Jakko A. Nieuwenhuijzen

Prostate Sparing Cystectomy for Bladder Cancer: 20-Year Single Center Experience

PURPOSE We evaluated long-term oncologic and functional results after prostate sparing cystectomy for bladder cancer. MATERIALS AND METHODS A total of 120 patients with cT1-4N0-3 bladder cancer were treated with prostate sparing cystectomy between 1994 and 2013, of whom 110 had a followup of 2 years or greater and were eligible for analysis. To rule out tumor in the bladder neck, prostatic urethra or prostate cancer all patients underwent preoperative transurethral biopsy of the bladder neck and prostatic urethra, prostate specific antigen measurement and transrectal ultrasound with biopsies. We assessed oncologic outcomes (disease specific and recurrence-free survival), recurrence rates, prostate cancer and functional results (continence, voiding, and erectile and ejaculatory function). RESULTS Mean patient ± SD age was 56.2 ± 8.3 years and median followup was 77.0 months (IQR 57-116). Two and 5-year disease specific survival rates were 76.2% and 66.5%, 2 and 5-year recurrence-free survival rates were 71.2% and 66.6%, and distant and local recurrence rates were 34.2% and 10.0%, respectively. One local recurrence was in the remnant prostatic urothelium. Prostate cancer was diagnosed in 2.7% of cases. Complete daytime and nighttime continence was achieved in 96.2% and 81.9% of patients, and erectile function and antegrade ejaculation were intact in 89.7% and 35.5%, respectively. CONCLUSIONS Our long-term data show that prostate sparing cystectomy is an oncologically safe procedure with excellent functional results in a subset of carefully selected patients with bladder cancer without evidence of urothelial carcinoma in the prostatic urethra/bladder neck and no prostate cancer.

Salvage cystectomy after failure of interstitial radiotherapy and external beam radiotherapy for bladder cancer

To evaluate the long‐term results of salvage cystectomy after interstitial radiotherapy (IRT) and external beam radiotherapy (EBRT) for transitional cell carcinoma, and to assess the morbidity and functional results of the different urinary diversions used.

Response to induction chemotherapy and surgery in non-organ confined bladder cancer: A single institution experience

AIM To evaluate the outcome of patients with locally advanced muscle-invasive and/or lymph node positive bladder cancer treated with induction chemotherapy and additional surgery. METHODS All patients who were treated with induction chemotherapy in our institution between 1990 and 2010, were retrospectively evaluated using an institutional database. Induction chemotherapy consisted of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), or a combination of gemcitabine with either cisplatin or carboplatin (GC). RESULTS In total 152 patients were identified, with a mean age of 59 years (range 31-76). One hundred and seven patients (70.4%) received MVAC, 35 patients received GC (23.0%) and 10 patients received GC after initial treatment with MVAC (6.6%). Median follow-up was 68 months (range 4-187 months). Overall 125 patients (82.2%) underwent cystectomy, whereas 12 patients (7.9%) received radiotherapy. Fifteen patients had no local treatment. Median overall survival was 18 months (95%CI 15-23 months). In 37.5% of patients with complete clinical response, residual disease was found at surgery (positive predictive value, PPV 62.5%). Complete pathological response was seen in 26.3% of patients, with a 5 year overall survival (OS) estimate of 54% (39%-74%). For patients with persisting node positive disease after induction chemotherapy and surgery OS was significantly worse (p < 0.0001). CONCLUSIONS Complete clinical and/or pathological response to induction chemotherapy results in a significant survival benefit. The accuracy of the current clinical response evaluation after induction chemotherapy is limited. Although surgery may be important for staging and prognostic purposes, its role is unclear in node positive disease after induction chemotherapy.

