Is There an Association between Urinary Incontinence and Mortality? A Retrospective Cohort Study.

PURPOSE: Previous studies have shown an association between urinary incontinence and increased mortality independently of demographics and health status. However, they do not account for the effect of frailty as a state of vulnerability. We evaluated whether there is an association between urinary incontinence and mortality and, if so, whether adjustment for a frailty index would affect the association. MATERIALS AND METHODS: We performed a cross-sectional study in a nationally representative sample of 2,282 community dwelling individuals 50 years old or older who were surveyed between 2003 and 2006. The study primary outcome was overall survival as reported on December 31, 2011. We used design adjusted Cox proportional hazards regression models to estimate the hazard of mortality associated with urinary incontinence. We adjusted the models for demographics and a validated 45-item frailty index incorporating an accumulation of deficits in the domains of health and independence. RESULTS: Of the individuals 23% reported having urinary incontinence at least a few times per week. Stress urinary incontinence and urge urinary incontinence were associated with a 13.3% (95% CI 7.2-19.7) and 18.4% (95% CI 8.3-29.4) increase in the frailty index, respectively. Without controlling for frailty individuals with urinary incontinence were at higher risk for death (HR 1.39, 95% CI 1.13-1.72). When adjusted for the frailty index, the association between urinary incontinence and mortality was no longer significant (HR 1.10, 95% CI 0.89-1.36). CONCLUSIONS: The association between urinary incontinence and mortality can be understood based on increased frailty in incontinent individuals. Urinary incontinence itself is not independently associated with mortality. In clinical practice these findings underscore the importance of screening for frailty in addition to urinary incontinence.

The effect of selection and referral biases for the treatment of localised prostate cancer with surgery or radiation.

BACKGROUND: Consultation with radiation oncologists, in addition to urologists, is advocated for patients diagnosed with prostate cancer. Treatment patterns for patients receiving consultation from radiation oncologists in addition to urologists have not previously been described. METHODS: We conducted a matched cohort study of men with newly diagnosed non-metastatic prostate cancer in Ontario, Canada. Patients who underwent consultation with a radiation oncologist prior to treatment were matched 1:1 with patients managed by a urologist alone based on tumour and patient characteristics. We examined rates of active treatment (surgery or radiotherapy) within one year following diagnosis. RESULTS: Among 5708 matched pairs (11,416 patients), those who received radiation oncology consultation were more likely to undergo active treatments whether they had intermediate or high-risk disease (88.6% vs. 65.9%, p < 0.0001; adjusted odds ratio 4.0, 95% CI: 3.6-4.4) or low-risk disease (56.1% vs. 13.3%, p < 0.0001; adjusted odds ratio 8.4, 95% CI: 6.7-10.6). This effect persisted after considering age, comorbidity, tumour volume and year of diagnosis. CONCLUSIONS: Patients newly diagnosed with prostate cancer who receive radiation oncology consultation are associated with a higher rate of active treatment, compared to patients managed by urologists only. Selection and referral biases, and unmeasured confounding such as patient preference must be considered as important factors attributing this association.

Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer: a population-based cohort study.

BACKGROUND: Studies of complications resulting from surgery or radiotherapy for prostate cancer have mainly focused on incontinence and erectile dysfunction. We aimed to assess other important complications associated with these treatments for prostate cancer. METHODS: We did a population-based retrospective cohort study, in which we used administrative hospital data, physician billing codes, and cancer registry data for men who underwent either surgery or radiotherapy alone for prostate cancer between 2002 and 2009 in Ontario, Canada. We measured the 5-year cumulative incidence of five treatment-related complication endpoints: hospital admissions; urological, rectal, or anal procedures; open surgical procedures; and secondary malignancies. FINDINGS: In the 32 465 patients included in the study, the 5-year cumulative incidence of admission to hospital for a treatment-related complication was 22·2% (95% CI 21·7-22·7), but was 2·4% (2·2-2·6) for patients whose length of stay was longer than 1 day. The 5-year cumulative incidence of needing a urological procedure was 32·0% (95% CI 31·4-32·5), that of a rectal or anal procedure was 13·7% (13·3-14·1), and that of an open surgical procedure was 0·9% (0·8-1·1). The 5-year cumulative incidence of a second primary malignancy was 3·0% (2·6-3·5). These risks were significantly higher than were those of 32 465 matched controls with no history of prostate cancer. Older age and comorbidity at the time of index treatment were important predictors for a complication in all outcome categories, but the type of treatment received was the strongest predictor for complications. Patients who were given radiotherapy had higher incidence of complications for hospital admissions, rectal or anal procedures, open surgical procedures, and secondary malignancies at 5 years than did those who underwent surgery (adjusted hazard ratios 2·08-10·8, p<0·0001). However, the number of urological procedures was lower in the radiotherapy than in the surgery group (adjusted hazard ratio 0·66, 95% CI 0·63-0·69; p<0·0001) INTERPRETATION: Complications after prostate cancer treatment are frequent and dependent on age, comorbidity, and the type of treatment. Patients and physicians should be aware of these risks when choosing treatment for prostate cancer, and should balance them with the clinical effectiveness of each therapy. FUNDING: Ajmera Family Chair in Urologic Oncology.

