Raj Satkunasivam

Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study

BACKGROUNDnConflicting evidence exists for the association between testosterone replacement therapy and mortality and cardiovascular events. The US Food and Drug Administration recently cautioned that testosterone replacement therapy might increase risk of heart attack and stroke, based on evidence from studies with short treatment duration and follow-up. No previous study has assessed the effect of duration of testosterone treatment on these outcomes. We aimed to assess the association between long-term use of testosterone replacement therapy and mortality, cardiovascular events, and prostate cancer diagnoses, using a time-varying exposure analysis.nnnMETHODSnWe did a population-based matched cohort study of men aged 66 years or older newly treated with testosterone replacement therapy and controls matched for age, region of residence, comorbidity, diabetes status, and index year from 2007-12 in Ontario, Canada, using data from the Ontario Drug Benefit database, the Canadian Institute for Health Information (CIHI) Discharge Abstract Database, the CIHI National Ambulatory Care Reporting System, the Ontario Health Insurance Plan database, the Ontario Myocardial Infarction Database, the Ontario Diabetes Database, the Ontario Cancer Registry, and the Registered Persons database. We assessed the association between cumulative testosterone replacement therapy exposure and mortality, cardiovascular events, and prostate cancer using marginal models with a time-varying testosterone exposure.nnnFINDINGSnWe included 10u2008311 men treated with testosterone replacement therapy and 28u2008029 controls between Jan 1, 2007, and June 30, 2012. Over a median follow-up of 5·3 years (IQR 3·6-7·5) in the testosterone replacement therapy group and 5·1 years (3·4-7·4) in the control group, patients treated with testosterone replacement therapy had lower mortality than did controls (hazard ratio [HR] 0·88, 95% CI 0·84-0·93). Patients in the lowest tertile of testosterone exposure had increased risk of mortality (HR 1·11, 95% CI 1·03-1·20) and cardiovascular events (HR 1·26, 95% CI 1·09-1·46) compared with controls. By contrast, those in the highest tertile of testosterone exposure had decreased risk of mortality (HR 0·67, 95% CI 0·62-0·73) and cardiovascular events (HR 0·84, 95% CI 0·72-0·98), with a significant trend across tertiles (p<0·0001). Risk of prostate cancer diagnosis was decreased for those with the highest tertile of exposure (HR 0·60, 95% CI 0·45-0·80) compared with controls, but not for those with the shortest exposure.nnnINTERPRETATIONnLong-term exposure to testosterone replacement therapy was associated with reduced risks of mortality, cardiovascular events, and prostate cancer. However, testosterone replacement therapy increased the risk of mortality and cardiovascular events with short durations of therapy. In view of the limitations of observational data and the potential for selection bias, these results warrant confirmation in a randomised trial.nnnFUNDINGnPhysicians Services Incorporated Foundation and Ajmera Family Chair in Urologic Oncology.

Cardiovascular and Skeletal-related Events Following Localized Prostate Cancer Treatment: Role of Surgery, Radiotherapy, and Androgen Deprivation.

OBJECTIVEnTo examine the impact of androgen deprivation therapy (ADT) and primary treatment modality on cardiovascular and skeletal-related events and to investigate potential effect modification in a contemporary cohort of patients treated for clinically localized prostate cancer.nnnSUBJECTS AND METHODSnWe conducted a retrospective cohort study using Surveillance, Epidemiology, and End Results-Medicare linked databases for men aged 65-79 years who underwent radical prostatectomy or radiotherapy for cT1 or cT2 prostate cancer from 2000 to 2008. We categorized treatment according to primary therapy and receipt of ADT. We described the cumulative incidence of cardiovascular and skeletal-related events.nnnRESULTSnAmong 60,156 men, 14,403 underwent surgery and 45,753 underwent radiotherapy. Median follow-up was 6.0 years. After adjusting for baseline differences, treatments with radiotherapy (adjusted hazard ratios [aHR] 1.16-1.28, Pu2009<.0001-.04) and ADT (aHR 1.18-1.32, Pu2009<.0001-.008) were each independently associated with increased risk of coronary heart disease, sudden cardiac death, fracture, and fracture requiring hospitalization. Radiotherapy was associated with an increased risk of myocardial infarction (aHR 1.20, Pu2009=u2009.02), whereas ADT was not (Pu2009=u2009.5). We did not identify a significant statistical interaction between primary and hormonal treatment.nnnCONCLUSIONnCare for cardiovascular and skeletal-related events is an important part of the survivorship phase for a significant proportion of patients with localized prostate cancer. Increasing use of ADT for patients with localized disease undergoing radiotherapy and the observed higher prevalence of these events in these patients should be considered when discussing the risks and benefits of treatment for localized prostate cancer and when formulating a survivorship plan.

