André N. Vis

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

BACKGROUNDnThe 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.nnnOBJECTIVEnTo 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.nnnDESIGN, SETTING, AND PARTICIPANTSnBetween 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.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnPrimary 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.nnnRESULTS AND LIMITATIONSnA 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.nnnCONCLUSIONSnAn immediate, single instillation after TURBT reduces the recurrence risk in NMIBC patients, independent of the number of adjuvant installations.nnnPATIENT SUMMARYnA 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.

Development of a patient decision aid for the treatment of localised prostate cancer: a participatory design approach.

AIMS AND OBJECTIVESnTo develop a patient decision aid and to prepare an overview of requirements for implementation.nnnBACKGROUNDnWe developed a decision aid that fits the preferences of patients and health care professionals to ensure adequate uptake in clinical practice.nnnDESIGNnA participatory design approach was used to acquire insight into preferences regarding the content and design of a decision aid and into barriers and aspects of the decision aid that facilitate implementation in clinical practice.nnnMETHODSnThree focus group interviews with patients, their partners and health care professionals were conducted. A prototype of the decision aid was developed and presented to patients (n = 14) and health care professionals (n = 13) in semi-structured interviews. Patients (n = 5) participated in a usability study. Data were analysed by two independent coders.nnnRESULTSnHealth care professionals considered medical information on treatments and side effects as the most important aspect to be included in the decision aid. Patients also focused on nonmedical considerations, such as location. Both expected the decision aid to support patients in making a treatment choice. According to health care professionals, the oncology nurse was the most suitable to discuss the decision aid with patients, while some patients preferred to discuss the patient decision aid with the urologist. The main barrier to implementation of the decision aid was said to be the expectation that it is time and money consuming, while the incorporation of the decision aid into clinical guidelines and basing the content on these guidelines, would promote implementation.nnnCONCLUSIONSnBy using a participatory design approach a patient decision aid was designed to meet patients and health care professionals needs. Insight was also gained on requirements for implementation.nnnRELEVANCE TO CLINICAL PRACTICEnWide-scale implementation of decision aids is desirable. An overview is provided of requirements for implementation to successfully incorporate a decision aid into clinical practice.

Risk of disease flare with LHRH agonist therapy in men with prostate cancer: Myth or fact?

OBJECTIVESnThe traditional assumption of a linear relationship between serum testosterone and prostate cancer growth has been seriously challenged, as overwhelming evidence contradicts its basic principles. Luteinizing hormone-releasing hormone (LHRH) agonists are known to cause a peak in serum testosterone level in the initial weeks of treatment, and prevention of the clinical sequelae of testosterone flare by concomitant use of antiandrogens is recommended. Along the present biological concept that there appears to be a limit to the ability of androgens to stimulate prostate cancer growth, termed the saturation model, the use of antiandrogens to prevent this disease flare is questioned. The purpose of this review is to gain historical and modern evidence to provide an objective and up-to-date basis for clinical decision making.nnnMETHODS AND MATERIALSnWe performed a comprehensive research of the electronic databases PubMed and Embase until April 1, 2014. Studies with the subject of disease flare in men with prostate cancer on LHRH agonist therapy were included, as were studies that assessed the efficacy of antiandrogens to prevent this flare. Case reports were included as well.nnnRESULTSnOverall, 25 studies considering disease flare were included: 9 randomized clinical trials with an LHRH agonist and an LHRH agonist/antiandrogen arm, 14 observational studies evaluating LHRH agonists only, and 2 case reports. The incidence of disease flare was reported between 0% and 83% owing to a wide set of clinical, biochemical, and radiological factors evaluated. In some of the randomized clinical trials, a statistically significant reduction of the incidence of disease flare by concomitant use of antiandrogens was reported. Most of these historical studies report on subjective worsening of disease symptoms as outcome measure. More objective outcome measures such as the prostate-specific antigen level did not seem to increase to higher than the baseline values.nnnCONCLUSIONSnAt present, there is a lack of compelling data showing definite disease progression during the short period of testosterone flare after initiation of LHRH agonist therapy. Based on the saturation model, presence of disease flare and the need to prevent this flare by concomitant use of antiandrogens might well be a misconception.