Healthcare utilization during transition to adult care in patients with spina bifida A population-based, longitudinal study in Ontario, Canada.

INTRODUCTION: Individuals with spina bifida (SB) may experience negative health outcomes because of an informal transition from pediatric to adult care that results in using the emergency room (ER ) for non-acute health problems. METHODS: We conducted a retrospective, population-based cohort study of all people with SB in Ontario, Canada turning 18 years old between 2002 and 2011. These patients were followed for five years before and after age 18. Primary outcome was the annual rate of ER visits. Secondary outcomes included rates of hospitalization, surgery, primary care, and specialist outpatient care. We estimated the association between age and primary and secondary outcomes using negative binomial growth curve models, adjusting for patient-level baseline covariates. RESULTS: Among the 1215 individuals with SB, there was no trend of ER visits seen with increasing age (relative risk [RR ] 0.99, 95% confidence interval [CI] 0.98-1.02); however, there was a significant increase in the rate of ER visits associated with turning 18 years (RR 1.14, 95% CI 1.03-1.27). Turning 18 years old was also associated with a decreased rate of hospital admissions (RR 0.79, 95% CI 0.66-0.95) and no change in surgeries (RR 0.80, 95% CI 0.64-1.02). Visits to primary care physicians remained stable over the same period (RR 0.96, 95% CI 0.90-1.01), while visits to SB-focused specialists decreased after age 18 (RR 0.81, 95% CI 0.75-0.87). CONCLUSIONS: In patients with SB, the rate of ER visits increased significantly at 18 years old, while hospital admissions and specialist physician visits decreased at the same time. Models of transitional care can aim to reduce non-urgent ER visits and facilitate regular specialist care.

Population based study of long-term rates of surgery for urinary incontinence after radical prostatectomy for prostate cancer.

PURPOSE: Urinary incontinence can be a significant complication of radical prostatectomy. It can be treated with post-prostatectomy surgical procedures. The long-term rate of patients who undergo these surgeries, including artificial urinary sphincter or urethral sling insertion, is not well described. We examined the long-term rate of post-prostatectomy incontinence surgery and factors influencing it. MATERIALS AND METHODS: We performed a population based study of 25,346 men who underwent radical prostatectomy for prostate cancer in Ontario, Canada between 1993 and 2006. We used hospital and cancer registry administrative data to identify patients from this cohort who were later treated with surgery for urinary incontinence. RESULTS: Of the 25,346 patients 703 (2.8%) underwent artificial urinary sphincter insertion and 282 (1.1%) underwent urethral sling placement a median of 2.9 years after prostatectomy. The probability of an artificial urinary sphincter/sling procedure increased with time from prostatectomy. Cumulative 5, 10 and 15-year Kaplan-Meier rates of an artificial urinary sphincter/sling procedure were 2.6% (95% CI 2.4-2.8), 3.8% (95% CI 3.6-4.1) and 4.8% (95% CI 4.4-5.3), respectively. Factors predicting surgery for incontinence were patient age at radical prostatectomy (HR 1.24 per decade, 95% CI 1.11-1.38, p = 0.0002), radiotherapy after surgery (HR 1.61, 95% CI 1.36-1.90, p <0.0001) and surgeon volume (49 or greater prostatectomies per year) (HR 0.59, 95% CI 0.46-0.77, p <0.0001). CONCLUSIONS: Of patients who undergo radical prostatectomy 5% are expected to be treated with surgery for urinary incontinence during a 15-year period. Increasing patient age, radiation treatment and low surgeon volume are associated with significantly higher risk.