Occurrence of and Risk Factors for Urological Intervention During Benign Hysterectomy: Analysis of the National Surgical Quality Improvement Program Database

OBJECTIVEnTo determine the occurrence of lower genitourinary tract (LGUT) injury during hysterectomy for benign disease and identify risk factors for LGUT injury, with a specific focus on the effect of hysterectomy modality.nnnMETHODSnWe performed a retrospective cohort study of patients undergoing hysterectomy for benign disease from 2010 t o 2014 using the American College of Surgeons National Surgical Quality Improvement Program, a multi-institutional prospective registry that captures perioperative surgical outcomes. We identified the occurrence of concomitant cystoscopy and therapeutic urologic interventions including endoscopic ureteric stenting, ureteric repair, bladder repair, cystectomy, and urinary diversion as a proxy for LGUT injuries. Adjusted odds ratios and 95% confidence intervals were calculated using multivariate logistic regression.nnnRESULTSnWe identified 101,021 patients treated with hysterectomy for benign disease: 18,610 (18.4%), 27,427 (27.2%), and 54,984 (54.4%) underwent vaginal, open, and laparoscopic hysterectomy, respectively. Cystoscopy was performed in 16,493 cases (16.3%). There were 2427 patients (2.4%) who underwent concomitant urologic intervention. Patients undergoing laparoscopic hysterectomy had increased occurrence of urologic intervention, excluding cystoscopy (adjusted odds ratio 1.47, 95% confidence interval 1.29-1.69), compared to vaginal hysterectomy; no differences were found between open and vaginal hysterectomy or laparoscopic and open hysterectomy. Larger uteri, a postoperative diagnosis of endometriosis, increasing comorbidity, and African American race were associated with an increased odd of urologic intervention whereas concomitant cystoscopy was associated with a decreased chance.nnnCONCLUSIONnThe incidence of lower genitourinary tract intervention in benign hysterectomy is significant and may be higher than previously reported. Predisposing patient factors and operative technique are key risk factors.

Association Between Primary Local Treatment and Non-prostate Cancer Mortality in Men With Nonmetastatic Prostate Cancer

OBJECTIVEnTo assess the association between local treatment modality, surgery or radiotherapy, and non-prostate cancer and cardiovascular mortality in patients treated for nonmetastatic prostate cancer, given the high competing risk of mortality in this population.nnnMETHODSnWe performed a population-based, retrospective cohort study of men treated for nonmetastatic prostate cancer in Ontario, Canada, from 2002 to 2009. Patients treated with surgery and radiotherapy were matched on demographics, comorbidity, and cardiovascular risk factors. The primary outcome was non-prostate cancer mortality. Outcomes were compared using the Fine and Gray subdistribution method with generalized estimating equations. We used a previously published technique to quantify the prevalence and strength of residual confounding necessary to account for observed results.nnnRESULTSnWe examined 5393 pairs of matched men. The 10-year cumulative incidence of non-prostate cancer mortality was higher among patients who underwent radiotherapy (12%) than surgery (8%; adjusted subdistribution hazard ratio [HR] 1.57, 95% confidence interval 1.35-1.83). Patients treated with radiotherapy also had an increased risk of cardiovascular mortality (adjusted HR 1.74, 95% confidence interval 1.27-2.37). Hypothetical residual confounders would have to be both strongly associated with non-prostate cancer mortality (HRsu2009>u20092.5) and have highly differential prevalence to nullify the observed effect.nnnCONCLUSIONnAmong patients carefully matched on cardiovascular risk factors, those treated with radiotherapy had an increased risk of non-prostate cancer mortality and cardiovascular disease. Because of the observational nature of the data, the potential for confounding remains. The magnitude and prevalence of potential residual confounders required to account for differences in treatment effects for prostate cancer was quantified.

Hospitalizations to Manage Complications of Modern Prostate Cancer Treatment in Older Men

