Muscle-invasive and Metastatic Bladder Cancer

8. FOLLOW UP

8.1. Follow-up in muscle invasive bladder cancer

An appropriate schedule for disease monitoring should be based on natural timing of recurrence; probability and site of recurrence; functional monitoring after urinary diversion and the potential available management options [570].

Nomograms on CSS following RC have been developed and externally validated, but their wider use cannot be recommended until further data become available [571,572].

Current surveillance protocols are based on patterns of recurrence drawn from retrospective series only. Combining this data is not possible since most retrospective studies use different follow-up regimens and imaging techniques. Additionally, reports of asymptomatic recurrences diagnosed during routine oncological follow-up and results from retrospective studies are contradictory [573-575]. From the Volkmer B, et al., series of 1,270 RC patients, no differences in OS were observed between asymptomatic and symptomatic recurrences [574]. Conversely, in the Giannarini, et al., series of 479 patients; those with recurrences detected during routine follow-up (especially in the lungs) and with secondary urothelial tumours as the site of recurrence, had a slightly higher survival [573]. Boorjian, et al., included 1,599 RC patients in their series, with 77% symptomatic recurrences. On multivariate analysis, patients who were symptomatic at recurrence had a 60% increased risk of death as compared to asymptomatic patients [575].

However, at this time, no data from prospective trials demonstrating the potential benefit of early detection of recurrent disease and its impact on OS are available [576].

8.2. Site of recurrence

8.2.1. Local recurrence

Local recurrence takes place in the soft tissues of the original surgical site or in LNs. Contemporary cystectomy has a 5–15% probability of pelvic recurrence which usually occurs during the first 24 months, most often within 6 to 18 months after surgery. However, late recurrences can occur up to five years after RC. Risk factors described are pathological stage, LNs, positive margins, extent of LND and peri-operative chemotherapy [577].

Patients generally have a poor prognosis after pelvic recurrence. Even with treatment, median survival ranges from four to eight months following diagnosis. Definitive therapy can prolong survival, but mostly provides significant palliation of symptoms. Trimodality management generally involves a combination of chemotherapy, radiation and surgery [576].

8.2.2. Distant recurrence

Distant recurrence is seen in up to 50% of patients treated with RC for MIBC. As with local recurrence, pathological stage and nodal involvement are risk factors [578]. Systemic recurrence is more common in locally-advanced disease (pT3/4), ranging from 32 to 62%, and in patients with LN involvement (range 52–70%) [579].

The most likely sites for distant recurrence are LNs, lungs, liver and bone. Nearly 90% of distant recurrences appear within the first three years after RC, mainly in the first two years, although late recurrence has been described after more than 10 years. Median survival of patients with progressive disease treated with platinum-based chemotherapy is 9–26 months [580-582]. However, longer survival (28–33% at 5 years) has been reported in patients with minimal metastatic disease undergoing TMT management, including metastasectomy [324,583].

8.2.3. Urothelial recurrences

After RC, the incidence of new urethral tumours was 4.4% (1.3–13.7%). Risk factors for secondary urethral tumours are urethral malignancy in the prostatic urethra/prostate (in men) and bladder neck (in women). Orthotopic neobladder was associated with a significant lower risk of urethral tumours after RC (OR: 0.44) [584].

There is limited data, and agreement, about urethral follow-up, with some authors recommending routine surveillance with urethral wash and urine cytology and others doubting the need for routine urethral surveillance. However, there is a significant survival advantage in men with urethral recurrence diagnosed asymptomatically vs. symptomatically, so follow-up of the male urethra is indicated in patients at risk of urethral recurrence [576]. Treatment is influenced by local stage and grade of urethral occurrence. In urethral CIS, BCG instillations have success rates of 83% [585]. In invasive disease, urethrectomy should be performed if the urethra is the only site of disease; in case of distant disease, systemic chemotherapy is indicated [3].

Upper urinary tract UCs occur in 4–10% of cases and represent the most common sites of late recurrence (3-year DFS following RC) [586]. Median OS is 10–55 months, and 60–67% of patients die of metastatic disease [576]. A meta-analysis found that 38% of UTUC recurrence was diagnosed by follow-up investigations, whereas in the remaining 62%, diagnosis was based on symptoms. When urine cytology was used during surveillance, the rate of primary detection was 7% vs. 29.6% with UUT imaging. The meta-analysis concluded that patients with non-invasive cancer are twice as likely to have UTUC as patients with invasive disease [587]. Multifocality increases the risk of recurrence by three-fold, while positive ureteral or urethral margins increase the risk by seven-fold. Radical nephroureterectomy can prolong survival [588].

