Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer.

BACKGROUND: Men undergoing treatment of clinically localised prostate cancer may experience a number of treatment-related complications, which affect their quality of life. METHODS: On the basis of population-based retrospective cohort of men undergoing surgery, with or without subsequent radiotherapy, or radiotherapy alone for prostate cancer in Ontario, Canada, we measured the incidence of treatment-related complications using administrative and billing data. RESULTS: Of 36 984 patients, 15 870 (42.9%) underwent surgery alone, 4519 (12.2%) underwent surgery followed by radiotherapy, and 16 595 (44.9%) underwent radiotherapy alone. For all end points except urologic procedures, the 5-year cumulative incidence rates were lowest in the surgery only group and highest in the radiotherapy only group. Intermediary rates were seen in the surgery followed by radiotherapy group, except for urologic procedures where rates were the highest in this group. Although age and comorbidity were important predictors, radiotherapy as the primary treatment modality was associated with higher rates for all complications (adjusted hazard ratios 1.6-4.7, P=0.002 to <0.0001). CONCLUSIONS: In patients treated for prostate cancer, radiation after surgery increases the rate of complications compared with surgery alone, though these rates remain lower than patients treated with radiation alone. This information may inform patient and physician decision making in the treatment of prostate cancer.

OnabotulinumtoxinA 100U provides significant improvements in overactive bladder symptoms in patients with urinary incontinence regardless of the number of anticholinergic therapies used or reason for inadequate management of overactive bladder.

INTRODUCTION: A prespecified pooled analysis of two placebo-controlled, phase 3 trials evaluated whether the number of prior anticholinergics used or reason for their discontinuation affected the treatment response to onabotulinumtoxinA 100U in overactive bladder (OAB) patients with urinary incontinence (UI). METHODS: Patients with symptoms of OAB received intradetrusor injections of onabotulinumtoxinA 100U or placebo, sparing the trigone. Change from baseline at week 12 in UI episodes/day, proportion of patients reporting a positive response ('greatly improved' or 'improved') on the treatment benefit scale (TBS), micturition and urgency were evaluated by number of prior anticholinergics (1, 2 or ≥ 3) and reason for their discontinuation (insufficient efficacy or side effects). Adverse events (AE) were assessed. RESULTS: Patients had taken an average of 2.4 anticholinergics before study enrolment. OnabotulinumtoxinA reduced UI episodes/day from baseline vs. placebo, regardless of the number of prior anticholinergics (-2.82 vs. -1.52 for one prior anticholinergic; -2.58 vs. -0.58 for two prior anticholinergics; and -2.92 vs. -0.73 for three or more prior anticholinergics; all p < 0.001). The proportion of TBS responders was higher with onabotulinumtoxinA vs. placebo (69.0% vs. 37.2% for one prior anticholinergic; 58.8% vs. 24.8% for two prior anticholinergics and 56.4% vs. 22.5% for three or more prior anticholinergics; all p < 0.001). Similar results were observed regardless of the reason for discontinuation. OnabotulinumtoxinA reduced the episodes of urgency and frequency of micturition vs. placebo in all groups. AEs were well tolerated, with a comparable incidence in all groups. CONCLUSION: In patients with symptoms of OAB who were inadequately managed by one or more anticholinergics, onabotulinumtoxinA 100U provided significant and similar treatment benefit and safety profile regardless of the number of prior anticholinergics used or reason for inadequate management of OAB. ClinicalTrials.gov: NCT00910845, NCT00910520.

Efficacy and safety of fesoterodine 8 mg in subjects with overactive bladder after a suboptimal response to tolterodine ER.

