Review article

Follow-up strategies and management of recurrence in urologic oncology bladder cancer:: Invasive bladder cancer

To investigate the oncologic outcomes of pT0 after robot-assisted radical cystectomy (RARC).

A retrospective review of the International Robotic Cystectomy Consortium database was performed. Patients with pT0 after RARC were identified and analyzed. Data were reviewed for demographics and pathologic outcomes. Kaplan-Meier curves were used to depict recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS). Multivariate stepwise Cox regression models were used to identify variables associated with RFS and OS.

Four hundred seventy-one patients (18%) with pT0 were identified. Median age was 68 years (interquartile range (IQR) 60-73), with a median follow up of 20 months (IQR 6-47). Thirty-seven percent received neoadjuvant chemotherapy and 5% had pN+ disease. Seven percent of patients experienced disease relapse; 3% had local and 5% had distant recurrence. Most common sites of local and distant recurrences were pelvis (1%) and lungs (2%). Five-year RFS, DSS, and OS were 88%, 93%, and 79%, respectively. Age (hazards ratio [HR] 1.05, 95% confidence interval [CI] 1.01-1.09, P = 0.02), pN+ve (HR 11.48, 95% CI 4.47-29.49, P < .01), and reoperations within 30 days (HR 5.53, 95% CI 2.08-14.64, P < .01) were associated with RFS. Chronic kidney disease (HR 3.24, 95% CI 1.45-7.23, P < .01), neoadjuvant chemotherapy (HR 0.41, 95% CI 0.18-0.92, P = .03), pN+ve (HR 4.37, 95% CI 1.46-13.06, P < .01), and reoperations within 30 days (HR 2.64, 95% CI, 1.08-6.43, P = .03) were associated with OS.

Despite pT0 status at RARC, 5% had pN+ disease and 7% of patients relapsed. Node status was the variable strongest associated with RFS and OS in pT0.

Several guidelines exist that address treatment of patients with nonmetastatic muscle-invasive bladder cancer (MIBC). However, most only briefly mention follow-up strategies for patients and hence the treating physician is often left to infer on what the preferred follow-up schema would be for an individual patient. Herein, we aim to synthesize recommendations for follow-up of patients with MIBC for easy reference.

A multidisciplinary MIBC expert panel from the International Bladder Cancer Network was assembled to critically assess currently available major guidelines on surveillance of MIBC patients. Recommendations for follow-up were extracted and critically evaluated. Important considerations for guideline assessment included both aspects of oncological and functional follow-up—frequency of visits, the use of different imaging modalities, the role of cytology and molecular markers, and the duration of follow-up.

An International Bladder Cancer Network expert consensus recommendation was constructed for the follow-up of patients with MIBC based on the currently available evidence-based data.

The follow-up of patients treated for muscle-invasive bladder cancer (MIBC) is of major importance because of the high incidence of recurrence and disease progression. The schedule and methods of the follow-up should reflect the individual’s clinical situation. After surgical treatment for MIBC the follow-up is based on the results of endoscopy, cytology, and computed tomography-urography. Patients with extravesical and node-positive disease should undergo the most intensive follow-up scheme because of the highest risk of recurrence associated. Following radical cystectomy, approximately 50% of the patients show tumor recurrence. A recurrence might be local and systemic, or might occur in the urethra or upper urinary tract. The follow-up of patients having risk factors for local or systemic recurrence would achieve maximum efficiency during the first 3 years. Monitoring of the urethra must be adapted to the risk factors for recurrence and continued for at least 5 years. The monitoring of the upper urinary tract should be continued lifetime. In case of bladder preservation treatment for MIBC, early endoscopy and imaging reassessment is required. Critical to good outcomes after bladder preservation surgery depend on appropriate patient selection. The oncological follow-up of MIBC is determined according to the tumor stage and grade, location, and the treatment modality administered, thus defining the risk of recurrence over time.

We evaluated the diagnostic accuracy of urinary cytology (UCy) for detecting recurrence in the remnant urothelium (RRU) after radical cystectomy (RC) for urothelial cancer.