Rates of primary and secondary treatments for patients on active surveillance for localized prostate cancer-A population-based cohort study.

BACKGROUND: The rate of primary and secondary treatment while on active surveillance (AS) for localized prostate cancer at the general population level is unknown. Our objective was to determine the patterns of secondary treatments after primary surgery or radiation for patients who undergo AS. METHODS: This was a population-based retrospective cohort study of men aged 50-80 years old in Ontario, Canada, between 2008 and 2016. We identified 26 742 patients with prostate cancer, a Gleason grade score ≤7, and an index prostate-specific antigen ≤10 ng/mL. Patients were categorized as undergoing AS with or without delayed primary treatment (DT; treatment >6 months after diagnosis) versus immediate treatment (IT; treatment ≤6 months). Patients receiving DT and IT were propensity score matched and the rate of secondary treatment (surgery or radiation ± androgen deprivation treatment) was compared using Cox proportional hazards models. RESULTS: We identified 10 214 patients who underwent AS and 11 884 patients who underwent IT. Among patients undergoing AS, 3724 (36.5%) eventually underwent DT and among them, 406 (10.9%) underwent secondary treatment. The median time to DT was 1.2 years (IQR 0.5-8.1 years). The relative rate of undergoing secondary treatment was similar in the DT vs IT group (HR 0.92; 95% CI: 0.79-1.08). The risk of death in the DT group was higher compared to patients who did not undergo treatment (HR 1.23, 95% CI: 1.01-1.49). CONCLUSIONS: Among patients with localized prostate cancer on AS, one third undergo DT. The rate of secondary treatment was similar between the DT and IT groups. Patients in the DT group may experience a higher risk of mortality compared to those who remained on AS.

Variation and Trends in Antidepressant Prescribing for Men Undergoing Treatment for Nonmetastatic Prostate Cancer: A Population-based Cohort Study.

Psychological distress is prevalent among men with prostate cancer (PCa). However, the variation in antidepressant use among individuals throughout the survivorship period is unknown. We sought to examine the variation and trends in receipt of antidepressants after PCa treatment, among patients with nonmetastatic PCa. Using population-based linked administrative data, we identified men ≥66 yr old who underwent surgery (n=4952), radiotherapy (n=4994), or surveillance (n=2136), and these men were matched to general population controls (n=57127). One year prior to PCa treatment, 7.7% of men received an antidepressant prescription, which increased to 10.5% in the year after treatment. In difference-in-differences analysis, adjusted for demographic and health characteristics, men had increased odds of antidepressant receipt up to 5 yr after surgery (odds ratio [OR] 1.49; 95% confidence interval [CI] 1.35-1.64; p≤0.0001) or radiotherapy (OR 1.33; 95% CI 1.21-1.47; p≤0.0001). Men did not have an increased risk of antidepressant receipt up to 5 yr after surveillance (OR 1.15; 95% CI 0.94-1.41; p=0.16). Limitations include the potential for selection bias and misclassification due to the retrospective design of the study and the use of administrative databases. Thus, men with nonmetastatic PCa who initially receive surgery or radiotherapy, but not those who initially undergo surveillance, have an increased risk of antidepressant receipt after treatment. PATIENT SUMMARY: In this report, we examined antidepressant prescription for men after treatment of nonmetastatic prostate cancer across the entire population of men ≥66 yr in Ontario, Canada, from 2002 to 2009. For men diagnosed with nonmetastatic prostate cancer, the risk of antidepressant receipt at 5 yr after treatment was significantly increased after surgery or radiotherapy, but not after surveillance. Providers and patients should consider the psychological effects of prostate cancer treatment during the survivorship period.

Pelvic Complications After Prostate Cancer Radiation Therapy and Their Management: An International Collaborative Narrative Review.