AIMS: To assess fesoterodine 8 mg efficacy over time and vs. placebo in subjects with overactive bladder (OAB) who responded suboptimally to tolterodine extended release (ER) 4 mg. METHODS: In a 12-week, double-blind trial, subjects with self-reported OAB symptoms for ≥ 6 months, mean of ≥ 8 micturitions and ≥ 2 to < 15 urgency urinary incontinence (UUI) episodes/24 h, and suboptimal response to tolterodine ER 4 mg (defined as ≤ 50% reduction in UUI episodes during 2-week run-in) were randomised to fesoterodine (4 mg for 1 week, 8 mg for 11 weeks) or placebo once daily. Change from baseline to week 12 in UUI episodes (primary end-point) was analysed in step-wise fashion: first, baseline vs. week 12 for fesoterodine; if significant, then change from baseline to week 12 for fesoterodine vs. placebo. RESULTS: By week 12, subjects receiving fesoterodine 8 mg had significantly greater improvement from baseline vs. placebo in UUI episodes, urgency episodes and scores on the Patient Perception of Bladder Control, Urgency Perception Scale and OAB Questionnaire Symptom Bother and Health-Related Quality of Life scales and domains (all p < 0.05). 50% and 70% UUI responder rates were also significantly higher with fesoterodine 8 mg vs. placebo at week 12 (p < 0.05). Dry mouth (placebo, 4%, 12/301; fesoterodine, 16.6%, 51/308) and constipation (placebo, 1.3%, 4/301; fesoterodine, 3.9%, 12/308) were the most frequent adverse events. CONCLUSIONS: Subjects who responded suboptimally to tolterodine ER 4 mg showed significant improvements in UUI and other OAB symptoms and patient-reported outcomes, with good tolerability, during treatment with fesoterodine 8 mg vs. placebo.

Safety and tolerability of the ß3 -adrenoceptor agonist mirabegron, for the treatment of overactive bladder: results of a prospective pooled analysis of three 12-week randomised Phase III trials and of a 1-year randomised Phase III trial.

AIMS: To evaluate the safety and tolerability of the ß3 -adrenoceptor agonist, mirabegron, in patients with overactive bladder (OAB). METHODS: Tolerability and safety data from three 12-week, randomised, placebo-controlled, double-blind, Phase III trials (Studies 046, 047 and 074) were pooled by treatment group. The three studies were of a similar design, although the assessed doses of mirabegron [25, 50 or 100 mg once daily (qd)] varied, and tolterodine extended release (ER) 4 mg was included as an active-control arm in Study 046 only. Tolerability and safety data from a 1-year, randomised, double-blind, Phase III trial (Study 049) are also presented. Safety variables included the incidence and severity of treatment-emergent adverse events (TEAEs), vital signs and electrocardiogram data. RESULTS: Mirabegron (25, 50 or 100 mg qd) was safe and well-tolerated in patients with OAB over 12-week (n = 2736) and 1-year (n = 1632) periods. The incidence of TEAEs and treatment discontinuations as a result of TEAEs was low; the majority were mild in severity and few were serious. Hypertension, nasopharyngitis and urinary tract infection were the most common TEAEs with mirabegron. The mirabegron tolerability profile was similar to that seen with placebo and tolterodine ER 4 mg, except for dry mouth, which occurred, on average, five times less frequently with mirabegron than tolterodine ER 4 mg. In the pooled 12-week analysis, mirabegron 50 mg was associated with placebo-adjusted mean increases of 0.4-0.6 mmHg in blood pressure and approximately one beat per minute in pulse rate, both reversible upon treatment discontinuation. The incidence of Major Adverse Cardiovascular Events as adjudicated by an independent cardiovascular committee was low and similar across treatment groups. CONCLUSION: The favourable tolerability profile of mirabegron in patients with OAB may allow improved treatment compliance compared with antimuscarinics, with important implications for patient outcomes.

Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies.

