Muscle-invasive and Metastatic Bladder Cancer

8. RECURRENT DISEASE

8.1. Intravesical recurrence

8.1.1. Post-trimodality therapy bladder recurrences and salvage cystectomy

A bladder-preserving TMT strategy requires a high level of patient compliance. Even if a patient has shown a clinical response to a TMT bladder-preserving strategy, the bladder remains a potential source of recurrence, hence long-term life-long bladder monitoring is essential, and patients should be counselled that this will be required.

The majority of recurrences post-TMT are non-invasive and can be treated with TURBT and bladder instillations with chemotherapy or BCG [2,406]. Non-muscle-invasive BC recurrences after complete response to TMT were reported in 25% of patients by the Boston group, over a decade after initial treatment in some cases [475]. An NMIBC recurrence was associated with a lower DSS, although in properly selected patients, intravesical BCG could avoid immediate salvage cystectomy.

8.1.2. Salvage cystectomy post-trimodality therapy

A retrospective, single-centre analysis grouped 265 patients into salvage cystectomy post-TMT; primary cystectomy; primary cystectomy with a history of non-TMT abdominal; or pelvic RT. Post-TMT salvage cystectomy was associated with a higher incidence of any late (HR: 2.3; p = 0.02) and major late complications (HR: 2.1; p < 0.05), but there was no difference in intraoperative and early complications, DSS (p = 0.8) or OS (p = 0.9) between the groups [476].

In contemporary series, salvage cystectomy is required in approximately 10-15% of patients treated with TMT due to invasive in-bladder recurrences and can be curative [400,402,406,417] (see Section 7.4). In fact, patients who required a salvage cystectomy for a recurrence had similar survival to those who did not require a salvage cystectomy [402].

Current data suggest that salvage cystectomy is feasible with acceptable morbidity. Major late complication rates were slightly higher but remain acceptable for salvage versus primary cystectomy, and there was no difference in intraoperative and early complications, DSS or OS [476,477].

In a retrospective analysis of 1,846 evaluable patients, only 34 patients received RT prior to orthotopic neobladder reconstruction. It was concluded that, following pelvic RT, a neobladder is possible in highly selected patients with statistically similar perioperative complication rates compared to patients who did not receive prior RT. Patient selection, with oncologic factors (positive urethral margins, nodal involvement and extravascular disease) more commonly than technical factors (adhesions/difficult dissection, bleeding, urethral stricture) influence conversion from a planned neobladder reconstruction [478].

8.1.3. Recommendation for salvage cystectomy

8.2. Pelvic 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 six 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 underutilisation of perioperative chemotherapy [479].

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 [457].

8.3. Upper tract recurrence

Upper urinary tract UCs occur in 4-10% of cases and represent the most common sites of late recurrence (three-year DFS following RC) [480]. Median OS is 10-55 months, and 60-67% of patients die of metastatic disease [457]. 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% versus 29.6% with upper urinary tract imaging. The meta-analysis concluded that patients with non-invasive cancer are twice as likely to have UTUC as patients with invasive disease [459]. Multifocality increases the risk of recurrence threefold, while positive ureteral or urethral margins increase the risk sevenfold. Radical nephroureterectomy can prolong survival [481].

8.4. Urethral recurrence

Urethral recurrence-related death is rare, and prophylactic urethrectomy does not show a survival benefit. However, inappropriate urethra preserving surgery in patients at high-risk of urethral recurrence may increase local recurrence. This may be responsible for poor survival after urethra preserving surgery rather than disease progression derived from urethral recurrence. Robotic urethra-preserving surgery has the potential to reduce unnecessary urethral and local recurrence without compromising survival [482]. In a systematic review, the incidence of new urethral tumours after RC is 4.4% (1.3-13.7%). Risk factors for secondary urethral tumours are urethral malignancy in the prostatic urethra/prostate (in males) and bladder neck (in females). Orthotopic neobladder was associated with a significant lower risk of urethral tumours after RC (OR: 0.44) [483].

There is limited data, and agreement, regarding 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 males with urethral recurrence diagnosed asymptomatically versus symptomatically, therefore follow-up of the male urethra is indicated in patients at risk of urethral recurrence [457]. Treatment is influenced by local stage and grade of urethral occurrence. In urethral CIS, BCG instillations have success rates of 83% [484]. 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].

8.5. 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 [485]. Systemic recurrence is more common in locally advanced disease (pT3/4), ranging from 32% to 62%, and in patients with LN involvement, ranging from 52 to 70% [486].

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 ten years. Median survival of patients with progressive disease treated with platinum-based chemotherapy is 9-26 months [487-489]. However, longer survival (28-33% at five years) has been reported in patients with minimal metastatic disease undergoing TMT management, including metastasectomy [490,491].

8.6. Summary of evidence and recommendations for specific recurrence sites