Men's Sexual Health Questionnaire score changes vs spontaneous sexual adverse event reporting in men treated with dutasteride/tamsulosin combination therapy for lower urinary tract symptoms secondary to benign prostatic hyperplasia: A post hoc analysis of a prospective, randomised, placebo-controlled study.

AIM: To assess the impact of baseline characteristics on Men's Sexual Health Questionnaire (MSHQ) total scores and to evaluate the clinical relevance of MSHQ changes and their association with spontaneously reported sexual adverse events (SexAEs) in patients with benign prostatic hyperplasia. METHODS: This was a post hoc analysis of the Phase 4 FDC116115 study, in which patients aged ≥50 years were randomised 1:1 to receive a fixed-dose combination of dutasteride 0.5 mg and tamsulosin 0.4 mg (DUT-TAM FDC), or placebo. End-points included: change in MSHQ total scores by baseline characteristics and SexAEs; cumulative distribution function for change from baseline to month 12 in MSHQ total score and the ejaculation, erection, satisfaction and sexual desire (libido) domain scores; and relationship between changes in MSHQ scores and SexAEs. RESULTS: The intent-to-treat population comprised 489 patients (DUT-TAM FDC, n = 243; placebo, n = 246). The mean reduction in total MSHQ score was greater in patients with SexAEs across both groups, compared with patients without SexAEs. Most patients reporting any SexAE (86% DUT-TAM FDC, 67% placebo) had a worsening of the MSHQ total score at month 12 compared with baseline. Specifically, 90% (DUT-TAM FDC) and 75% (placebo) of patients reporting an ejaculation SexAE and 73% (DUT-TAM FDC) and 87% (placebo) of patients reporting an erection SexAE had a worsening of MSHQ ejaculation and erection domain scores, respectively, at month 12. A threshold effect for incident SexAE was observed; patients showing a decrease of approximately 6-10 points in the total MSHQ score were more likely to report SexAEs. CONCLUSION: Findings support the clinical utility of the MSHQ tool in assessing the impact of DUT-TAM on sexual function by linking numerical changes in MSHQ scores to spontaneously reported SexAEs for the first time. The threshold effect for incidence of SexAEs warrants further investigation to determine its clinical relevance.

Evaluation of the impact of dutasteride/tamsulosin combination therapy on libido in sexually active men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH): A post hoc analysis of a prospective randomised placebo-controlled study.

AIMS: Five-α reductase inhibitor (5ARI) therapy has been associated with sexual dysfunction in some patients. This study assessed the impact of a fixed-dose combination of the 5ARI dutasteride 0.5 mg and the α1 -adrenoceptor antagonist tamsulosin 0.4 mg (DUT-TAM FDC) on Men's Sexual Health Questionnaire (MSHQ) domain scores in patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH). METHODS: This was a post hoc analysis of a double-blind, randomised, placebo-controlled, parallel-group, multicentre study in sexually active patients, aged ≥50 years, with a confirmed clinical diagnosis of BPH. Sexual activity, sexual desire, and bother domain scores of the MSHQ were assessed at baseline and at Months 1, 3, 6, 9, and 12. Correlation between MSHQ sexual activity/desire scores and ejaculation, erection, and satisfaction domains at baseline was also evaluated. RESULTS: In the intent-to-treat population (N = 489), 243 and 246 patients were randomised to DUT-TAM FDC and placebo groups, respectively. Compared with placebo, DUT-TAM FDC therapy resulted in statistically significant reductions (worsening) from baseline in adjusted mean MSHQ sexual activity and bother domain scores at Months 1, 3, 6, 9, and 12 (all P < 0.05) and in adjusted mean MSHQ sexual desire domain scores at Months 6, 9, and 12 (all P < 0.05). Significant moderate correlations in the expected direction were observed at baseline between the sexual activity/desire domains and the ejaculation, erection, and satisfaction domains (P < 0.0001). CONCLUSIONS: These findings help clarify the degree and impact of libido changes in sexually active men treated with DUT-TAM FDC and may support clinical decision-making.

A prospective randomised placebo-controlled study of the impact of dutasteride/tamsulosin combination therapy on sexual function domains in sexually active men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH).