INTRODUCTION: To examine pooled efficacy data from three, large phase III studies comparing mirabegron (50 and 100 mg) with placebo, and pooled safety data including additional mirabegron 25 mg and tolterodine extended release (ER) 4 mg results. METHODS: This prespecified pooled analysis of three randomised, double-blind, placebo-controlled, 12-week studies, evaluated efficacy and safety of once-daily mirabegron 25 mg (safety analysis), 50 or 100 mg (efficacy and safety analyses) and tolterodine ER 4 mg (safety analysis) for the treatment of symptoms of overactive bladder (OAB). Co-primary efficacy measures were change from baseline to Final Visit in the mean number of incontinence episodes/24 h and mean number of micturitions/24 h. Key secondary efficacy end-points included mean number of urgency episodes/24 h and mean volume voided/micturitions, while other end-points included patient-reported outcomes according to the Treatment Satisfaction-Visual Analogue Scale (TS-VAS) and responder analyses [dry rate (posttreatment), ≥ 50% reduction in incontinence episodes/24 h, ≤ 8 micturitions/24 h (post hoc analysis)]. The safety analysis included adverse event (AE) reporting, laboratory assessments, ECG, postvoid residual volume and vital signs (blood pressure, pulse rate). RESULTS: Mirabegron (50 and 100 mg once daily) demonstrated statistically significant improvements compared with placebo for the co-primary end-points, key secondary efficacy variables, TS-VAS and responder analyses (all comparisons p < 0.05). Mirabegron is well tolerated and demonstrates a good safety profile. The most common AEs (≥ 3%) included hypertension, nasopharyngitis and urinary tract infection (UTI); the incidence of hypertensive events and UTIs decreased with increasing dose. For mirabegron, the incidence of the bothersome antimuscarinic AE, dry mouth, was at placebo level and of a lesser magnitude than tolterodine. CONCLUSION: The efficacy and safety of mirabegron are demonstrated in this large pooled clinical trial dataset in patients with OAB.

The surgical management of upper tract stone disease among spinal cord-injured patients.

STUDY DESIGN: Retrospective cohort study, using linked, population-based health-care data. OBJECTIVES: To describe the incidence, management and outcomes of surgically treated kidney stones after spinal cord injury (SCI). To evaluate the impact of a past history of kidney stones on the occurrence of kidney stones. SETTING: Ontario, Canada. METHODS: A total of 5121 patients were followed a median of 4 years after an incident SCI (occurring between 2002 and 2011). The primary outcome was surgical intervention for upper tract kidney stones. RESULTS: In follow-up, 66 patients (1.3%) had 89 episodes of surgically treated kidney stones. Treatments included: ureteroscopic lithotripsy (34%), ureteral stent/percutaneous nephrostomy (30%), shockwave lithotripsy (19%) or percutaneous nephrolithotripsy (17%). Following stone treatment, the 30-day mortality rate was low, and the 30-day admission rate to an intensive care unit was 12%. A history of surgically treated kidney stones before SCI (compared with no such history) was associated with a higher risk of kidney stones after SCI (27 vs 3 per 1000 person-years; adjusted hazard ratio 14.74, 95% confidence interval 5.69-38.22). CONCLUSION: During intermediate follow-up after SCI, surgically treated upper tract kidney stones occur in 1.3% of patients. Ureteroscopy with lithotripsy is the most common treatment. A history of surgically managed kidney stones before SCI portends a higher risk of stones after SCI.

Measurability of non-small-cell lung cancer on chest radiographs.

Response rates to various drug regimens are determined in multi-center trials by radiographic measurement of tumor dimensions before and after treatment. The way in which lesions are measured may affect the reported results. Lesions due to primary lung cancer may be more difficult to assess than rounded peripheral metastases. No previous study has assessed the variability of tumor measurements in patients with primary lung cancer. Nineteen radiographs from 12 patients with non-small-cell lung cancer (NSCLC) were shown to 25 experienced readers on two separate occasions. Pre- and post-treatment (combined chemotherapy and radiotherapy) radiographs were first shown separately, unidentified and in random order. Three months later, they were shown side by side with the facility for comparison. A decrease in tumor size of greater than or equal to 50% was considered as a "response." Viewing paired films together increased the viewers ability to measure tumors compared with reading each film of the radiographic pair individually. Fifty-one percent of unmeasurable pairs became measurable when read together, whereas 13% of previously measurable pairs now became unmeasurable. The interobserver variation in measurements was 10% to 265%, while the intraobserver variation was 4% to 10%. The correlation between responses calculated on the first and second readings often was no better than chance alone. Subjective impressions of degree of improvement showed no good correlation with response rates measured objectively. Because of the large variation in measurements and consequently in response rate, we recommend that all radiographs be reviewed by a single observer for any particular study, and pre- and post-treatment radiographs be evaluated together.

