Occult lymph node metastases in patients without residual muscle-invasive bladder cancer at radical cystectomy with or without neoadjuvant chemotherapy: a nationwide study of 5417 patients.

PURPOSE: Little is known about the prevalence of occult lymph node metastases (LNM) in muscle-invasive bladder cancer (MIBC) patients with pathological downstaging of the primary tumor. We aimed to estimate the prevalence of occult LNM in patients without residual MIBC at radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC) or neoadjuvant radiotherapy (NAR), and to assess overall survival (OS). METHODS: Patients with cT2-T4aN0M0 urothelial MIBC who underwent RC plus pelvic lymph node dissection (PLND) with curative intent between January 1995-December 2013 (retrospective Netherlands Cancer Registry (NCR) cohort) and November 2017-October 2019 (prospective NCR-BlaZIB cohort (acronym in Dutch: BlaaskankerZorg In Beeld; in English: Insight into bladder cancer care)) were identified from the nationwide NCR. The prevalence of occult LNM was calculated and OS of patients with <(y)pT2N0 vs. <(y)pT2N+ disease was estimated by the Kaplan-Meier method. RESULTS: In total, 4657 patients from the NCR cohort and 760 patients from the NCR-BlaZIB cohort were included. Of 1374 patients downstaged to <(y)pT2, 4.3% (N = 59) had occult LNM 4.1% (N = 49) of patients with cT2-disease and 5.6% (N = 10) with cT3-4a-disease. This was 4.0% (N = 44) in patients without NAC or NAR, 4.5% (N = 10) in patients with NAC, and 13.5% (N = 5) in patients with NAR but number of patients treated with NAR and downstaged disease was small. The prevalence of <(y)pT2N+ disease was 4.2% (N = 48) in the NCR cohort and 4.6% (N = 11) in the NCR-BlaZIB cohort. For patients with <(y)pT2N+ and <(y)pT2N0, median OS was 3.5 years (95% CI 2.5-8.9) versus 12.9 years (95% CI 11.7-14.0), respectively. CONCLUSION: Occult LNM were found in 4.3% of patients with cT2-4aN0M0 MIBC with (near-) complete downstaging of the primary tumor following RC plus PLND. This was regardless of NAC or clinical T-stage. Patients with occult LNM showed considerable worse survival. These results can help in counseling patients for bladder-sparing treatments.

Superior efficacy of neoadjuvant chemotherapy and radical cystectomy in cT3-4aN0M0 compared to cT2N0M0 bladder cancer.

In this study, we compared complete pathological downstaging (pCD, ≤(y)pT1N0) and overall survival (OS) in patients with cT2 versus cT3-4aN0M0 UC of the bladder undergoing radical cystectomy (RC) with or without neoadjuvant chemo- (NAC) or radiotherapy (NAR). A population-based sample of 5,517 patients, who underwent upfront RC versus NAC + RC or NAR + RC for cT2-4aN0M0 UC between 1995-2013, was identified from the Netherlands Cancer Registry. Data were retrieved from individual patient files and pathology reports. pCD-rates were compared using Chi-square tests and OS was estimated by Kaplan-Meier analyses. Multivariable analyses were conducted to determine odds (OR) and hazard ratios (HR) for pCD-status and OS, respectively. We included 4,504 (82%) patients with cT2 and 1,013 (18%) with cT3-4a UC. Median follow-up was 9.2 years. In cT2 UC, pCD-rate was 25% after upfront RC versus 43% (p < 0.001) and 33% (p = 0.130) after NAC + RC and NAR + RC, respectively. In cT3-4a UC, pCD-rate was 8% after upfront RC versus 37% (p < 0.001) and 16% (p = 0.281) after NAC + RC and NAR + RC, respectively. In cT2 UC, 5-year OS was 57% and 51% for NAC + RC and upfront RC, respectively (p = 0.135), whereas in cT3-4a UC, 5-year OS was 55% for NAC + RC versus 36% for upfront RC (p < 0.001). In multivariable analysis for OS, NAC was beneficial in cT3-4a UC (HR: 0.67, 95%CI 0.51-0.89) but not in cT2 UC (HR: 0.91, 95%CI 0.72-1.15). NAR did not influence OS. In conclusion, NAC + RC was associated with superior pCD compared to RC alone and NAR + RC. Superior OS for NAC + RC compared to RC alone was especially evident in cT3-4a disease.

Concomitant CIS on TURBT does not impact oncological outcomes in patients treated with neoadjuvant or induction chemotherapy followed by radical cystectomy.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy. PATIENTS AND METHODS: Patients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes. RESULTS: Of 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the 'CIS' versus 'no-CIS' groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63-1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01-1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23-2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34-0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82-1.35; p = 0.70). CONCLUSION: In this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.

Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment.

BACKGROUND: Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. PATIENTS AND METHODS: We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201). RESULTS: We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type. CONCLUSIONS: FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting.

Differences in histopathological evaluation of standard lymph node dissections result in differences in nodal count but not in survival.