OBJECTIVE: To prospectively assess the impact of the fixed-dose combination (FDC) of the 5α-reductase inhibitor (5ARI), dutasteride 0.5 mg and the α1 -adrenoceptor antagonist, tamsulosin 0.4 mg (DUT-TAM FDC) therapy on sexual function domain scores in sexually active men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH), using the Men's Sexual Health Questionnaire (MSHQ). PATIENTS AND METHODS: This European and Australian double-blind, placebo-controlled, parallel-group study was conducted at 51 centres. INCLUSION CRITERIA: age ≥50 years, International Prostate Symptom Score ≥12, prostate volume ≥30 cc, prostate-specific antigen 1.5-10 ng/mL. Patients were randomised 1:1 to DUT-TAM FDC therapy or placebo for 12 months. The change from baseline to Month 12 on the total MSHQ (primary endpoint) and MSHQ erection, ejaculation and satisfaction domains (secondary outcome) was assessed, using a mixed model repeated measures analysis. Safety was evaluated. RESULTS: The intention-to-treat population included 489 patients (243 DUT-TAM FDC therapy; 246 placebo). A significant decrease (worsening) was observed with DUT-TAM FDC therapy versus placebo on the total MSHQ score (-8.7 vs -0.7; standard error [se]: 0.81, 0.78; P < 0.001), and the ejaculation (-7.5 vs -0.6; se: 0.56, 0.55; P < 0.001) and satisfaction (-0.6 vs +0.3; se: 0.3, 0.29, P = 0.047) domains, but not the erection domain (-1.0 vs -0.5; se: 0.19, 0.19, P = 0.091). CONCLUSION: This is the first domain-specific quantitative evaluation of DUT-TAM FDC therapy on sexual function in men with LUTS secondary to BPH. The observed changes in the MSHQ with DUT-TAM FDC therapy were mainly driven by changes in the ejaculation domain. These findings will help give context to erectile and ejaculatory dysfunction AEs reported spontaneously in earlier 5ARI studies.

Circulating and intraprostatic sex steroid hormonal profiles in relation to male pattern baldness and chest hair density among men diagnosed with localized prostate cancers.

BACKGROUND: Prospective cohort studies of circulating sex steroid hormones and prostate cancer risk have not provided a consistent association, despite evidence from animal and clinical studies. However, studies using male pattern baldness as a proxy of early-life or cumulative androgen exposure have reported significant associations with aggressive and fatal prostate cancer risk. Given that androgens underlie the development of patterned hair loss and chest hair, we assessed whether these two dermatological characteristics were associated with circulating and intraprostatic concentrations of sex steroid hormones among men diagnosed with localized prostate cancer. METHODS: We included 248 prostate cancer patients from the NCI Prostate Tissue Study, who answered surveys and provided a pre-treatment blood sample as well as fresh frozen adjacent normal prostate tissue. Male pattern baldness and chest hair density were assessed by trained nurses before surgery. General linear models estimated geometric means and 95% confidence intervals (95%CIs) of each hormone variable by dermatological phenotype with adjustment for potential confounding variables. Subgroup analyses were performed by Gleason score (<7 vs ≥7) and race (European American vs. African American). RESULTS: We found strong positive associations of balding status with serum testosterone, dihydrotestosterone (DHT), estradiol, and sex hormone-binding globulin (SHBG), and a weak association with elevated intraprostatic testosterone. Conversely, neither circulating nor intraprostatic sex hormones were statistically significantly associated with chest hair density. Age-adjusted correlation between binary balding status and three-level chest hair density was weak (r = 0.05). There was little evidence to suggest that Gleason score or race modified these associations. CONCLUSIONS: This study provides evidence that balding status assessed at a mean age of 60 years may serve as a clinical marker for circulating sex hormone concentrations. The weak-to-null associations between balding status and intraprostatic sex hormones reaffirm differences in organ-specific sex hormone metabolism, implying that other sex steroid hormone-related factors (eg, androgen receptor) play important roles in organ-specific androgenic actions, and that other overlapping pathways may be involved in associations between the two complex conditions.