Relationship Between Body Mass Index and Serum Testosterone Concentration in Patients Receiving Luteinizing Hormone-releasing Hormone Agonist Therapy for Prostate Cancer

OBJECTIVEnTo evaluate the relationship between the body mass index (BMI) and serum testosterone concentrations in men receiving luteinizing hormone-releasing hormone (LHRH) agonist therapy for prostate cancer.nnnMATERIALS AND METHODSnA total of 66 white men were included in the present study. All subjects had received LHRH agonist therapy for ≥ 3 months. The BMI was calculated, and the subjects were classified as normal weight (i.e. BMI <25 kg/m(2)), overweight (BMI 25-30 kg/m(2)), or obese (BMI >30 kg/m(2)). The serum testosterone concentration was determined using the highly sensitive isotope dilution-liquid chromatography-tandem mass spectrometry technique. The sex hormone-binding globulin level was determined using an immunometric assay, and the free serum testosterone concentration was calculated.nnnRESULTSnThe median serum testosterone concentration of the patients with a BMI <25 kg/m(2) was 5.5 ng/dL. The patients with a BMI of 25-30 kg/m(2) had a median serum testosterone concentration of 3.8 ng/dL. Those patients with a BMI >30 kg/m(2) had a median concentration of 5.7 ng/dL. No significant difference in the serum testosterone concentrations among the 3 groups was found. The sex hormone-binding globulin levels declined with an increasing BMI. The concentration of free testosterone was significantly greater in the obese men.nnnCONCLUSIONnUsing an ultrasensitive technique of serum testosterone measurement, the present data have shown that no difference exists in the serum testosterone concentration in the castrate range among normal weight, overweight, and obese patients receiving LHRH agonist therapy for prostate cancer. From our findings and current knowledge, more stringent follow-up or changes in dosage or dosage intervals of LHRH agonist therapy in those with a greater or high BMI is not warranted.

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.

Serum testosterone plays an important role in the metastatic ability of castration resistant prostate cancer

PurposeProstate cells are dependent on androgens for growth and proliferation. Androgen deprivation therapy is the recommended treatment for advanced/metastatic prostate cancer. Under this therapy, prostate cancer will inevitably progress to castration resistant prostate cancer (CRPC). Despite putative castration resistance, testosterone might still play a crucial role in the progression of CRPC. The goal of this study was to determine the role of testosterone in the formation of metastases of CRPC in both in vitro and in vivo settings.MethodsIn vitro, the effect of testosterone and the non-aromatizable androgen methyltrienolone on migration, invasion and proliferation of a castration-resistant prostate cancer rat cell line (Dunning R3327-MATLyLu) was assessed using a transwell assay and a sulforhodamine B assay and immunohistochemical detection of ki67. Androgen receptor status was determined using Western blot. In vivo, Copenhagen rats were divided in four groups (males, females, castrated males and females with testosterone suppletion) and inoculated with MATLyLu cells. Tumor size was assessed daily.ResultsTestosterone increased cell migration and invasion in a concentration-dependent manner in vitro. Testosterone did not affect in vitro cell proliferation. No difference was shown between the effect of testosterone and methyltrienolone. In vivo, in groups with higher levels of circulating testosterone, more rats had (micro)metastases compared with groups with low levels of testosterone. No effect was observed on primary tumor size/growth.ConclusionsDespite assumed castration resistance, progression of prostate cancer is still influenced by androgens. Therefore, continuous suppression of serum testosterone in patients who show disease progression during castration therapy is still warranted.

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

AIMnSeveral 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.nnnPATIENTS & METHODSnA 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.nnnRESULTSnA 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.nnnCONCLUSIONnReported 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 pu2009=u20090.12; specificity pu2009=u20090.57).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

BACKGROUNDnIn 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.nnnOBJECTIVESnTo validate whether specific subgroups of patients with non-muscle-invasive bladder cancer (NMIBC) benefit from an immediate instillation with MMC.nnnPATIENTS AND METHODSnAll 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.nnnRESULTSnThe 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.nnnCONCLUSIONSnIn 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.