Incidence, Clinicopathological Risk Factors, Management and Outcomes of Nonmuscle Invasive Recurrence after Complete Response to Trimodality Therapy for Muscle Invasive Bladder Cancer.

PURPOSE: We describe the incidence, clinicopathological risk factors, management and outcomes of recurrent nonmuscle invasive bladder cancer after a complete response to trimodality therapy of muscle invasive bladder cancer. MATERIALS AND METHODS: We retrospectively reviewed the records of 342 patients with cT2-4aN0M0 muscle invasive bladder cancer and a complete response after trimodality therapy from 1986 to 2013. Using competing risks analyses we examined the association between baseline clinicopathological variables and nonmuscle invasive bladder cancer outcomes. Kaplan-Meier and the generalized Fleming-Harrington test were used to compare disease specific and overall survival. RESULTS: At a median followup of 9 years nonmuscle invasive bladder cancer recurred in 85 patients (25%) who had had a complete response. On Kaplan-Meier analysis baseline carcinoma in situ was associated with recurrent nonmuscle invasive bladder cancer (p = 0.02). However, on multivariate analysis carcinoma in situ and other baseline clinicopathological characteristics did not predict such recurrence. Patients with recurrent nonmuscle invasive bladder cancer had worse 10-year disease specific survival than those without recurrence (72.1% vs 78.4%, p = 0.002), although overall survival was similar (p = 0.66). Of the 39 patients (46%) who received adjuvant intravesical bacillus Calmette-Guérin 29 (74%) completed induction therapy and 19 (49%) reported bacillus Calmette-Guérin toxicity. Three-year recurrence-free and progression-free survival after induction bacillus Calmette-Guérin was 59% and 63%, respectively. CONCLUSIONS: After a complete response to trimodality therapy nonmuscle invasive bladder cancer recurred in 25% of patients, developing in some of them more than a decade after trimodality therapy. No baseline clinicopathological characteristics were associated with such recurrence after a complete response. Patients with nonmuscle invasive bladder cancer recurrence had worse disease specific survival than those without such recurrence but similar overall survival. Adjuvant intravesical bacillus Calmette-Guérin had a reasonable toxicity profile and efficacy in this population. Properly selected patients with recurrent nonmuscle invasive bladder cancer after a complete response may avoid immediate salvage cystectomy.

The prognostic effect of salvage surgery and radiotherapy in patients with recurrent primary urethral carcinoma.

BACKGROUND: To evaluate the impact of salvage therapy (ST) on overall survival (OS) in recurrent primary urethral cancer (PUC). PATIENTS: A series of 139 patients (96 men, 43 women; median age = 66, interquartile range: 57-77) were diagnosed with PUC at 10 referral centers between 1993 and 2012. The modality of ST of recurrence (salvage surgery vs. radiotherapy) was recorded. Kaplan-Meier analysis with log-rank was used to estimate the impact of ST on OS (median follow-up = 21, interquartile range: 5-48). RESULTS: The 3-year OS for patients free of any recurrence (I), with solitary or concomitant urethral recurrence (II), and nonurethral recurrence (III) was 86.5%, 74.5%, and 48.2%, respectively (P = 0.002 for I vs. III and II vs. III; P = 0.55 for I vs. II). In the 80 patients with recurrences, the modality of primary treatment of recurrence was salvage surgery in 30 (37.5%), salvage radiotherapy (RT) in 8 (10.0%), and salvage surgery plus RT in 5 (6.3%) whereas 37 patients did not receive ST for recurrence (46.3%). In patients with recurrences, those who underwent salvage surgery or RT-based ST had similar 3-year OS (84.9%, 71.6%) compared to patients without recurrence (86.7%, P = 0.65), and exhibited superior 3-year OS compared to patients who did not undergo ST (38.0%, P<0.001 compared to surgery, P = 0.045 to RT-based ST, P = 0.29 for surgery vs. RT-based ST). CONCLUSIONS: In this study, patients who underwent ST for recurrent PUC demonstrated improved OS compared to those who did not receive ST and exhibited similar survival to those who never developed recurrence after primary treatment.

Long-term results of adjuvant versus early salvage postprostatectomy radiation: A large single-institutional experience.

PURPOSE: The purpose of this study was to evaluate freedom from biochemical failure (FFBF), freedom from androgen deprivation therapy (FFADT), freedom from distant metastases (FFDM), and overall survival (OS) after adjuvant radiation therapy (ART) versus early salvage radiation therapy (ESRT) in men with prostate cancer and adverse pathologic features (pT3 and/or positive surgical margins). METHODS AND MATERIALS: Of 718 patients consecutively treated with postoperative radiation therapy (RT) for prostate cancer between 1992 and 2013, we retrospectively identified 171 men receiving ART and 230 receiving ESRT (RT delivered at a prostate-specific antigen level ≤0.5 ng/mL) who had adverse pathologic features. Postirradiation FFBF (BF was defined as prostate-specific antigen level rise to ≥0.2 ng/mL), FFADT, FFDM, and OS were compared using Kaplan-Meier and Cox regression methods. Propensity score (PS)-matching was performed to estimate treatment effects while accounting for covariates predicting treatment allocation. RESULTS: Median follow-up was 7.4 and 8.0 years for patients treated with ART and ESRT, respectively. Ten-year FFBF (69% vs 56%, P = .003) and 10-year FFADT (88% vs 81%, P = .046) rates were higher after ART; however, FFDM and OS did not significantly differ. After PS-matching, ART was associated with improved FFBF (P < .0001), FFADT (P = .0001), and FFDM (P = .02). Findings were confirmed in multivariable analyses in unmatched and PS-matched cohorts. Sensitivity analyses showed that FFBF benefit associated with ART lost statistical significance only after 38% of ART patients were assumed to have been cured by surgery and excluded from the model. This corresponds to the upper bound of patients with adverse pathologic features who did not recur after observation in prior randomized trials. CONCLUSIONS: Postoperative RT confers excellent long-term cancer control. These results suggest ART may be associated with improved FFBF, FFADT, and FFDM, but comparable OS. Given the retrospective study design, these findings should be interpreted with caution. Optimal timing of postoperative RT further awaits results of ongoing trials.