Can we use baseline characteristics to assess which men with moderately symptomatic benign prostatic hyperplasia at risk of progression will benefit from treatment? A post hoc analysis of data from the 2-year CONDUCT study.

PURPOSE: To investigate (in a post hoc analysis of the 2-year CONDUCT study) the characteristics and clinical outcomes of men with moderately symptomatic benign prostatic hyperplasia (BPH) at risk of progression who benefitted from lifestyle changes alone. METHODS: Patients were given lifestyle advice and randomized to a fixed-dose combination (FDC) of dutasteride and tamsulosin or watchful waiting (WW) and followed for 24 months. Patients in the WW group were escalated to tamsulosin if any follow-up International Prostate Symptom Score (IPSS) was equal or greater than the baseline value. Improvements in symptoms (change in IPSS) and quality of life [measured by BPH Impact Index (BII) and question 8 of the IPSS (IPSS-Q8)] were analysed in the FDC group, men who initiated tamsulosin (WW-TAM) and men who received no medical intervention (WW-no treatment) and the impact of baseline variables on IPSS determined. RESULTS: The adjusted mean decrease in IPSS, BII and IPSS-Q8 at each post-baseline visit over 24 months appeared greater in the FDC (n = 369) and WW-no treatment groups (n = 144) than in the WW-TAM group (n = 229). IPSS improvements appeared similar in the FDC group and WW-no treatment subgroup, except in patients with the greatest degree of bother at baseline (BII 7-13). CONCLUSION: BII at baseline may be a more relevant indicator than symptom severity as to whether a patient with moderate symptoms should receive medical therapy or not.

Understanding patient and physician perceptions of benign prostatic hyperplasia in Asia Pacific, Latin America and the Commonwealth of Independent States: the Prostate Research on Behaviour and Education (PROBE) II survey.

AIM: To assess attitudes and beliefs towards benign prostatic hyperplasia (BPH)/ lower urinary tract symptoms (LUTS) and its treatment among patients and physicians in Latin America, Asia Pacific and the Commonwealth of Independent States (CIS). METHODS: Cross-sectional, quantitative study conducted between December 2014 and September 2015. Separate questionnaires were administered to BPH/LUTS patients receiving drug treatment for their condition and to practising physicians who treat patients with BPH/LUTS. RESULTS: In total, 1094 patients and 202 physicians completed a questionnaire. Most patients (61%) felt very/fairly well informed about BPH/LUTS, and 60% of physicians perceived patients to be very/somewhat informed. Overall, 70% of physicians felt that it would be valuable to raise awareness of BPH/LUTS and encourage men to consult a physician. The first symptoms most commonly noticed by patients were need to urinate more frequently, slower/weaker stream and nocturia. At first consultation, 71% of patients recalled providing a urine sample, 57% having a blood test for prostate-specific antigen and 56% a digital rectal examination being performed. Over two thirds of patients (69%) were satisfied with their current medication; highest satisfaction rates (among both patients and physicians) were reported for alpha blockers and 5ARIs, either as monotherapies or used in combination. Patients were prepared to wait longer for symptom relief in order to have a reduced risk of surgery. Most physicians (90%) thought that at least some patients believe BPH/LUTS to be a progressive condition. Most physicians thought that patients were very/fairly concerned about BPH surgery (92%) and acute urinary retention (72%); 52% of physicians thought treatment adherence was "extremely" important. CONCLUSIONS: This study provides valuable insights into the attitudes and beliefs of patients and physicians in Asia Pacific, Latin America and CIS about BPH/LUTS and its management. It also highlights areas of discordance between patient/physician perceptions and beliefs about BPH/LUTS, and potential areas of focus to improve the experience of affected patients.

Efficacy and safety of a fixed-dose combination of dutasteride and tamsulosin treatment (Duodart(®) ) compared with watchful waiting with initiation of tamsulosin therapy if symptoms do not improve, both provided with lifestyle advice, in the management of treatment-naïve men with moderately symptomatic benign prostatic hyperplasia: 2-year CONDUCT study results.