Balanitis xerotica obliterans involving anterior urethra.

Balanitis xerotica obliterans (BXO) is known to affect the urethral meatus, glans, and prepuce. We describe a case of biopsy-proved BXO that involves not only the usual areas but the anterior urethra as well. Of added interest is the subsequent development of squamous cell carcinoma in the fossa navicularis. The literature is reviewed.

Early experience with intraoperative cavernous nerve stimulation with penile tumescence monitoring to improve nerve sparing during radical prostatectomy.

OBJECTIVES: To determine if intraoperative stimulation of the cavernous nerves while monitoring changes in penile tumescence to map the course of these nerves would result in an improvement in nerve sparing and erectile function after radical prostatectomy. METHODS: Patients were eligible for this pilot study if they were undergoing a radical prostatectomy and were candidates for a nerve-sparing approach. Erectile function was assessed by patient self-reporting and questionnaire before surgery and by patient self-reporting periodically 12 months after surgery. A cavernous nerve stimulator and tumescence-monitoring device was used during radical prostatectomy to identify the course of the cavernous nerves and guide the surgeon in avoiding nerve damage. Patients were monitored for any evidence of complications and/or adverse events for 1 year from time of surgery. RESULTS: Twenty-six patients were recruited to the trial. Nerve stimulation and tumescence monitoring was performed in 23 patients. Twenty-one of 23 patients demonstrated a tumescence response to intraoperative nerve stimulation. Nineteen of 21 patients reported erectile function preoperatively. Seventeen (89%) of 19 patients demonstrated a tumescence response during surgery. Sixteen (94%) of the 17 patients who demonstrated a response to nerve stimulation and for whom the surgery was guided by the tumescence response reported the ability to have erections after surgery. No side effects due to the use of the device were reported. Only 3 (12%) of 25 patients had positive margins confined to the lateral margin and/or apex whose modifications associated with nerve sparing could conceivably have altered margin status. CONCLUSIONS: These clinical data suggest that an intraoperative tumescence response to cavernous nerve stimulation may guide the surgeon in preserving cavernous nerves and improving erectile function after radical prostatectomy.

Patient perspective of long-term outcome of augmentation cystoplasty for neurogenic bladder.

OBJECTIVES: Although the urologic outcomes of augmentation cystoplasty for neurogenic bladder dysfunction are well known, additional information about the patient perspective is needed. The aim of this study was to assess patient perspective using a standardized questionnaire. METHODS: Fifty-nine patients, who had undergone augmentation enterocystoplasty as part of reconstruction mainly to correct hyperactive bladders and incontinence, were subjected to a questionnaire after a median of 76.1 postoperative months. The questionnaire addressed medications, catheterization, incontinence, bowel dysfunction, and satisfaction with urinary tract management. The urologic outcomes regarding upper and lower tract changes, complications, and reinterventions were documented as well. RESULTS: The patients experienced a significant increase in bladder capacity and decrease in pressure at capacity (P < 0.0001). Normal upper tracts remained normal and there was either improvement or stabilization of hydronephrosis. Twenty-four patients (40.6%) had one or more complications, with 21 requiring reinterventions. Twenty-five percent of patients required the reintervention within the first 25 months, and the median time to reintervention was almost 10 years. Thirty-five patients took medications such as anticholinergics, antidiarrheals, or antibiotics. Fifty-six patients were treated with clean intermittent catheterization (CIC) at a mean interval of 4.6 hours. Seven patients had some difficulty with CIC. Thirty-nine patients (67%) were dry, and 17 had mild and 3 severe incontinence. Eleven patients (18.6%) reported bowel dysfunction, although 7 had it preoperatively. Almost all patients were very satisfied with their urologic management. CONCLUSIONS: The high degree of patient satisfaction attests to the value of the procedure. The complication and reintervention rates underscore the importance of long-term follow-up.