OBJECTIVE: To analyse whether the reported differences in nodal yield at pelvic lymph node dissection (PLND) for bladder cancer, between two hospitals, are reflected in the survival rates. PATIENTS AND METHODS: We assessed follow-up data of all 174 patients (mean age: 62.7, median follow-up: 3 years) who underwent PLND between 1 January 2007 and 31 December 2009 at two different hospitals. PLND was performed according to a standardized template by the same urologists for comparable bladder cancer patients. Mean number of reported lymph nodes was 16 at hospital A versus 28 at hospital B. We compared the overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) between both cohorts and performed a multivariate analysis. RESULTS: The cumulative probability for 2-year OS, DSS and RFS for hospital A are 61, 64 and 54 %, versus 58, 58 and 53 % for hospital B, respectively. Kaplan-Meier survival curves did not reveal statistically significant differences between both groups (OS: p log-rank = 0.75, DSS: p log-rank = 0.56, and RFS: p log-rank = 0.80). Also after adjustment for pT stage and neoadjuvant chemotherapy, survival was not significantly different between hospital A and hospital B. CONCLUSION: Despite differences in lymph node yield in PLND specimens, this study reveals no significant differences in survival outcomes between both hospitals. Standardized histopathological methods should be agreed upon by pathologists before integrating nodal yield and subsequent lymph node density as indicators of the quality of surgery and as prognostic factors.

Performance curve of basic skills in single-incision laparoscopy versus conventional laparoscopy: is it really more difficult for the novice?

BACKGROUND: Single-incision laparoscopy is a step forward toward nearly scarless surgery. Concern has been raised that single-incision laparoscopy is technically more challenging than conventional laparoscopy. This study researched the performance curves of novice trainees for single-incision laparoscopy (SILS) versus conventional laparoscopy for performing two basic tasks on a box trainer. METHODS: In this study, 20 novice participants performed two tasks (peg transfer and a dissection task) on a standard box trainer. All the participants practiced each task 11 times and were randomized in two groups. The first group performed the tasks on a box trainer through three incisions. The second group used a single-incision access with the same box trainer. The assessment scores for errors and time were recorded. The 2nd, 8th, and 11th runs of both tasks in both settings were assessed to objectify the gain in basic laparoscopic skills. RESULTS: The performance curves for both groups improved significantly in terms of both time and errors in performing the two tasks [P < 0.01, analysis of variance (ANOVA)]. For the first task, no significant difference in time between the two groups was observed at the top of the performance curve (mean, 212 ± 64 vs. 182 ± 48 s), but the SILS group performed with fewer errors (1.3 ± 1.5 vs. 2.7 ± 2.11). However, the difference was not significant (P = 0.10). The dissection task was performed faster in the SILS group (mean, 205 ± 78 vs. 243 ± 40 s; P = 0, 18) with fewer errors (0.7 ± 1.05 vs. 1.9 ± 2.1; P = 0. 12), but the difference was not significant. CONCLUSION: This study showed a significant improvement in basic skills for both the SILS and conventional laparoscopy settings after 11 repetitions. These data suggest that box training shows no significant difference between conventional laparoscopic and single-incision laparoscopic settings in terms of error or time in performing basic tasks at a low complexity level for the novice. These data also show significant improvement in basic skills over a relatively short period.

FDG-PET/CT for response evaluation of invasive bladder cancer following neoadjuvant chemotherapy.

PURPOSE: We investigated the accuracy of FDG-PET/CT response identification following neoadjuvant or induction chemotherapy (NAIC) for invasive bladder cancer (BC) as to better select patients for radical cystectomy (RC). METHODS: Between 2010 and 2014, 37 cT1-4N1-3 BC patients received a FDG-PET/CT before and after NAIC followed by RC. Metabolic lymph node (LN) response was evaluated according to EORTC recommendations. Additionally, primary tumor response was evaluated for 23 patients by means of delayed pelvic imaging after forced diuresis. Gold standard was response on pathologic analysis of RC specimens. Response was defined as partial response (pPR, any pathologic downstaging) or complete response (pCR, 

The colon shuffle: A modified urinary diversion.

AIM: To assess the results of a urinary diversion in patients who already have a colostomy or simultaneously require a (rectum) colon resection. The diversion is created from the distal part of the transected colon with a simultaneously created new colostomy contra-laterally (if necessary). This procedure is known in our institute as the 'colon shuffle'. MATERIALS AND METHODS: All patients who underwent a colon shuffle in the period of 2003 and 2013 in our institute (Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital) were identified. Comorbidity was scored using the Charlson comorbidity index. Local or systemic treatment prior to surgery was reported (e.g. external beam radiotherapy, systemic chemotherapy). Surgical complications were reported according to the Clavien-Dindo classification. RESULTS: Twenty-one patients (14 male; 7 female) underwent a colon shuffle procedure in our institute, with a mean age of 61.5 years. The majority (90.4%) of these patients had been subjected to radiotherapy on the pelvic region in the past. Although short-term complications (<30 days) were seen in 52.4% of these patients, major complications such as anastomotic leakage of the bowel and fecal peritonitis were not seen in this high-risk group of patients. CONCLUSION: The colon shuffle offers an elegant solution for patients who require a urinary diversion simultaneously with a colostomy or for patients who already have a colostomy from previous surgery.