We conducted a 10-year retrospective analysis of a prospectively collected, single-center RC database comprising 177 patients who had undergone follow-up examinations at our department with ≥ 1 available postoperative UCy specimen. UCy specimens were classified using the Papanicolaou scheme.

In total, 957 cytology specimens were collected. Negative UCy results were noted in 927 (96.8%), atypical urothelial cells in 19 (2.0%), and suspicious/positive for malignancy in 11 (1.2%) cases. RRU was diagnosed in 16 patients (9.1%) during a mean follow-up period of 37 months (range, 1-118 months). The mean interval from RC to RRU was 34.7 months. Only 2 of 11 positive UCy specimens (18.2%) were falsely positive, for an overall sensitivity and specificity of 56.3% and 98.8% for predicting RRU, respectively. Urethral recurrence was diagnosed by UCy alone before the patients had developed symptoms in 8 of 12 cases (66.7%). Patients with clinical symptoms at the diagnosis of RRU had poorer cancer-specific survival rates than those of asymptomatic patients, although this trend was not statistically significant (P = .496). Moreover, positive UCy findings were associated with significantly lower overall survival (P < .001) and cancer-specific survival (P = .04) compared with negative UCy findings.

Our results underline the predictive value of UCy in the surveillance of the remnant urothelium, with early detection of urethral recurrence before the development of clinical symptoms.

To evaluate the efficacy of follow-up based on the patterns of recurrence, relapse presentation and survival after cystectomy, and to define a risk adjusted follow-up schedule.

The records of 343 patients with regular follow-up after cystectomy were reviewed for primary site of recurrence, accompanying symptoms, means of recurrence diagnosis, and clinicopathological factors. Based on Cox proportional hazard models, and the results of imaging studies low and high risk groups are identified and a risk adjusted follow-up protocol is proposed.

The risk of a recurrence was related to increasing pT, tumour positive lymph nodes, tumour positive surgical margins, and pre-operative dilatation of the upper urinary tract, and low and high risk groups were defined consequently. 84% of all recurrences occurred within 2 years, with only one recurrence beyond 2 years in the low risk group. Although the minority of all patients (34%) is asymptomatic at time of recurrence, symptomatic recurrences were adversely associated with survival. CT-scans and chest X-rays accounted for 90% of the diagnostic tools to detect a recurrence in patients without symptoms.

Asymptomatic patients may benefit from early treatment after disease recurrence. A risk adjusted follow-up strategy based on stage of disease and additional clinicopathological factors can dichotomise patients at high and low risk for recurrence. The small benefit in survival after early detection has to be confirmed in future studies, and weighed against the available treatment options of recurrences and their subsequent costs.

We evaluated the outcome in patients with late recurrence of urothelial carcinoma after radical cystectomy.

We identified 2,091 patients who underwent radical cystectomy at our institution between 1980 and 2006. Survival was estimated using the Kaplan-Meier method and compared based on recurrence timing (less than 5 years vs 5 or greater) and location (urothelial vs nonurothelial) using the log rank test. Cox proportional hazard regression models were used to evaluate variables associated with late recurrence and death from bladder cancer.

Median postoperative followup was 16.6 years. Late recurrence was identified in 82 patients (3.9%). On multivariate analysis younger age (p = 0.0008), nonmuscle invasive disease (p = 0.01) and prostatic urethral involvement (p <0.0001) were significantly associated with an increased risk of late recurrence. Five-year post-recurrence cancer specific survival was significantly worse after recurrence within 5 years from radical cystectomy vs after late recurrence (17% vs 37%, p = 0.001). Patients with nonurothelial late recurrence had adverse 5-year cancer specific survival compared to those with urothelial late recurrence (19% vs 67%, p <0.0001). On multivariate analysis younger patient age (HR 1.01, p = 0.003), muscle invasive disease (HR 1.31, p <0.0001) and nonurothelial recurrence site (HR 2.76, p <0.0001) but not time to recurrence (p = 0.38) were associated with a significantly increased risk of death from bladder cancer following recurrence after radical cystectomy.

Late recurrence is uncommon after radical cystectomy. Younger patient age, nonmuscle invasive disease and prostatic urethral involvement were associated with a significantly increased risk of late recurrence. Interestingly, time to recurrence was not associated with a subsequent risk of patient death.