CONTEXT: Radiotherapy used for treating localized prostate cancer is effective at prolonging cancer-specific and overall survival. Still, acute and late pelvic toxicities are a concern, with gastrointestinal (GI) and genitourinary (GU) sequelae being most common as well as other pelvic complications. OBJECTIVE: To present a critical review of the literature regarding the incidence and risk factors of pelvic toxicity following primary radiotherapy for prostate cancer and to provide a narrative review regarding its management. EVIDENCE ACQUISITION: A collaborative narrative review of the literature from 2010 to present was conducted. EVIDENCE SYNTHESIS: Regardless of the modality used, the incidence of acute high-grade pelvic toxicity is low following conventionally fractionated external beam radiotherapy (EBRT). After moderate hypofractionation, the crude cumulative incidences for late grade 3 or higher (G3+) GI and GU complications are as high as 6% and 7%, respectively. After extreme hypofractionation, the 5-yr incidences of G2+ GU and GI toxicities are 3-9% and 0-4%, respectively. Following brachytherapy monotherapy, crude rates of late G3+ GU toxicity range from 6% to 8%, while late GI toxicity is rare. With combination therapy (EBRT and brachytherapy), the cumulative incidence of late GU toxicity is high, between 18% and 31%; however, the prevalence is lower at 4-14%. Whole pelvic radiotherapy remains a controversial treatment option as there is increased G3+ GI toxicity compared with prostate-only treatment, with no overall survival benefit. Proton beam therapy appears to have similar toxicity to photon therapies currently in use. With respect to specific complications, urinary obstruction and urethral stricture are the most common severe urinary toxicities. Rectal and urinary bleeding can be recurrent long-term toxicities. The risk of hip fracture is also increased following prostate radiotherapy. The literature is mixed on the risk of in-field secondary pelvic malignancies following prostate radiotherapy. Urinary and GI fistulas are rare complications. Management of these toxicities may require invasive treatment and reconstructive surgery for refractory and severe symptoms. CONCLUSIONS: There has been progress in the delivery of radiotherapy, enabling the administration of higher doses with minimal tradeoff in terms of slightly increased or equal toxicity. There is a need to focus future improvements in radiotherapy on sparing critical structures to reduce GU and GI morbidities. While complications such as fistulae, bone toxicity, and secondary malignancy are rare, there is a need for higher-quality studies assessing these outcomes and their management. PATIENT SUMMARY: In this report, we review the literature regarding pelvic complications following modern primary prostate cancer radiotherapy and their management. Modern radiotherapy technologies have enabled the administration of higher doses with minimal increases in toxicity. Overall, high-grade long-term toxicity following prostate radiotherapy is uncommon. Management of late high-grade pelvic toxicities can be challenging, with patients often requiring invasive therapies for refractory cases.

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

OBJECTIVE: To 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. METHODS: We 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. RESULTS: We 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 (HRs > 2.5) and have highly differential prevalence to nullify the observed effect. CONCLUSION: Among 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.

Null association between androgen-deprivation therapy and nonprostate cancer mortality among older men with nonmetastatic prostate cancer.

BACKGROUND: Androgen-deprivation therapy (ADT) has been associated with cardiovascular risk factors and the development of cardiovascular disease in men with metastatic prostate cancer. We sought to examine the effect of ADT on nonprostate cancer mortality among patients with nonmetastatic prostate cancer. METHODS: We performed a population-based, retrospective cohort study of men aged 66 years and older treated with surgery or radiotherapy for nonmetastatic prostate cancer in Ontario, Canada from 2002 to 2009 using administrative datasets (including the Ontario Cancer Registry, Ontario Drug Benefit, and Ontario Health Insurance Plan). Analysis was performed between September 2016 and April 2017. ADT exposure was operationalized as a time-varying binary and cumulative dose exposure. Primary and secondary outcomes were nonprostate cancer mortality and cardiovascular mortality, respectively. The Fine and Gray subdistribution method with generalized estimating equations was used to calculate subdistribution hazard ratios (sdHR), while accounting for competing risks. RESULTS: We examined 20,651 men treated for nonmetastatic prostate cancer. Median follow-up was 7.4 years and median ADT exposure was 6.4 months. ADT was not significantly associated with nonprostate cancer mortality (sdHR = 0.75, 95% CI: 0.37-1.50) or cardiovascular mortality (sdHR = 1.16, 95% CI: 0.37-3.63) when operationalized as a binary time-varying exposure. Similar results were obtained when we examined ADT cumulative dose exposure. CONCLUSIONS: ADT is not associated with nonprostate cancer mortality or cardiovascular mortality in a large, population-based cohort of older men with localized prostate cancer treated by surgery or radiation therapy.