Psoas abscess after operation on lumbar spine.

A case of pyogenic psoas abscess is reported. It was found many years after lumbar spine operation, although the patient had confusing symptoms during the whole period. The last presenting symptoms were fever, chills, back pain, and hematuria. Ultrasonography provided conclusive information about the abscess.

Current status of injectable agents for female stress urinary incontinence.

The purpose of this review is to summarize the results of reports of injectable agents for the treatment of female urinary stress incontinence. Five agents were reviewed: collagen, Teflon, autologous fat, silicone microparticles, and silicone microballoons. Collagen was the most frequently reported agent and yielded short-term cure and improved rates of 74%-100%. This deteriorated to approximately 57% with longer term follow-up. Teflon has similarly lower longer term than short-term success rates, at 33%-76%. The reported local complications and the potential for particle migration have resulted in its lack of widespread acceptance. Autologous fat has yielded the lowest success rate. Longer term success in a small number of silicone microparticle articles was similar to the other injectables at approximately 60%. Early success with silicone microballoons was 70%. The technique is generally free of major morbidity. The indication for injectables is intrinsic sphincter deficiency but hypermobility is not a contraindication. Long-term durability, cost effectiveness, and some safety issues still have to be addressed by further clinical trials.

Female clear cell adenocarcinoma arising within a urethral diverticulum.

Clear cell adenocarcinomas arising from female urethral diverticulae are rare. The optimal management of this clinical entity is uncertain. Two cases managed by a combination of surgery and XRT (radiotherapy) are presented. The common histopathological findings and treatment options are highlighted. Individualized patient management in a multi-disciplinary setting is recommended.

Neoadjuvant chemoradiotherapy and multivisceral resection for primary locally advanced adherent colon cancer: a single institution experience.

BACKGROUND: Although there is an extensive body of literature on the role of neoadjuvant chemoradiotherapy (CRT) in the management of rectal cancer, its role in primary locally advanced adherent colon cancer (LAACC) is unclear. OBJECTIVE: To analyzed the outcomes of neoadjuvant CRT and multivisceral resection in the management of LAACC patietns. METHODS: We retrospectively reviewed our institutional Colorectal Carcinoma Database for 33 patients with potentially resectable, non-metastatic primary LAACC who received neoadjuvant CRT followed by multivisceral resection. CRT consisted of external beam radiation (45-50 Gy in 25 daily fractions) and concurrent 5-FU infusion (225 mg/m(2)/day). RESULTS: There were 21 males and 12 females. Median age was 64 (31-83) and median follow-up was 36 months. All patients had microscopically clear resection margins (R0). Complete pathologic response was documented in 1 patient (3%) and 66% had ypT4b disease. Post-operative complications were observed in 36% of patients with no 30-day mortality. The 3-year overall survival and 3-year disease-free survival were 85.9% and 73.7% respectively. Two patients developed a local recurrence. CONCLUSIONS: Neoadjuvant CRT and en-bloc multivisceral resection may result in high rates of R0 resection and excellent local control with acceptable morbidity and mortality in selected patients with LAACC.

Tolerability of solifenacin and oxybutynin immediate release in older (> 65 years) and younger (≤ 65 years) patients with overactive bladder: sub-analysis from a Canadian, randomized, double-blind study.