OBJECTIVEnTo assess rates of treatment-related hospitalizations following surgery and radiotherapy in the treatment of clinically localized prostate cancer, given the importance of hospitalizations in healthcare resource utilization.nnnMETHODSnWe conducted a population-based retrospective cohort study of patients aged 65-79 years receiving radical prostatectomy (open or minimally invasive) or radiotherapy (brachytherapy or external beam) from 2001 to 2008 in the Surveillance, Epidemiology & End Results-Medicare linked databases. We assessed treatment-related hospitalizations. We analyzed the role of primary treatment on the number of complications per patient in each category using negative binomial regression.nnnRESULTSnAmong 60,476 men, 14,492 underwent primary surgery and 45,984 underwent primary radiotherapy. Over a median follow-up of 5.6 years, the surgery group had significantly lower rates of hospital admissions (8.9 vs 20.3/1000 person-years) than the radiation group. For both groups, admissions peaked within 2 years of treatment, but continued at a steady rate for 10 years. After adjustment for confounders, patients treated with radiation had higher incidence of hospital admissions (relative rate [RR]u2009=u20091.8, 95% confidence interval [CI]: 1.8-1.9, Pu2009<u2009.0001), compared to those having surgery. Stratified analysis showed an increased rate of hospitalizations of 1 day and 2 or more days (RR 3.1, 95% CI: 2.7-3.7 and RR 1.6, 95% CI 1.4-1.8, respectively) for patients treated with radiotherapy. The use of adjuvant/salvage therapies significantly increased rates of hospitalization. The results were robust to analysis using propensity-score matching.nnnCONCLUSIONnTreatment-related hospitalizations are more common following radiotherapy than surgery in the treatment of clinically localized prostate cancer. Limitations include a lack of treatment detail and residual confounding due to observational study design.

Isolated brain metastasis from a small renal mass

The identification of small renal masses is increasing. Active surveillance is a guideline-approved management strategy for select patients with small renal masses. Metastases during the observation of small renal masses are uncommon, and no cases of brain metastasis have been reported. We report the case of a 73-year-old man who presented with tonic–clonic seizures as the result of a brain metastasis from a small renal mass (3.5u2005cm in maximal dimension). Treatment with whole brain radiotherapy was undertaken successfully. The patient will undergo surveillance with consideration for systemic therapy at the time of progression.

Tumour front inflammation and necrosis are independent prognostic predictors in high-grade urothelial carcinoma of the bladder

Aims Inflammation and necrosis have been associated with prognosis in multiple epithelial malignancies. Our objective was to evaluate inflammation and necrosis in a cohort of patients with high-grade urothelial carcinomas of the bladder to determine their association with pathological parameters and their prognostic effect on relapse-free and disease-specific survival. Methods A retrospective cohort that underwent radical cystectomy for urothelial carcinomas (n=235) was evaluated for invasive front and central inflammation using the Klintrup-Makinen assessment method. Necrosis was scored using a four-point scale. The relationship of inflammation and necrosis with stage, nodal status, carcinoma in situ, tumour size, margin status and vascular space invasion and the impact on relapse-free and disease-specific survival were calculated using appropriate statistical tests. Results On multivariate analysis, invasive front inflammation (p=0.003) and necrosis (p=0.000) were independent predictors of relapse-free survival. Both invasive front inflammation (p=0.009) and necrosis (p=0.002) again were independent predictors of disease-specific survival. For pathological features, low invasive front inflammation was associated with lymphovascular space invasion (p=0.008), a positive soft tissue margin (p=0.028) and carcinoma in situ (p=0.042). Necrosis was statistically associated with tumours >3 cm in size (p=0.013) and carcinoma in situ (p<0.001). Conclusions Necrosis and invasive front inflammation are additional histological variables with independent prognostic relevance in high-grade urothelial carcinoma of the bladder.

Association between use of antithrombotic medication and hematuria-related complications

Importance Antithrombotic medications are among the most commonly prescribed medications. Objective To characterize rates of hematuria-related complications among patients taking antithrombotic medications. Design, Setting, and Participants Population-based, retrospective cohort study including all citizens in Ontario, Canada, aged 66 years and older between 2002 and 2014. The final follow-up date was December 31, 2014. Exposures Receipt of an oral anticoagulant or antiplatelet medication. Main Outcomes and Measures Hematuria-related complications, defined as emergency department visit, hospitalization, or a urologic procedure to investigate or manage gross hematuria. Results Among 2 518 064 patients, 808 897 (mean [SD] age, 72.1 [6.8] years; 428 531 [53%] women) received at least 1 prescription for an antithrombotic agent over the study period. Over a median follow-up of 7.3 years, the rates of hematuria-related complications were 123.95 events per 1000 person-years among patients actively exposed to antithrombotic agents vs 80.17 events per 1000 person-years among patients not exposed to these drugs (difference, 43.8; 95% CI, 43.0-44.6; Pu2009<u2009.001, and incidence rate ratio [IRR], 1.44; 95% CI, 1.42-1.46). The rates of complications among exposed vs unexposed patients (80.17 events/1000 person-years) were 105.78 for urologic procedures (difference, 33.5; 95% CI, 32.8-34.3; Pu2009<u2009.001, and IRR, 1.37; 95% CI, 1.36-1.39), 11.12 for hospitalizations (difference, 5.7; 95% CI, 5.5-5.9; Pu2009<u2009.001, and IRR, 2.03; 95% CI, 2.00-2.06), and 7.05 for emergency department visits (difference, 4.5; 95% CI, 4.3-4.7; Pu2009<u2009.001, and IRR, 2.80; 95% CI, 2.74-2.86). Compared with patients who were unexposed to thrombotic agents, the rates of hematuria-related complications were 191.61 events per 1000 person-years (difference, 117.3; 95% CI, 112.8-121.8) for those exposed to both an anticoagulant and antiplatelet agent (IRR, 10.48; 95% CI, 8.16-13.45), 140.92 (difference, 57.7; 95% CI, 56.9-58.4) for those exposed to anticoagulants (IRR, 1.55; 95% CI, 1.52-1.59), and 110.72 (difference, 26.5; 95% CI, 25.9-27.0) for those exposed to antiplatelet agents (IRR, 1.31; 95% CI, 1.29-1.33). Patients exposed to antithrombotic agents, compared with patients not exposed to these drugs, were more likely to be diagnosed as having bladder cancer within 6 months (0.70% vs 0.38%; odds ratio, 1.85; 95% CI, 1.79-1.92). Conclusions and Relevance Among older adults in Ontario, Canada, use of antithrombotic medications, compared with nonuse of these medications, was significantly associated with higher rates of hematuria-related complications (including emergency department visits, hospitalizations, and urologic procedures to manage gross hematuria).