Adjuvant Versus Salvage Radiotherapy for Patients With Adverse Pathological Findings Following Radical Prostatectomy: A Decision Analysis.

Background: Patients undergoing surgery for prostate cancer who have adverse pathological findings experience high rates of recurrence. While there are data supporting adjuvant radiotherapy compared to a wait-and-watch strategy to reduce recurrence rates, there are no randomized controlled trials comparing adjuvant radiotherapy with the other standard of care, salvage radiotherapy (radiotherapy administered at the time of recurrence). Methods: We constructed a health state transition (Markov) model employing two-dimensional Monte Carlo simulation using a lifetime horizon to compare the quality-adjusted survival associated with postoperative strategies using adjuvant or salvage radiotherapy. Prior to analysis, we calibrated and validated our model using the results of previous randomized controlled trials. We considered clinically important oncological health states from immediately postoperative to prostate cancer-specific death, commonly described complications from prostate cancer treatment, and other causes of mortality. Transition probabilities and utilities for disease states were derived from a literature search of MEDLINE and expert consensus. Results: Salvage radiotherapy was associated with an increased quality-adjusted life expectancy (QALE) (58.3 months) as compared with adjuvant radiotherapy (53.7 months), a difference of 4.6 months (standard deviation 8.8). Salvage radiotherapy had higher QALE in 53% of hypothetical cohorts. There was a minimal difference in overall life expectancy (-0.1 months). Examining recurrence rates, our model showed validity when compared with available randomized controlled data. Conclusions: A salvage radiotherapy strategy appears to provide improved QALE for patients with adverse pathological findings following radical prostatectomy, compared with adjuvant radiotherapy. As these findings reflect, population averages, specific patient and tumor factors, and patient preferences remain central for individualized management.

Effect of radical prostatectomy surgeon volume on complication rates from a large population-based cohort.

INTRODUCTION: Surgical volume can affect several outcomes following radical prostatectomy (RP). We examined if surgical volume was associated with novel categories of treatment-related complications following RP. METHODS: We examined a population-based cohort of men treated with RP in Ontario, Canada between 2002 and 2009. We used Cox proportional hazard modeling to examine the effect of physician, hospital and patient demographic factors on rates of treatment-related hospital admissions, urologic procedures, and open surgeries. RESULTS: Over the study interval, 15 870 men were treated with RP. A total of 196 surgeons performed a median of 15 cases per year (range: 1-131). Patients treated by surgeons in the highest quartile of annual case volume (>39/year) had a lower risk of hospital admission (hazard ratio [HR]=0.54, 95% CI 0.47-0.61) and urologic procedures (HR=0.69, 95% CI 0.64-0.75), but not open surgeries (HR=0.83, 95% CI 0.47-1.45) than patients treated by surgeons in the lowest quartile (<15/year). Treatment at an academic hospital was associated with a decreased risk of hospitalization (HR=0.75, 95% CI 0.67-0.83), but not of urologic procedures (HR=0.94, 95% CI 0.88-1.01) or open surgeries (HR=0.87, 95% CI 0.54-1.39). There was no significant trend in any of the outcomes by population density. CONCLUSIONS: The annual case volume of the treating surgeon significantly affects a patient's risk of requiring hospitalization or urologic procedures (excluding open surgeries) to manage treatment-related complications.

Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis.

