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Background: Nonurothelial carcinoma (UC) malignancies have traditionally been considered to have a more aggressive clinical course, and little is known about their response to neoadjuvant therapy. We examined the effect of neoadjuvant chemotherapy (NAC) on a large population of patients with bladder cancer (BCa) with different histologic variants (HVs). Patients and Methods: We relied on a retrospective, multicenter database of 2858 patients with BCa who had undergone radical cystectomy with or without NAC from 1990 to 2017. Pure and mixed HVs were grouped into 6 categories: squamous cell carcinoma (SCC; n = 283; 45%), other subtypes (n = 95; 15%), micropapillary (n = 85; 14%), adenocarcinoma (n = 65; 10%), small cell (n = 54; 8.6%), and sarcomatous (n = 47; 7.6%). Kaplan-Meier and Cox regression analyses were used to examine cancer-specific survival (CSS) according to the HV, using pure UC as the reference. Logistic regression models were used to examine the odds of clinical-to-pathologic downstaging after NAC according to the HV. Results: Overall, we identified 2229 cases of pure UC and 629 cases of BCa with HVs at radical cystectomy. Of the 450 NAC-treated patients, only those patients with SCC (n = 44; 9.8%) had had worse CSS (median CSS, 33 vs. 116 months; P

The availability of new potent systemic therapies for urothelial carcinoma may change the way we use standard chemotherapy perioperatively. In particular, identifying which patients with muscle-invasive bladder cancer (MIBC) would benefit from adjuvant chemotherapy (AC) is compelling. From a multicenter database we selected 950 patients with cT2–4N0M0 MIBC treated with radical cystectomy (RC), with or without neoadjuvant chemotherapy (NAC), and AC. We used Kaplan-Meier analyses to test 1-yr recurrence-free survival (RFS) rates according to AC use. Nomogram-derived probabilities of 1-yr recurrence after RC were plotted against actual recurrence rates according to AC use. Overall, we did not see evidence of an AC effect on the 1-yr RFS rate (p = 0.6). Conversely, the 1-yr RFS rate was higher among patients with pT3–4 or pN1 disease who received AC (75% vs 54%; p < 0.001). We were unable to demonstrate a difference between AC and no AC among patients who received prior NAC (1-yr RFS 57% vs 76%; p = 0.057). As the most important finding, AC was associated with incremental RFS benefits only for patients with a nomogram-derived 1-yr recurrence probability of >40%. Patient summary: Maximizing disease control with adjuvant chemotherapy was beneficial for patients with muscle-invasive bladder cancer who had a calculated recurrence risk of >40% and did not impact cancer recurrence in lower-risk disease. Therefore, patient stratification using the nomogram available for predicting recurrence is advisable pending external validation. © 2019 European Association of Urology Adjuvant chemotherapy after neoadjuvant treatment and radical cystectomy for muscle-invasive bladder cancer should be offered only to patients with a high risk of 1-yr recurrence. Time-based endpoints may be more useful to help data interpretation for the next adjuvant and neoadjuvant immunotherapy studies. © 2019 European Association of Urology

Background: Several ongoing phase 2 trials are evaluating new neoadjuvant therapy regimens in patients with muscle-invasive bladder cancer (MIBC). The 1-yr recurrence-free survival (RFS) after radical cystectomy (RC), with or without perioperative chemotherapy, can be used to model statistical assumptions and interpret outcomes from these studies. Objective: To provide a benchmark for predicting 1-yr RFS in patients with cT2–4N0 MIBC. Design, setting, and participants: We identified 950 patients with clinical stage T2–4N0 MIBC undergoing RC at 27 centers between 1990 and 2016. We assessed 1-yr RFS rates for patients managed with no perioperative chemotherapy, neoadjuvant chemotherapy (NAC), adjuvant chemotherapy (AC), or NAC followed by AC. Cox regression analyses tested for 1-yr postsurgical RFS predictors. A Cox-based nomogram was developed to estimate 1-yr RFS and its accuracy was assessed in terms of Harrell's c-index, a calibration plot, and decision curve analysis. We report 1-yr RFS rates across the nomogram tertiles. Results and limitations: The 1-yr RFS rates were 67.9% (95% confidence interval [CI] 64–72) after no perioperative chemotherapy, 76.9% (95% CI 72–83%) after NAC, 77.8% (95% CI 71–85%) after AC, and 57% (95% CI 37–87) after NAC + AC. On multivariable analysis, positive surgical margins (p = 0.002), pT stage (p < 0.0001), and pN stage (p