OBJECTIVE: To investigate whether a fixed-dose combination (FDC) of 0.5 mg dutasteride and 0.4 mg tamsulosin is more effective than watchful waiting with protocol-defined initiation of tamsulosin therapy if symptoms did not improve (WW-All) in treatment-naïve men with moderately symptomatic benign prostatic hyperplasia (BPH) at risk of progression. PATIENTS AND METHODS: This was a multicentre, randomised, open-label, parallel-group study (NCT01294592) in 742 men with an International Prostate Symptom Score (IPSS) of 8-19, prostate volume ≥30 mL and total serum PSA level of ≥1.5 ng/mL. Patients were randomised to FDC (369 patients) or WW-All (373) and followed for 24 months. All patients were given lifestyle advice. The primary endpoint was symptomatic improvement from baseline to 24 months, measured by the IPSS. Secondary outcomes included BPH clinical progression, impact on quality of life (QoL), and safety. RESULTS: The change in IPSS at 24 months was significantly greater for FDC than WW-All (-5.4 vs -3.6 points, P < 0.001). With FDC, the risk of BPH progression was reduced by 43.1% (P < 0.001); 29% and 18% of men in the WW-All and FDC groups had clinical progression, respectively, comprising symptomatic progression in most patients. Improvements in QoL (BPH Impact Index and question 8 of the IPSS) were seen in both groups but were significantly greater with FDC (P < 0.001). The safety profile of FDC was consistent with established profiles of dutasteride and tamsulosin. CONCLUSION: FDC therapy with dutasteride and tamsulosin, plus lifestyle advice, resulted in rapid and sustained improvements in men with moderate BPH symptoms at risk of progression with significantly greater symptom and QoL improvements and a significantly reduced risk of BPH progression compared with WW plus initiation of tamsulosin as per protocol.

The REDUCE Follow-Up Study: low rate of new prostate cancer diagnoses observed during a 2-year, observational, followup study of men who participated in the REDUCE trial.

PURPOSE: The primary objective of the REDUCE (REduction by DUtasteride of prostate Cancer Events) Follow-Up Study was to collect data on the occurrence of newly diagnosed prostate cancers for 2 years beyond the 4-year REDUCE study. MATERIALS AND METHODS: The 4-year REDUCE study evaluated prostate cancer risk reduction in men taking dutasteride. This 2-year observational study followed men from REDUCE with a clinic visit shortly after study conclusion and with up to 2 annual telephone calls during which patient reported data were collected regarding prostate cancer events, chronic medication use, prostate specific antigen levels and serious adverse events. No study drug was provided and all biopsies during the 2-year followup were performed for cause. The primary objective was to collect data on the occurrence of new biopsy detectable prostate cancers. Secondary end points included assessment of Gleason score and serious adverse events. RESULTS: A total of 2,751 men enrolled in the followup study with numbers similar to those of the REDUCE former treatment groups (placebo and dutasteride). Few new prostate cancers were detected during the 2-year followup period in either former treatment group. A greater number of cancers were detected in the former dutasteride group than in the former placebo group (14 vs 7 cases). No Gleason score 8-10 prostate cancers were detected in either former treatment group based on central pathology review. No new safety issues were identified during the study. CONCLUSIONS: Two years of followup of the REDUCE study cohort demonstrated a low rate of new prostate cancer diagnoses in the former placebo and dutasteride treated groups. No new Gleason 8-10 cancers were detected.

Evaluation of a 3-item screening tool to identify men with benign prostatic enlargement/obstruction in a primary care cohort.

BACKGROUND: Benign prostatic hyperplasia (BPH), a progressive condition and common cause of lower urinary tract symptoms (LUTS), is underdiagnosed in primary care, impacting patient outcomes. Here, we evaluate the utility of a BPH screening tool in general practice, to identify men confirmed to have BPH after urologist assessment of diagnostic test results. METHODS: A 3-item questionnaire was developed to discriminate between LUTS due to BPH versus other conditions and was translated and validated cross-culturally. Its utility was assessed in a cohort study (FDC116114/NCT02757963) conducted in 47 centers across France, Germany, Italy, Russia, and Spain. The study enrolled men ≥50 years of age presenting to general practice clinics with a score of ≥3 on the BPH screening tool or ≥8 on the International Prostate Symptom Score (IPSS). In total, 561 men completed the study. The primary endpoint was the proportion of patients with a urologist-confirmed BPH diagnosis among those with a positive result on the BPH screening tool (score ≥3) and serum prostate specific antigen (PSA) ≥2 ng/mL. RESULTS: The primary endpoint was fulfilled; 88.3% (95% CI: 84.9, 91.2) of patients had urologist-confirmed BPH diagnoses among those with positive results on the BPH screening tool and serum PSA≥2 ng/mL, similar to the proportion seen with IPSS≥8 and serum PSA≥2 ng/mL (87.7%; 95% CI: 84.6, 90.4). CONCLUSIONS: The BPH screening tool, in conjunction with serum PSA, demonstrated adequate predictive value by allowing general practitioners to quickly screen men presenting with different medical conditions but identified as having urological symptoms.