OBJECTIVE: To determine the association between exposure to radiotherapy for the treatment of prostate cancer and subsequent second malignancies (second primary cancers). DESIGN: Systematic review and meta-analysis of observational studies. DATA SOURCES: Medline and Embase up to 6 April 2015 with no restrictions on year or language. STUDY SELECTION: Comparative studies assessing the risk of second malignancies in patients exposed or unexposed to radiotherapy in the course of treatment for prostate cancer were selected by two reviewers independently with any disagreement resolved by consensus. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted study characteristics and outcomes. Risk of bias was assessed with the Newcastle-Ottawa scale. Outcomes were synthesized with random effects models and Mantel-Haenszel weighting. Unadjusted odds ratios and multivariable adjusted hazard ratios, when available, were pooled. MAIN OUTCOME MEASURES: Second cancers of the bladder, colorectal tract, rectum, lung, and hematologic system. RESULTS: Of 3056 references retrieved, 21 studies were selected for analysis. Most included studies were large multi-institutional reports but had moderate risk of bias. The most common type of radiotherapy was external beam; 13 studies used patients treated with surgery as controls and eight used patients who did not undergo radiotherapy as controls. The length of follow-up among studies varied. There was increased risk of cancers of the bladder (four studies; adjusted hazard ratio 1.67, 95% confidence interval 1.55 to 1.80), colorectum (three studies; 1.79, 1.34 to 2.38), and rectum (three studies; 1.79, 1.34 to 2.38), but not cancers of the hematologic system (one study; 1.64, 0.90 to 2.99) or lung (two studies; 1.45, 0.70 to 3.01), after radiotherapy compared with the risk in those unexposed to radiotherapy. The odds of a second cancer varied depending on type of radiotherapy: treatment with external beam radiotherapy was consistently associated with increased odds while brachytherapy was not. Among the patients who underwent radiotherapy, from individual studies, the highest absolute rates reported for bladder, colorectal, and rectal cancers were 3.8%, 4.2%, and 1.2%, respectively, while the lowest reported rates were 0.1%, 0.3%, and 0.3%. CONCLUSION: Radiotherapy for prostate cancer was associated with higher risks of developing second malignancies of the bladder, colon, and rectum compared with patients unexposed to radiotherapy, but the reported absolute rates were low. Further studies with longer follow-up are required to confirm these findings.

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

OBJECTIVE: To 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. SUBJECTS AND METHODS: We 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. RESULTS: Among 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, P <.0001-.04) and ADT (aHR 1.18-1.32, P <.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, P = .02), whereas ADT was not (P = .5). We did not identify a significant statistical interaction between primary and hormonal treatment. CONCLUSION: Care 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.

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

BACKGROUND: Conflicting 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. METHODS: We 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. FINDINGS: We included 10 311 men treated with testosterone replacement therapy and 28 029 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. INTERPRETATION: Long-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. FUNDING: Physicians' Services Incorporated Foundation and Ajmera Family Chair in Urologic Oncology.

Surgery Versus Radiotherapy for Clinically-localized Prostate Cancer: A Systematic Review and Meta-analysis.

CONTEXT: To date, there is no Level 1 evidence comparing the efficacy of radical prostatectomy and radiotherapy for patients with clinically-localized prostate cancer. OBJECTIVE: To conduct a meta-analysis assessing the overall and prostate cancer-specific mortality among patients treated with radical prostatectomy or radiotherapy for clinically-localized prostate cancer. EVIDENCE ACQUISITION: We searched Medline, EMBASE, and the Cochrane Library through June 2015 without year or language restriction, supplemented with hand search, using Preferred Reporting Items for Systematic Reviews and Meta-Analysis and Meta-analysis of Observational Studies in Epidemiology guidelines. We used multivariable adjusted hazard ratios (aHRs) to assess each endpoint. Risk of bias was assessed using the Newcastle-Ottawa scale. EVIDENCE SYNTHESIS: Nineteen studies of low to moderate risk of bias were selected and up to 118 830 patients were pooled. Inclusion criteria and follow-up length varied between studies. Most studies assessed patients treated with external beam radiotherapy, although some included those treated with brachytherapy separately or with the external beam radiation therapy group. The risk of overall (10 studies, aHR 1.63, 95% confidence interval 1.54-1.73, p<0.00001; I(2)=0%) and prostate cancer-specific (15 studies, aHR 2.08, 95% confidence interval 1.76-2.47, p < 0.00001; I(2)=48%) mortality were higher for patients treated with radiotherapy compared with those treated with surgery. Subgroup analyses by risk group, radiation regimen, time period, and follow-up length did not alter the direction of results. CONCLUSIONS: Radiotherapy for prostate cancer is associated with an increased risk of overall and prostate cancer-specific mortality compared with surgery based on observational data with low to moderate risk of bias. These data, combined with the forthcoming randomized data, may aid clinical decision making. PATIENT SUMMARY: We reviewed available studies assessing mortality after prostate cancer treatment with surgery or radiotherapy. While the studies used have a potential for bias due to their observational design, we demonstrated consistently higher mortality for patients treated with radiotherapy rather than surgery.