OBJECTIVE: Overactive bladder (OAB) is a common condition whose prevalence increases with age. Antimuscarinic agents are the pharmacologic treatment of choice, but adverse events such as dry mouth may lead to early discontinuation. The purpose of this analysis was to compare the incidence and severity of dry mouth and other adverse events with solifenacin 5 mg/day and oxybutynin immediate release (IR) 15 mg/day in patients ≤ 65 years and >65 years in the Canadian VECTOR study (VEsicare in Comparison To Oxybutynin for oveRactive bladder patients). RESEARCH DESIGN AND METHODS: VECTOR was a randomized, multicentre, prospective, double-blind, double-dummy study in 132 subjects with ≥ 1 urgency episode per 24 h, with or without urgency incontinence, and ≥ 8 micturitions per 24 h for ≥ 3 months. After a 2-week washout, patients received solifenacin 5 mg once daily or oxybutynin IR 5 mg tid for 8 weeks. For the current post-hoc analysis, adverse events were evaluated in subgroups of patients ≤ 65 years and >65 years, using a full logistic regression model, multinomial logit regression model and reduced model. CLINICAL TRIAL REGISTRATION: NCT00431041. RESULTS: The incidence and severity of dry mouth and other adverse events with solifenacin were similar between younger and older patients. In both age subgroups, solifenacin 5 mg/day was associated with fewer episodes and lower severity of dry mouth, and a lower discontinuation rate, compared with oxybutynin IR 15 mg/day. CONCLUSIONS: Solifenacin 5 mg/day was better tolerated than oxybutynin IR 15 mg/day in younger (≤ 65 years) and older (> 65 years) subgroups. Solifenacin was equally well tolerated in both age subgroups. Limitations of the analysis were that the study was not preplanned to perform post-hoc subgroup analysis, patients knew that dry mouth was a primary outcome, and the study used fixed doses of each drug.

Canadian cost-effectiveness analysis of solifenacin compared to oxybutynin immediate-release in patients with overactive bladder.

OBJECTIVE: To estimate the cost effectiveness of solifenacin 5 mg/day compared to oxybutynin immediate-release (IR) 15 mg/day in patients with overactive bladder, from the perspective of the Canadian healthcare (payer) system. RESEARCH DESIGN AND METHODS: A Markov model was adapted to estimate the incremental cost per quality-adjusted life-year (QALY) of solifenacin and oxybutynin IR over a 1-year time horizon, based on efficacy and discontinuation data from the Canadian VECTOR (VEsicare in Comparison To Oxybutynin for oveRactive bladder patients) study. In the model, patients who discontinued treatment were offered tolterodine extended release 4 mg/day as second-line. Model robustness was tested using various sensitivity analyses. Utility values were derived from published literature; incontinence pads were included in a secondary analysis. RESULTS: In the base-case analysis, total costs over 1 year were CAN$695 and CAN$550 in the solifenacin and oxybutynin IR groups, respectively. When including incontinence pad costs, there was an incremental saving of CAN$1,831 per patient with solifenacin. Solifenacin was associated with an incremental QALY gain of 0.01 over 1 year. In the base-case analysis without incontinence pads, the incremental cost-utility ratio for solifenacin was CAN$14,092. Probabilistic analyses showed no overlap in the 95% confidence intervals for total costs or QALYs with or without incontinence pads. Solifenacin was cost effective in >90% of cases, based on a willingness-to-pay threshold of CAN$50,000 per additional QALY, irrespective of whether pad costs were included in the model. The most influential variables were the discontinuation rates and the cost of incontinence pads. Limitations of the analysis relate mainly to the fact that data in the VECTOR study were collected using a direct questioning approach, which might have increased the reporting of dry mouth. CONCLUSIONS: Solifenacin 5 mg/day was a cost-effective treatment compared with oxybutynin IR 15 mg/day. TRIAL REGISTRATION: NCT00431041 (of the VECTOR study, upon which the analysis in this paper was based).