Computer recognition of cancer in the urinary bladder using optical coherence tomography and texture analysis.

The vast majority of bladder cancers originate within 600 microm of the tissue surface, making optical coherence tomography (OCT) a potentially powerful tool for recognizing cancers that are not easily visible with current techniques. OCT is a new technology, however, and surgeons are not familiar with the resulting images. Technology able to analyze and provide diagnoses based on OCT images would improve the clinical utility of OCT systems. We present an automated algorithm that uses texture analysis to detect bladder cancer from OCT images. Our algorithm was applied to 182 OCT images of bladder tissue, taken from 68 distinct areas and 21 patients, to classify the images as noncancerous, dysplasia, carcinoma in situ (CIS), or papillary lesions, and to determine tumor invasion. The results, when compared with the corresponding pathology, indicate that the algorithm is effective at differentiating cancerous from noncancerous tissue with a sensitivity of 92% and a specificity of 62%. With further research to improve discrimination between cancer types and recognition of false positives, it may be possible to use OCT to guide endoscopic biopsies toward tissue likely to contain cancer and to avoid unnecessary biopsies of normal tissue.

Relative Bioavailability of Fixed-Dose Combinations of Tamsulosin and Dutasteride: Results From 2 Randomized Trials in Healthy Male Volunteers.

The relative bioavailabilities of dutasteride/tamsulosin hydrochloride 0.5 mg/0.2 mg fixed-dose combination (FDC) capsules compared with coadministered reference products (1 dutasteride 0.5-mg capsule [Avodart® ] + 1 tamsulosin hydrochloride 0.2-mg orally disintegrating tablet [Harnal D® ]) were investigated in 2 clinical trials under fasted and fed conditions (ClinicalTrials.gov NCT02184585 and NCT02509104). Both trials were open-label, randomized, single-dose, crossover studies in healthy male adults aged 18-65 years. Trial 1 evaluated 2 formulations (FDC1 and FDC2), and trial 2 evaluated a third formulation (FDC3). The primary end points were dutasteride area under the concentration-time curve from time 0 to t (AUC(0-t) ) and peak plasma concentration (Cmax ) and tamsulosin AUC(0-∞) , AUC(0-t) , and Cmax . The formulations were considered to be bioequivalent if the 90%CIs for the geometric mean ratios for each end point were within the range of 0.80-1.25. For FDC1 in trial 1, bioequivalence criteria were not met for dutasteride Cmax or AUC in the fasted state or for tamsulosin Cmax in the fasted or fed states. For FDC2 in trial 1, all bioequivalence criteria were met except for tamsulosin Cmax in the fasted state. For FDC3 in trial 2, bioequivalence criteria were met for all dutasteride and tamsulosin end points in both the fed and fasted states. Safety profiles were similar for all FDC formulations and combination treatments.

The emergence of imaging technology in advanced prostate cancer.

Rapid advances in imaging technology have whetted our collective appetites for practical clinical applications to assist the physician and patient in therapeutic decisions. Current limitations of imaging technology are being addressed by the convergence of technology in materials science, the computer industry, and biology which have led to improvements of diagnostic imaging. Refinements in image acquisition, fusion of images, and outcomes data now suggest use for image-guided therapy. Novel imaging agents and technologies appear to provide improved capabilities to detect malignant lymph nodes. Future applications of optical coherence tomography, electron paramagnetic resonance imaging, nanotechnology, and other forms of molecular imaging promise further refinements to enhance our diagnostic armamentarium.

