine months later, and then yearly for five years. | Weak |
Patients with high-risk and those with very high-risk tumours treated conservatively should undergo cystoscopy and urinary cytology at three months. If negative, subsequent cystoscopy and cytology should be repeated every three months for a period of two years, and every six months thereafter until five years, and then annually lifelong. | Weak |
Perform cystoscopy at three months for patients with intermediate-risk Ta low-grade tumours. If negative, subsequent cystoscopy can be repeated every six months for two years, and then annually for ten years. The subgroup of intermediate-risk that are high grade should be followed up as high-risk. | Weak |
Take regular and long-term upper tract imaging (computed tomography urography) for high-risk and very high-risk tumours. | Weak |
Perform endoscopy under anaesthesia and bladder biopsies when office cystoscopy shows suspicious findings or if urinary cytology is positive. | Strong |
During follow-up in patients with positive cytology and no visible tumour in the bladder, mapping biopsies or PDD-guided biopsies (if equipment is available) and investigation of extravesical locations (CT urography, prostatic urethra biopsy) are recommended. | Strong |