Long-term Outcomes After Bladder-preserving Tri-modality Therapy for Patients with Muscle-invasive Bladder Cancer: An Updated Analysis of the Massachusetts General Hospital Experience.

BACKGROUND: Tri-modality therapy (TMT) is a recognized treatment strategy for selected patients with muscle-invasive bladder cancer (MIBC). OBJECTIVE: Report long-term outcomes of patients with MIBC treated by TMT. DESIGN, SETTING, AND PARTICIPANTS: Four hundred and seventy-five patients with cT2-T4a MIBC were enrolled on protocols or treated as per protocol at the Massachusetts General Hospital between 1986 and 2013. INTERVENTION: Patients underwent transurethral resection of bladder tumor followed by concurrent radiation and chemotherapy. Patients with less than a complete response (CR) to chemoradiation or with an invasive recurrence were recommended to undergo salvage radical cystectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Disease-specific survival (DSS) and overall survival (OS) were calculated using the Kaplan-Meier method. RESULTS AND LIMITATIONS: Median follow-up for surviving patients was 7.21 yr. Five- and 10-yr DSS rates were 66% and 59%, respectively. Five- and 10-yr OS rates were 57% and 39%, respectively. The risk of salvage cystectomy at 5 yr was 29%. In multivariate analyses, T2 disease (OS hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.44-0.75, DSS HR: 0.51, 95% CI: 0.36-0.73), CR to chemoradiation (OS HR: 0.61, 95% CI: 0.46-0.81, DSS HR: 0.49, 95% CI: 0.34-0.71), and presence of tumor-associated carcinoma in situ (OS HR: 1.56, 95% CI: 1.17-2.08, DSS HR: 1.50, 95% CI: 1.03-2.17) were significant predictors for OS and DSS. When evaluating our cohort over treatment eras, rates of CR improved from 66% to 88% and 5-yr DSS improved from 60% to 84% during the eras of 1986-1995 to 2005-2013, while the 5-yr risk of salvage radical cystectomy rate decreased from 42% to 16%. CONCLUSIONS: These data demonstrate high rates of CR and bladder preservation in patients receiving TMT, and confirm DSS rates similar to modern cystectomy series. Contemporary results are particularly encouraging, and therefore TMT should be discussed and offered as a treatment option for selected patients. PATIENT SUMMARY: Tri-modality therapy is an alternative to radical cystectomy for patients with muscle-invasive bladder cancer, and is associated with comparable long-term survival and high rates of bladder preservation.

Oncological Outcomes of Patients with Concomitant Bladder and Urethral Carcinoma.

INTRODUCTION: The study aimed to investigate oncological outcomes of patients with concomitant bladder cancer (BC) and urethral carcinoma. METHODS: This is a multicenter series of 110 patients (74 men, 36 women) diagnosed with urethral carcinoma at 10 referral centers between 1993 and 2012. Kaplan-Meier analysis was used to investigate the impact of BC on survival, and Cox regression multivariable analysis was performed to identify predictors of recurrence. RESULTS: Synchronous BC was diagnosed in 13 (12%) patients, and the median follow-up was 21 months (interquartile range 4-48). Urethral cancers were of higher grade in patients with synchronous BC compared to patients with non-synchronous BC (p = 0.020). Patients with synchronous BC exhibited significantly inferior 3-year recurrence-free survival (RFS) compared to patients with non-synchronous BC (63.2 vs. 34.4%; p = 0.026). In multivariable analysis, inferior RFS was associated with clinically advanced nodal stage (p < 0.001), proximal tumor location (p < 0.001) and synchronous BC (p = 0.020). CONCLUSION: The synchronous presence of BC in patients diagnosed with urethral carcinoma has a significant adverse impact on RFS and should be an impetus for a multimodal approach.

Prognostic factors and outcomes in primary urethral cancer: results from the international collaboration on primary urethral carcinoma.

PURPOSE: To evaluate risk factors for survival in a large international cohort of patients with primary urethral cancer (PUC). METHODS: A series of 154 patients (109 men, 45 women) were diagnosed with PUC in ten referral centers between 1993 and 2012. Kaplan-Meier analysis with log-rank test was used to investigate various potential prognostic factors for recurrence-free (RFS) and overall survival (OS). Multivariate models were constructed to evaluate independent risk factors for recurrence and death. RESULTS: Median age at definitive treatment was 66 years (IQR 58-76). Histology was urothelial carcinoma in 72 (47 %), squamous cell carcinoma in 46 (30 %), adenocarcinoma in 17 (11 %), and mixed and other histology in 11 (7 %) and nine (6 %), respectively. A high degree of concordance between clinical and pathologic nodal staging (cN+/cN0 vs. pN+/pN0; p < 0.001) was noted. For clinical nodal staging, the corresponding sensitivity, specificity, and overall accuracy for predicting pathologic nodal stage were 92.8, 92.3, and 92.4 %, respectively. In multivariable Cox-regression analysis for patients staged cM0 at initial diagnosis, RFS was significantly associated with clinical nodal stage (p < 0.001), tumor location (p < 0.001), and age (p = 0.001), whereas clinical nodal stage was the only independent predictor for OS (p = 0.026). CONCLUSIONS: These data suggest that clinical nodal stage is a critical parameter for outcomes in PUC.