Relationships between Circulating and Intraprostatic Sex Steroid Hormone Concentrations.

Background: Sex hormones have been implicated in prostate carcinogenesis, yet epidemiologic studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically verified benign prostate tissue from prostate cancer cases.Methods: Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race, and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race, and age were assessed as potential effect modifiers.Results: Circulating sex steroid hormone concentrations had low-to-moderate correlations with, and explained small proportions of variations in, intraprostatic sex steroid hormone concentrations. Androstane-3α,17ß-diol glucuronide (3α-diol G) explained the highest variance of tissue concentrations of 3α-diol G (linear regression r2 = 0.21), followed by serum testosterone and tissue dihydrotestosterone (r2 = 0.10), and then serum estrone and tissue estrone (r2 = 0.09). There was no effect modification by Gleason score, race, or age.Conclusions: Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu.Impact: The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating hormones with prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(11); 1660-6. ©2017 AACR.

The evolution of imaging in advanced prostate cancer.

Medical advances will be driven by the enhancement of imaging for diagnosis, refinement of treatment, and evaluation of treatment efficacy. The convergence of technology in materials science, biology, and the computer industry has greatly advanced diagnostic imaging. Precision in control of the spatial and temporal properties of light and its heterogeneous scattering properties have extended our capability for imaging. Refinements in radioimmunoscintigraphy for image acquisition, fusion of images, and outcome data now suggest use for image-guided therapy. Novel MRI agents appear to provide significant imaging capabilities to detect malignant lymph nodes. Future applications of optical coherence tomography, electron paramagnetic resonance imaging, nanotechnology, molecular imaging, and hyperspectral spectroscopy promise further refinements to image tissues for diagnosis.

Evaluation of superficial bladder transitional-cell carcinoma by optical coherence tomography.

BACKGROUND AND PURPOSE: Optical coherence tomography (OCT) is a new modality that allows noninvasive examination of the internal structure of biological tissue in vivo with a spatial resolution of 10 to 15 microm. This study evaluated the clinical application of OCT to determine epithelial and subepithelial anatomic structure and invasiveness of bladder epithelial lesions. MATERIALS AND METHODS: The OCT examination was performed with a 980-nm 10 mW superluminescent diode using a 2.7-mm-diameter optical fiber positioned cystoscopically. A total of 261 scans of 1.5 seconds' duration, which generated 200 x 200-pixel images, were performed on 87 areas in 24 patients at high risk of having transitional-cell carcinoma (TCC). Lesions, visually suspect, and normal areas were photographed, scanned, and biopsied. The scans were evaluated independently before comparison with histopathology findings. RESULTS: Of the 87 areas, 29 of 36 visually suspect areas and 35 of 35 normal areas, were correctly diagnosed with OCT. Of the 16 areas with papillary TCC, all 16 were diagnosed correctly as tumor, and 9 of 10 were diagnosed correctly as invasive, including 6 with lamina propria invasion only. Papillary and flat tumors, carcinoma in situ, inflammation, chronic cystitis, and von Brunn's nests were scanned. Overall, OCT had a sensitivity of 100%, overall specificity of 89%, positive predictive value of 75%, and negative predictive value of 100%. The accuracy was 92%. The positive predictive value for invasion was 90%. CONCLUSION: Optical coherence tomography is a simple, portable, promising modality for evaluation of bladder lesions and depth of tumor penetration. Further refinement of this technology may lead to the development of an optical surrogate for biopsy.

A randomised, double-blind study comparing the addition of bicalutamide with or without dutasteride to GnRH analogue therapy in men with non-metastatic castrate-resistant prostate cancer.