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

OBJECTIVE: To 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. METHODS: We 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. RESULTS: Among 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] = 1.8, 95% confidence interval [CI]: 1.8-1.9, P < .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. CONCLUSION: Treatment-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.

New Rates of Interventions to Manage Complications of Modern Prostate Cancer Treatment in Older Men.

BACKGROUND: Interventions to treat complications from prostate cancer (PCa) treatment are common and affect the course of a patient's life. OBJECTIVE: To examine rates of complications other than urinary incontinence and impotence for older patients treated for PCa. DESIGN, SETTING, AND PARTICIPANTS: Population-based retrospective cohort study of patients aged 65-79 yr receiving radical prostatectomy or radiotherapy (RT) from 2001 to 2008 in the US Surveillance Epidemiology and End Results and Medicare linked databases. OUTCOME MEASURES AND STATISTICAL ANALYSIS: Complications were organised in three categories: urologic procedures, rectal-anal procedures, and major surgeries. We analysed the role of primary treatment on the number of complications using negative binomial regression. RESULTS AND LIMITATIONS: Among 60476 men, 14492 underwent primary surgery and 45984 underwent primary RT; 33418 (55%) experienced at least one complication (mean: 2.6 complications per patient). For both groups, complications peaked within 2 yr of treatment but continued at a steady rate for 10 yr. Patients treated with radiation had higher rates of urologic procedures (adjusted relative rate [aRR]: 1.25; 95% confidence interval [CI], 1.2-1.3; p<0.0001) and rectal-anal procedures (aRR: 1.4; 95% CI, 1.4-1.5; p<0.0001) but a lower rate of major surgeries (aRR: 0.9; 95% CI, 0.8-0.9; p<0.0001) compared with those having surgery. Because patients treated with RT were older and more comorbid, selection bias limits the strength of conclusions that can be drawn from this data. CONCLUSIONS: Complications are common following PCa cancer treatment and occur many years after treatment. The primary treatment is an important predictor of complication rates that may inform treatment decisions and long-term survivorship plans. PATIENT SUMMARY: We examined complications after prostate cancer treatment in a large American population. Patients treated with radiotherapy rather than surgery had higher rates of complications requiring urologic procedures and rectal-anal procedures but lower rates of open surgeries. However, we were only able to examine men aged >65 yr, and this, along with the observational study technique, means that these results may not apply to all patients and that factors beyond those that we could measure may have affected these results.

Complications after radical prostatectomy or radiotherapy for prostate cancer: results of a population-based, propensity score-matched analysis.

OBJECTIVE: To assess rates of treatment-related complications after radical prostatectomy or radiotherapy monotherapy, using propensity score matching to account for baseline differences between these patient populations. METHODS: On the basis of a population-based study of men undergoing surgery or radiotherapy for prostate cancer in Ontario between 2002 and 2009, we undertook a propensity score-matched analysis including age, comorbidity, and year of treatment to assess treatment-related complication end points. These included hospital admission; urologic, rectal, or anal procedures; open surgeries; and secondary malignancies. RESULTS: From the original cohort of 32,465 patients, 15,870 (48.9%) had surgery and 16,595 (51.1%) had radiation. Propensity score matching produced 8797 pairs (17,594 patients). Among these, when compared with patients treated with surgery, those treated with radiation experienced fewer admissions to hospital (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.78-0.92) and urologic procedures (HR, 0.50; 95% CI, 0.46-0.53) at year 1 but higher rates at year 3 (HR, 5.65; 95% CI, 4.61-6.91 and HR, 1.86; 95% CI, 1.62-2.13, respectively) and year 5. Although there was no significant difference in open surgeries at year 1, patients undergoing radiotherapy were at higher risk by year 3 (HR, 2.06; 95% CI, 1.23-3.47) and this rose by year 5. Over the study period, patients undergoing radiotherapy experienced more rectal-anal procedures (HR, 2.64; 95% CI, 2.37-2.95) and were diagnosed with more secondary malignancies (HR, 2.44; 95% CI, 1.16-5.14). Direct matching produced similar results. CONCLUSION: From a propensity score-matched analysis, we found that patients undergoing radiation therapy for prostate cancer had higher rates of long-term complications in all 5 categories studied than patients undergoing surgery.