8.3. Time schedule for surveillance

Although, based on low level evidence only, some follow-up schedules have been suggested, guided by the principle that recurrences tend to occur within the first years following initial treatment. A schedule suggested by the EAU Guidelines Panel includes a CT scan (every 6 months) until the third year, followed by annual imaging thereafter. Patients with multifocal disease, NMIBC with CIS or positive ureteral margins are at higher risk of developing UTUC, which can develop late (> 3 years). In those cases, monitoring of the UUT is mandatory during follow-up. Computed tomography is to be used for imaging of the UUT [587].

The exact time to stop follow-up is not well known and recently a risk-adapted schedule has been proposed, based on the interaction between recurrence risk and competing health factors that could lead to individualised recommendations and may increase recurrence detection. Elderly and very low-risk patients (those with NMIBC or pT0 disease at final cystectomy report) showed a higher competing risk of non-BC mortality when compared with their level of BC recurrence risk. On the other hand, patients with locally-advanced disease or LN involvement are at a higher risk of recurrence for more than 20 years [589]. However, this model has not been validated, does not differentiate between pure UC or variant histologies, and does not incorporate several risk factors related to non-BC mortality. Subtype tumours (including urothelial subtypes, non-urothelial subtypes, and mixed subtypes) might be associated with a greater recurrence risk than pure UC. Recently, a different follow-up scheme for patients with subtype tumours has been proposed [590]. In case of pT0 patients with previous subtype in TURB or in those in the age range between 60 and 79 years, the follow-up should be longer than in pure UC since the risk of recurrence persists over time. Similar to pure UC, patients older than 80 years with subtype tumours might not need oncologic surveillance given the higher risk of non-BC mortality compared to the risk of recurrence whereas patients younger than 60 years should be offered extended surveillance (> 10 years) since the risk of recurrence will exceed that of non-BC mortality [590]. Future prospective studies are needed to answer the question whether a more intense follow- up for subtypes should be considered.

Furthermore, the prognostic implications of the different sites of recurrence should be considered. Local and systemic recurrences have a poor prognosis and early detection of the disease will not influence survival [591]. Despite this, the rationale for a risk-adapted schedule for BC surveillance appears to be promising and deserves further investigation.

Since data for follow-up strategies are sparse, a number of key questions were included in a recently held consensus project [81,82]. Outcomes for all statements for which consensus was achieved are listed in Section 8.6.

8.4. Follow-up of functional outcomes and complications

Apart from oncological surveillance, patients with a urinary diversion need functional follow-up. Complications related to urinary diversion are detected in 45% of patients during the first five years of follow-up. In a series of 131 patients, this rate increased to 94% in those surviving > 15 years [592].

General functional complications are diverse and include: vitamin B12 deficiency, metabolic acidosis, worsening of renal function, urinary infections, urolithiasis and ureteroenteric stricture [593]. Benign ureteroenteric strictures may occur in up to 20% of patients [593]. Based on SEER data, cystectomy was found to be associated with a 21% increased risk of fractures compared to no RC due to chronic metabolic acidosis and subsequent long-term bone loss [591]. Since low vitamin B12 levels have been reported in 17% of patients with bowel diversion, in case of cystectomy and bowel diversion, vitamin B12 levels should be measured annually [81,82,594]. In a series of 3,360 patients who underwent RC for MIBC, 29% progressed to advanced chronic kidney disease within 12 months [595].

In a retrospective study comparing various forms of intestinal diversion, ileal conduits had fewer late complications than continent abdominal pouches or orthotopic neobladders [594]. The main long- term complications in ileal conduit patients are stomal complications in up to 24% and functional and/or morphological changes of the UUT in up to 30% of patients [594,596,597]. At 15 years of follow-up, 50% of patients developed UUT changes and 38% developed urolithiasis [598].

The main specific complications in patients with a neobladder are continence problems and emptying dysfunction [576]. Clifford et al., prospectively evaluated continence outcomes in male patients undergoing orthotopic neobladder diversion [599]. Day-time continence increased from 59% at less than three months post-operatively to 92% after 12 to 18 months. Night-time continence increased from 28% at less than three months post-operatively to 51% after 18 to 36 months. Also of interest is the urinary bother in females with an orthotopic neobladder. Bartsch and co-workers reported day-time and night-time continence rates of 70.4% and 64.8%, respectively, in 56 female neobladder patients. Emptying disfunction is especially common in women: approximately two-thirds need to catheterise their neobladder, while almost 45% do not void spontaneously at all [600]. There seems to be a correlation between voiding patterns and nerve preservation; in 66 women bilateral preservation of autonomic nerves decreased the need for catheterisation to between 3.4–18.7% (CI: 95%) [601].

In a single-centre series of 259 male patients, long-term follow-up after orthotopic bladder substitution (median 121 months [range 60–267]), showed that excellent long-term functional outcomes can be achieved in high-volume centres with dedicated teams [602].

8.5. Summary of evidence and recommendations for specific recurrence sites

8.6. EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer [81,82]*

*Only statements which met the a priori consensus threshold across all three stakeholder groups are listed (defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa).CT = computed tomography.