BACKGROUND: Bicalutamide blocks androgen action and is frequently used in men with non-metastatic, castration-resistant prostate cancer (CRPC). By reducing intracellular dihydrotestosterone, dutasteride (dual 5-alpha reductase inhibitor) could increase the effectiveness of bicalutamide in this setting. The objective of the study is therefore to prospectively evaluate dutasteride plus bicalutamide in men with asymptomatic, non-metastatic CRPC with rising prostate-specific antigen (PSA). METHODS: Prostate cancer patients with rising PSA whilst on first-line androgen deprivation therapy (ADT) were randomised (1:1) in a double-blind trial to receive bicalutamide 50mg plus placebo or bicalutamide 50mg plus dutasteride 3.5mg once daily for 18 months. Randomisation was stratified by centre; treatment assignments were generated using GlaxoSmithKline's RandAll System. Subjects who completed 18 months could participate in the 2-year extension. Central laboratory and study sites/monitors remained treatment-blinded. Primary end-point was time to disease progression (TDP) up to 42 months (defined as PSA progression from baseline or nadir, radiographic disease progression, death from prostate cancer or receipt of rescue medication). FINDINGS: There was no statistically significant difference in TDP in 127 men treated with bicalutamide/dutasteride (n=62) compared with bicalutamide/placebo (n=65) (hazard ratio (HR)=0.94 [95% confidence interval (CI) 0.61, 1.46]; p=0.79). The estimated median TDP was 425 days (95% CI 302, 858) in the bicalutamide/placebo group and 623 days (95% CI 369, 730) in the bicalutamide/dutasteride group. There was no statistically significant difference between the treatment groups for any secondary efficacy end-points, including time to treatment failure or PSA response. In the multivariate analysis, age, non-White race, higher baseline testosterone and lower baseline PSA were associated with longer TDP. Adverse events were comparable between treatment groups. INTERPRETATION: In men with non-metastatic CRPC, adding dutasteride to bicalutamide did not significantly prolong TDP. Prospective data are provided concerning the common practice of using bicalutamide in this setting.

Uteroglobin: a potential novel tumor suppressor and molecular therapeutic for prostate cancer.

Currently, there are very few diagnostic or therapeutic strategies targeted at controlling tumor growth and progression towards metastasis. Uteroglobin (UG) is a naturally occurring, small, stable, secretory protein that is normally expressed by most cells of epithelial origin but is known to be lost during the progression of prostate, lung, and uterine cancers to invasive malignancy. Uteroglobin -/- knockout mice appear to be extremely cancer prone. Both pharmacological and transgenic reconstitution of recombinant human UG (rhUG) to prostate, lung, and endometrial tumor cell lines markedly inhibits their invasiveness and antagonizes the neoplastic phenotype. In preliminary studies, rhUG inhibited angiogenesis in the ex vivo rat aorta model and showed antitumor activity against human prostate tumor cells (PC-3) in the chick chorioallantoic membrane assay, reducing both tumor volume and vascularity. A recent in vivo pilot study showed that twice daily dosing with rhUG resulted in a statistically significant increase in survival without evidence of toxicity in severe combined immunodeficient mice challenged with a PC-3 cell metastasizing tumor. Thus, rhUG may slow the progression of cancer by inhibiting both tumor cell invasiveness and tumor angiogenesis. It therefore holds the potential to serve as a new weapon in the arsenal of cytostatic, antimetastatic, adjuvant treatment for cancer. In this paper, we will briefly discuss the therapeutic potential of uteroglobin-based strategies for managing prostate cancer.

Photodynamic therapy for refractory superficial bladder cancer: long-term clinical outcomes of single treatment using intravesical diffusion medium.