Value of an Immediate Intravesical Instillation of Mitomycin C in Patients with Non–muscle-invasive Bladder Cancer: A Prospective Multicentre Randomised Study in 2243 patients

BACKGROUND The efficacy of an immediate single chemotherapy instillation after transurethral resection of a bladder tumour (TURBT) in patients with non-muscle-invasive bladder cancer (NMIBC) remains a topic of debate. Evidence is even more scarce when an immediate instillation is followed by adjuvant instillations. OBJECTIVE To compare the effect of a mitomycin C (MMC) instillation within 24h to an instillation 2 wk after TURBT in patients with NMIBC with or without adjuvant instillations. DESIGN, SETTING, AND PARTICIPANTS Between 1998 and 2003, 2844 NMIBC patients were randomised for immediate versus delayed MMC instillation after TURBT. Patients were categorised in low-risk (LOR), intermediate-risk (IMR), and high-risk (HIR) groups. Total numbers of instillations in these groups were 1, 9, and 15, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary end point was 3-yr recurrence risk for the IMR and HIR groups and 5-yr risk for the LOR group. Secondary outcomes were time to recurrence and incidence of adverse events. Analyses were performed with the log-rank test, Cox-regression, and χ2 test in SPSS. RESULTS AND LIMITATIONS A total of 2243 patients were eligible on an intention-to-treat basis. Recurrence risks were 43% and 46% in the LOR group (5-yr follow-up, p=0.11), 20% and 32% in the IMR group (3-yr follow-up, p=0.037), and 28% and 35% in the HIR group (3-yr follow-up, p=0.007), for an immediate and a delayed instillation, respectively. For all patients, the recurrence risk was 27% (95% confidence interval [CI], 24-30) in the immediate and 36% (95% CI, 33-39) in the delayed instillation group (p<0.001) with a 27% reduction in relative recurrence risk (hazard ratio: 0.73, 95% CI, 0.63-0.85, p<0.001). The incidence of adverse events did not differ significantly between treatment groups (immediate instillation 25%, delayed instillation 22%, p=0.08). The risk groups in our study differ slightly from the current guidelines, which is a limitation of our study. CONCLUSIONS An immediate, single instillation after TURBT reduces the recurrence risk in NMIBC patients, independent of the number of adjuvant installations. PATIENT SUMMARY A single instillation of chemotherapy after the resection of non-muscle-invasive bladder cancer reduces the recurrence risk, even if patients are treated with an adjuvant schedule of instillations.

Follow-up after cystectomy: regularly scheduled, risk adjusted, or symptom guided? Patterns of recurrence, relapse presentation, and survival after cystectomy.

AIMS 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. PATIENTS AND METHODS 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. RESULTS 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. CONCLUSIONS 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.

Customized Tool for the Validation of Optical Coherence Tomography in Differentiation of Prostate Cancer

Objective: To design and demonstrate a customized tool to generate histologic sections of the prostate that directly correlate with needle-based optical coherence tomography pullback measurements. Materials and Methods: A customized tool was created to hold the prostatectomy specimens during optical coherence tomography measurements and formalin fixation. Using the tool, the prostate could be sliced into slices of 4 mm thickness through the optical coherence tomography measurement trajectory. In this way, whole-mount pathology slides were produced in exactly the same location as the optical coherence tomography measurements were performed. Full 3-dimensional optical coherence tomography pullbacks were fused with the histopathology slides using the 3-dimensional imaging software AMIRA, and images were compared. Results: A radical prostatectomy was performed in a patient (age: 68 years, prostate-specific antigen: 6.0 ng/mL) with Gleason score 3 + 4 = 7 in 2/5 biopsy cores on the left side (15%) and Gleason score 3 + 4 = 7 in 1/5 biopsy cores on the right side (5%). Histopathology after radical prostatectomy showed an anterior located pT2cNx adenocarcinoma (Gleason score 3 + 4 = 7). Histopathological prostate slides were produced using the customized tool for optical coherence tomography measurements, fixation, and slicing of the prostate specimens. These slides correlated exactly with the optical coherence tomography images. Various structures, for example, Gleason 3 + 4 prostate cancer, stroma, healthy glands, and cystic atrophy with septae, could be identified both on optical coherence tomography and on the histopathological prostate slides. Conclusion: We successfully designed and applied a customized tool to process radical prostatectomy specimens to improve the coregistration of whole mount histology sections to fresh tissue optical coherence tomography pullback measurements. This technique will be crucial in validating the results of optical coherence tomography imaging studies with histology and can easily be applied in other solid tissues as well, for example, lung, kidney, breast, and liver. This will help improve the efficacy of optical coherence tomography in cancer detection and staging in solid organs.