Postoperative Radiotherapy in Locally Advanced Prostate Cancer: A Question of Who and When

Despite three large randomized controlled trials demonstrating that adjuvant radiotherapy decreases prostatespecific antigen (PSA) recurrence and may decrease metastatic progression and mortality, there has been a progressive decline in the number of patients receiving this treatment [1]. As with most treatment decisions, the choice between adjuvant and salvage radiotherapy depends on balancing the intended benefits with potential harms. The potential benefit of adjuvant radiotherapy is improved cancer control at the potential expense of treatment-related toxicity. Demonstration of equivalent oncologic outcomes would justify routine adoption of salvage radiotherapy given the potential to avoid the treatment-related inconvenience, cost, and toxicity associated with adjuvant therapy. To assess oncologic outcomes between adjuvant and early salvage radiotherapy, in this issue of European Urology Fossati and colleagues [2] report on a multi-institutional, retrospective cohort study examining metastasis-free and overall survival among patients with pT3pN0 prostate cancer with undetectable postoperative PSA levels. Unlike prior reports, salvage radiotherapy was administered at a PSA level 0.5 ng/ml according to the protocol, and the mean PSA level at the time of early salvage radiotherapy was 0.2 ng/ml, in keeping with modern ‘‘early salvage’’ radiotherapy. The authors demonstrate that adjuvant and early salvage radiotherapy were associated with similar 8-yr metastasisfree survival (92% vs 91%; p = 0.9) and overall survival (89% vs 92%; p = 0.9) [2]. This persisted after adjustment for pathologic stage, grade, margin status, and year of surgery.

Morbidity and Mortality of Radical Nephrectomy for Patients With Disseminated Cancer: An Analysis of the National Surgical Quality Improvement Program Database

OBJECTIVEnTo determine the effect of disseminated cancer on perioperative outcomes following radical nephrectomy.nnnMETHODSnWe conducted a retrospective cohort study of patients undergoing radical nephrectomy for kidney cancer from 2005 to 2014 using the American College of Surgeons National Surgical Quality Improvement Program, a multi-institutional prospective registry that captures perioperative surgical complications. Patients were stratified according to the presence (nu2009=u2009657) or absence (nu2009=u20097143) of disseminated cancer at the time of surgery. We examined major complications (death, reoperation, cardiac event, or neurologic event) within 30 days of surgery. Secondary outcomes included pulmonary, infectious, venous thromboembolic, and bleeding complications; prolonged length of stay; and concomitant procedures (bowel, liver, spleen, pancreas, and vascular procedures). Adjusted odds ratio (aOR) and 95% confidence interval (95% CI) were calculated using multivariate logical regression models.nnnRESULTSnPatients with disseminated cancer were older and more likely to be male, have greater comorbidities, and have undergone open surgery. Major complications were more common among patients with disseminated cancer (7.8%) than those without disseminated cancer (3.2%; aOR 2.01, 95% CI 1.46-2.86). Mortality was significantly higher in patients with disseminated cancer (3.2%) than those without disseminated cancer (0.5%; Pu2009<u2009.0001). Pulmonary (aOR 1.68, 95% CI 1.09-2.59), thromboembolic (aOR 1.72, 95% CI 1.01-2.96), and bleeding complications (aOR 2.12, 95% CI 1.73-2.60) were more common among patients with disseminated cancer as was prolonged length of stay (aOR 1.27, 95% CI 1.06-1.53).nnnCONCLUSIONnNephrectomy in patients with disseminated cancer is a morbid operation with significant perioperative mortality. These data may be used for preoperative counseling of patients undergoing cytoreductive nephrectomy.