BACKGROUND: Diffuse superficial transitional-cell carcinoma (TCC) refractory to standard therapies poses a clinical dilemma. Photodynamic therapy (PDT), which uses an interaction between absorbed light and a retained photosensitizing agent to destroy tissue, has been used to treat diffuse superficial bladder TCC, although there are few reports of long-term outcomes. PATIENTS AND METHODS: A series of 34 patients, 29 with TCC carcinoma in situ (CIS) and 5 with multiple small papillary stage T(a) or T(1) lesions, received porfimer sodium (P) 48 hours before whole-bladder PDT with 630-nm laser light. A 0.02% soybean emulsion diffusion medium was instilled into the bladder, and the laser optical fiber was positioned under triplanar sonography prior to PDT. The mean follow-up was 52 months. RESULTS: At 3 months, a complete response (CR) in 14 (44%) of the 32 evaluable patients, a partial response (PR) in 4 (12%), and no response (NR) in 14 (44%). Four of the five patients with extensive papillary lesions did not respond. The NR rate for patients with CIS with or without resected papillary lesions was 37%. The mean time to recurrence in the CR group was 9.8 months, and five members of this group (36%) underwent cystectomy (mean time 20 months) for persistent/progressive disease (N = 3) or bladder contracture (N = 2). In the NR group, 6 (43%) underwent cystectomy (mean time 14 months) for persistent/progressive disease. Metastatic bladder cancer was the cause of death in only 4 of the 12 patients who have died. Of the remaining 22 patients, 15 are still alive and have an intact bladder, nine with no disease and six with only superficial disease. CONCLUSION: This is the first report of long-term results following whole-bladder PDT using diffusion medium for isotropic light distribution. More than half of the patients with TCC refractory to traditional intravesical therapy received benefit from a single PDT session. Patients with extensive flat papillary lesions do not appear to respond well. Patients who achieve a CR have less likelihood of and longer time interval before needing cystectomy for progressive disease than NR patients. Our PDT protocol is associated with minimal morbidity in these high-risk patients.

Cost effectiveness of treatment for benign prostatic hyperplasia: an economic model for comparison of medical, minimally invasive, and surgical therapy.

PURPOSE: To evaluate the cost effectiveness of minimally invasive therapy relative to medical (alpha-blocker) therapy and transurethral resection (TURP) for patients with moderate to severe symptoms of benign prostatic hyperplasia (BPH). METHODS: We constructed a decision-analytic Markov model for a hypothetical cohort of 65-year-old men with moderate to severe BPH symptoms. Microwave thermotherapy was selected to represent minimally invasive treatment. Cost-effectiveness analysis was performed with 25 health states using the 3 treatments, 5 short-term clinical events, and 17 possible long-term outcomes. Each health state had an associated cost and utility. Quality of life (QoL) and utility estimates were obtained by interviewing 13 men with BPH symptoms using the standard gamble reference methods. Patients were classified as risk averse (RA) or non-risk averse (NRA) on the basis of their attitudes to risk. We calculated the incremental cost effectiveness of microwave thermotherapy relative to medical therapy and TURP over 5 years after treatment initiation. Event probabilities were obtained from the literature, a consensus panel, and published randomized clinical trials. RESULTS AND CONCLUSIONS: The utility values generated were internally consistent and externally valid for a hypothetical cohort of 10,000 RA patients. Microwave thermotherapy was preferred by the NRA group, while medical therapy was preferred by the RA group. Surgery was least preferred by both groups. Microwave thermotherapy had a small incremental cost but improved QoL in comparison with medical therapy. Microwave thermotherapy had a higher utility and lower cost than TURP and thus was dominant over TURP. This analytical method can be applied to evaluate the cost effectiveness of any BPH therapy.

Virtual reality surgical simulation for lower urinary tract endoscopy and procedures.

BACKGROUND AND PURPOSE: To provide a realistic experience of lower urinary tract endoscopic procedures, we have developed and continue to expand a computer-based surgical simulator that incorporates a surgical tool interface with anatomic detail and haptic feedback. METHODS: Surface-based geometric data for the lower urinary tract were generated from the National Library of Medicine Visible Human dataset. The three-dimensional texture map of the surface geometry was developed from recorded endoscopic video procedures. Geometry and associated texture maps were rendered in real time using the Silicon Graphics Extreme Impacts program. The surgical interface device incorporated all normal ranges of motion and resistance that occur within an actual operative environment. The hands-on endoscopic device attached to the interface device was provided by Circon-ACMI, Inc. Urologic residents evaluated the program for correlation with actual endoscopic procedures. RESULTS: Texture-mapped digitized images provided a close anatomic similarity to actual videoendoscopic images. Virtual endoscopy of the lower urinary tract was reproducible and closely simulated actual visual and tactile endoscopic experience. CONCLUSIONS: Virtual reality surgical simulation is feasible for a variety of lower urinary tract procedures. This system coordinates visual perception with appropriate haptic feedback in both longitudinal and rotational axes. These types of procedures may be incorporated into future educational experiences for urologists to introduce new techniques and to provide documentation of surgical experience.