The diagnostic accuracy of methylation markers in urine for the detection of bladder cancer : A systematic review

AIM Several urinary hypermethylation-markers (hmDNA) have been described for bladder cancer (BC) detection, but none have been able to replace cystoscopy yet. We systematically reviewed and evaluated current literature on urinary hmDNA markers for BC diagnostics. PATIENTS & METHODS A systematic search of PubMed, EMBASE.com and The Cochrane Library up to February 2017 using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, was conducted. RESULTS A total of 30/42 studies included compared gene panels, with varying sensitivities (52-100%) and specificities (0-100%). Considerable heterogeneity across studies was observed and most was case-control studies. CONCLUSION Reported diagnostic accuracy of urinary hmDNA for BC detection is highly variable and there is a lack of validation studies. Recent studies indicate that complementary markers are needed to allow for clinical implementation.

The effect of timing of an immediate instillation of mitomycin C after transurethral resection in 941 patients with non‐muscle‐invasive bladder cancer

To investigate whether the timing of an immediate instillation of mitomycin C (on the day of transurethral resection of bladder tumour [TURBT] or 1 day later) has an impact on time to recurrence of non‐muscle‐invasive bladder cancer (NMIBC).

Local staging with multiparametric MRI in daily clinical practice: diagnostic accuracy and evaluation of a radiologic learning curve

PurposeTo estimate the diagnostic accuracy of multiparametric MRI (mpMRI) for the detection of locally advanced prostate cancer (T-stage 3–4) prior to radical prostatectomy, in a multicenter cohort representing daily clinical practice. In addition, the radiologic learning curve for the detection of locally advanced disease is evaluated.MethodsPreoperative mpMRI findings of 430 patients (2012–2016) were compared to pathology results following radical prostatectomy. The diagnostic accuracy (sensitivity, specificity, PPV, and NPV) for the detection of locally advanced disease was calculated and compared for all years separately, to evaluate the presence of a radiological learning curve.ResultsOf all 137 patients with locally advanced disease, 62 patients were preoperatively detected with mpMRI [sensitivity 45.3% (95% CI 36.9–53.6%), specificity 75.8% (CI 70.9–80.7%), PPV 46.6% (CI 38.1–55.1%), and NPV 74.7% (CI 69.8–79.7%)]. The diagnostic accuracy did not improve significantly over time (sensitivity p = 0.12; specificity p = 0.57).ConclusionsIn daily clinical practice, the diagnostic accuracy of mpMRI for the detection of locally advanced prostate cancer remains limited. It, therefore, seems questionable whether mpMRI is adequate to guide preoperative decision-making. No significant radiologic learning curve for the detection of locally advance disease was observed.

An immediate, single intravesical instillation of mitomycin C is of benefit in patients with non–muscle-invasive bladder cancer irrespective of prognostic risk groups

BACKGROUND In a recent meta-analysis, subgroups of patients were defined that may not benefit from a single, immediate instillation with chemotherapy. This led to a change in the European Association of Urology bladder cancer guidelines. In a previous paper, our group confirmed the efficacy of an immediate instillation of mitomycin C (MMC). However, prognostic groups in that study differ from those in the meta-analysis. Therefore, we performed a reanalysis using contemporary risk groups. OBJECTIVES To validate whether specific subgroups of patients with non-muscle-invasive bladder cancer (NMIBC) benefit from an immediate instillation with MMC. PATIENTS AND METHODS All 2,243 NMIBC patients enrolled in our randomized controlled trial between 1998 and 2003 were analyzed. Treatment effect was investigated for all subgroups, including subgroups that did not benefit from an immediate instillation according to the meta-analysis. Time to recurrence was assessed using Kaplan-Meier curves and multivariable Cox regression. Differences in treatment effect between subgroups was tested using the variable treatment by covariate interactions in a Cox regression model. RESULTS The difference in time to recurrence was statistically significant in favor of an immediate instillation with MMC (P < 0.001) which corresponds to a 25% risk reduction (hazard ratio: 0.75, 95% confidence interval, 0.64-0.88, P < 0.001). Treatment effect of an immediate instillation with MMC did not differ significantly between any of the subgroups. CONCLUSIONS In contrast to the recommendations in the European Association of Urology guidelines, we could not identify any subgroup of patients with NMIBC who do not benefit from an immediate instillation with MMC after transurethral resection.