Background: Limited information is available about the pattern of relapse after perioperative chemotherapy with radical cystectomy (RC) vs. RC alone in muscle-invasive bladder cancer. Patients and Methods: Data from 1082 patients of the Retrospective International Study of Invasive/Advanced Cancer of the Urothelium database, treated from February 1990 to December 2013 at 27 centers in the United States, Europe, Israel, and Canada, were collected. Locoregional relapse was defined as any pelvic lymph node or soft tissue-only recurrences. Cumulative incidence methods were used to estimate time to locoregional relapse (TTR L ). Cox regression analyses were performed and a nomogram for 12-month locoregional relapse-free survival (RFS) was developed. The nomogram was applied to an external data set (n = 1021). Results: A total of 517 patients (47.8%) developed a relapse: 177 (16.4%) exclusive locoregional relapse. In multivariable analyses, perioperative chemotherapy was associated with longer TTR L (P

Background: The effect of local treatment on survival in advanced-stage patients has gained interest in several malignancies; however, limited data exist regarding urothelial carcinoma (UC). Objective: To test the impact of surgery of the primary tumor site on cancer-specific mortality (CSM) and overall mortality (OM) in patients affected by metastatic UC. Design, setting, and participants: Individual patient-level data from a multicenter collaboration, including metastatic UC patients treated with first-line cisplatin- or carboplatin-based chemotherapy administered between January 2006 and January 2011 from hospitals in the USA, Europe, Israel, and Canada. Outcome measurements and statistical analysis: Univariable and multivariable Cox regression analyses were used to assess the effect of surgery on CSM and OM in patients affected by metastatic UC using 3-mo landmark analyses. Subgroup analyses were performed on the basis of the number of metastasis sites involved and including only patients treated with surgery before the start of chemotherapy. Results and limitations: Of the 326 patients included in the study, 47 (14%) were treated with surgery of the primary tumor site. Median (interquartile range) follow-up was 43 (33–45) mo. Of the patients treated with surgery, 28 (60%) were affected by a primary bladder cancer and 19 (40%) by a primary upper urinary tract tumor. On multivariable analyses, surgery was associated with a protective effect on CSM (hazard ratio [HR]: 0.59, confidence interval [CI]: 0.35–0.98, p = 0.04) and OM (HR: 0.45, CI: 0.37–0.99, p = 0.04) compared with patients treated with chemotherapy only. Similar results were found considering patients only surgically treated before the start of chemotherapy. After stratifying according to the number of metastatic sites, surgery has an effect on survival in patients with only one metastatic site, while no survival benefit was observed in patients with two or more metastatic sites. The study is limited by its retrospective nature. Conclusions: We found that surgery of the primary tumor site is associated with improved survival in patients with metastatic UC who received standard chemotherapy. This effect disappears in patients affected by two or more metastatic sites. Our results need to be validated in a high-quality prospective trial. Patient summary: In our multicenter, retrospective series, surgery in metastatic urothelial cancer patients improve survival compared with patients treated with chemotherapy only. This effect was evident in patients with limited disease extent, identified as one metastatic site. Patients affected by metastatic urothelial carcinoma treated with surgery in the primary tumor site in addition to standard chemotherapy recorded improved survival compared with patients treated with chemotherapy only. This effect is preponderant in patients with a single metastatic site. © 2019 European Association of Urology

In contemporary cohorts of patients who have received perioperative chemotherapy for muscle-invasive bladder cancer, no substantial differences were found between robot-assited radical cystectomy (RARC) and open radical cystectomy, and the number of lymph nodes removed was higher with RARC. © 2017 European Association of Urology Background: Little is known about the outcomes of robot-assisted radical cystectomy (RARC) compared to open radical cystectomy (ORC) combined with perioperative chemotherapy for muscle-invasive urothelial bladder cancer (UBC). Objective: To evaluate surgical and oncological outcomes for RARC and ORC in multimodal treatment. Design, setting, and participants: Data from 28 centres were collected for cystectomies performed between January 2000 and July 2013. Intervention: RARC or ORC combined with perioperative chemotherapy for UBC. Outcome measures and statistical analysis: Fisher's exact tests, χ 2 tests, and Wilcoxon rank-sum tests were used to compare the RARC and ORC groups. Logistic and Cox regression analyses were performed to evaluate potential prognostic factors. Results and limitations: A total of 688 patients (n = 603 ORC and n = 85 RARC) were analysed; 60.6% received neoadjuvant chemotherapy, and 45.1% adjuvant chemotherapy. No significant differences in baseline characteristics were found between the groups. The median time from surgery to adjuvant chemotherapy was 1.9 mo for both RARC and ORC groups. The median number of lymph nodes removed was 21 (interquartile range [IQR] 14–35) for RARC and 13 (IQR 8–21) for ORC (p < 0.001); the results were confirmed in subgroup analyses. Multivariable analyses revealed no difference in the rate of positive surgical margins (p = 0.54 and p = 0.78), rate of neobladder diversion (p = 0.33 and p = 0.51), relapse-free survival (p = 0.31 and p = 0.23), and overall survival (p = 0.63 and p = 0.69). The retrospective nature of the data is the major limitation. Conclusions: In this study, no differences in efficacy outcomes or ability to deliver adjuvant chemotherapy were observed between RARC and ORC. The increasing use of RARC is justifiable from an oncological viewpoint. Patient summary: In a retrospective study of patients who received perioperative chemotherapy for urothelial bladder cancer, we found no difference in key outcomes between robot-assisted radical cystectomy (RARC) and open radical cystectomy. Performing RARC seems to be justifiable in the multidisciplinary setting. © 2017 European Association of Urology

Purpose: We evaluated the impact of the number of cycles of platinum based, first line chemotherapy (fewer than 6 cycles vs the conventional 6 cycles or more) on the survival of patients with metastatic urothelial carcinoma. Materials and Methods: We used the RISC (Retrospective International Study of Invasive/Advanced Cancer of the Urothelium) database. The association of the number of cycles of chemotherapy with overall survival was investigated by Cox multiple regression analysis after controlling for recognized prognostic factors. We excluded patients who received fewer than 3 or more than 9 platinum chemotherapy cycles to reduce confounding factors. The primary analysis was a comparison of overall survival for 3 to 5 vs 6 to 9 cycles using 6-month landmark analysis when 281 death events were observed. Results: Of the 1,020 patients in the RISC 472 received cisplatin or carboplatin, of whom 338 and 134, respectively, were evaluable. A total of 157 patients received 3 to 5 cycles (median 4) and 315 received 6 to 9 cycles (median 6). There was no significant difference in overall survival between 3 to 5 and 6 to 9 cycles (HR 1.02, 95% CI 0.78–1.33, p = 0.91). No significant interactions were observed for the type of platinum (p = 0.09) and completed planned chemotherapy (p = 0.56). The limitations of a hypothesis generating, retrospective analysis applied. Conclusions: Four cycles of platinum based, first line chemotherapy appeared adequate and did not significantly compromise the survival of patients with advanced urothelial carcinoma. The omission of excessive cycles may avoid unnecessary cumulative toxicity and facilitate a better transition to second line therapy and investigational switch maintenance therapy strategies. These results require prospective validation but they may impact practice in select patients. © 2018 American Urological Association Education and Research, Inc.

Background The available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of cisplatin-treated patients. Objective To develop a new model based on real-world patients. Design, setting, and participants Individual patient-level data from 29 centers were collected, including metastatic UC and first-line cisplatin- or carboplatin-based chemotherapy administered between January 2006 and January 2011. Intervention First-line, platinum-based, combination chemotherapy. Outcome measurements and statistical analysis The population was randomly split into a development and a validation cohort. Generalized boosted regression modelling was used to screen out irrelevant variables and address multivariable analyses. Two nomograms were built to estimate OS probability, the first based on baseline factors and platinum agent, the second incorporating objective response (OR). The performance of the above nomograms and that of other available models was assessed. We plotted decision curves to evaluate the clinical usefulness of the two nomograms. Results and limitations A total of 1020 patients were analyzed (development: 687, validation: 333). In a platinum-stratified Cox model, significant variables for OS were performance status (p