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Supplementary Figure from Replication of Overall Survival, Progression-Free Survival, and Overall Response in Chemotherapy Arms of Non–Small Cell Lung Cancer Trials Using Real-World Data

Purpose:The utility of real-world data (RWD) for use as external controls in drug development is informed by studies that replicate trial control arms for different endpoints. The purpose of this study was to replicate control arms from four non–small cell lung cancer (NSCLC) randomized controlled trials (RCT) to analyze overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) using RWD.Patients and Methods:This study used RWD from a nationwide de-identified database and a clinico-genomic database to replicate OS, PFS, and ORR endpoints in the chemotherapy control arms of four first-line NSCLC RCTs evaluating atezolizumab [IMpower150–wild-type (WT), IMpower130-WT, IMpower131, and IMpower132]. Additional objectives were to develop a definition of real-world PFS (rwPFS) and to evaluate the real-world response rate (rwRR) endpoint.Results:Baseline demographic and clinical characteristics were balanced after application of propensity score weighting methods. For rwPFS and OS, RWD external controls were generally similar to their RCT control counterparts. Across all four trials, the hazard ratio (HR) point estimates comparing trial controls with external controls were closer to 1.0 for the PFS endpoint than for the OS endpoint. An exploratory assessment of rwRR in RWD revealed a slight but nonsignificant overestimation of RCT ORR, which was unconfounded by baseline characteristics.Conclusions:RWD can be used to reasonably replicate the OS and PFS of chemotherapy control arms of first-line NSCLC RCTs. Additional studies can provide greater insight into the utility of RWD in drug development.

Supplementary Table from Replication of Overall Survival, Progression-Free Survival, and Overall Response in Chemotherapy Arms of Non–Small Cell Lung Cancer Trials Using Real-World Data

Purpose: The utility of real-world data (RWD) for use as external controls in drug development is informed by studies that replicate trial control arms for different endpoints. The purpose of this study was to replicate control arms from four non–small cell lung cancer (NSCLC) randomized controlled trials (RCT) to analyze overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) using RWD. Patients and Methods: This study used RWD from a nationwide de-identified database and a clinico-genomic database to replicate OS, PFS, and ORR endpoints in the chemotherapy control arms of four first-line NSCLC RCTs evaluating atezolizumab [IMpower150–wild-type (WT), IMpower130-WT, IMpower131, and IMpower132]. Additional objectives were to develop a definition of real-world PFS (rwPFS) and to evaluate the real-world response rate (rwRR) endpoint. Results: Baseline demographic and clinical characteristics were balanced after application of propensity score weighting methods. For rwPFS and OS, RWD external controls were generally similar to their RCT control counterparts. Across all four trials, the hazard ratio (HR) point estimates comparing trial controls with external controls were closer to 1.0 for the PFS endpoint than for the OS endpoint. An exploratory assessment of rwRR in RWD revealed a slight but nonsignificant overestimation of RCT ORR, which was unconfounded by baseline characteristics. Conclusions: RWD can be used to reasonably replicate the OS and PFS of chemotherapy control arms of first-line NSCLC RCTs. Additional studies can provide greater insight into the utility of RWD in drug development.

Background Central nervous system (CNS) metastasis is common in advanced melanoma patients. New treatment options have improved overall prognosis, but information is lacking for patients with CNS metastases. We investigated treatment patterns and survival outcomes in older melanoma patients with and without CNS metastases. Methods A retrospective analysis of SEER‐Medicare, a population‐based linked database, was undertaken in patients aged > 65 years with advanced melanoma diagnosed from 2004 to 2011 and followed until 2013. Results A total of 2522 patients were included. CNS metastases were present in 24.8% of patients at initial metastatic diagnosis; 16.5% developed CNS metastases during follow‐up. Chemotherapy was the most common treatment regardless of CNS metastases. Overall survival (OS) was better for patients without CNS metastases (median, 9.5 months; 95% confidence interval [CI], 8.8‐10.2) vs patients with CNS metastases (3.63 months; 95% CI, 3.4‐3.9). Among patients with CNS metastases, median OS for targeted therapy, immunotherapy, and chemotherapy was 6 (95% CI, 2.5‐9.6), 5.5 (95% CI, 3.8‐7.5), and 4.5 (95% CI, 3.8‐5.4) months, respectively, vs 2.4 (95% CI, 2.1‐2.7) and 2.1 (95% CI, 1.8‐2.7) months for local radiotherapy and no treatment, respectively. Stereotactic radiosurgery demonstrated higher OS vs whole‐brain radiation therapy (median, 4.98 [95% CI, 3.5‐7.5] vs 2.4 [95% CI, 2.1‐2.7] months). Conclusion Patients with CNS metastases from melanoma remain a population with high unmet medical need despite recent advances in treatment. Systemic treatments (eg, BRAF‐targeted therapy and immunotherapy) and stereotactic radiosurgery demonstrated meaningful but modest improvements in OS. Further explorations of combinations of radiotherapy, BRAF‐targeted therapies, and immunotherapies are needed., This retrospective, population‐based analysis of older patients with advanced melanoma demonstrated that patients with central nervous system (CNS) metastases have limited treatment options and poor survival outcomes. Improved survival was observed for patients with CNS metastases treated with BRAF‐targeted therapy or immunotherapy, but significant unmet medical need remains.

PURPOSE Eastern Cooperative Oncology Group performance status (ECOG PS) is an important predictor for receipt of treatment and overall survival (OS) but is often unreported in routine care. We developed a proxy for baseline ECOG PS using electronic health records (EHRs). METHODS We analyzed patients who were diagnosed with advanced non-small cell lung cancer (aNSCLC), advanced bladder cancer (aBCa), and advanced melanoma (aMEL) between 2011 and 2018 and had a baseline (reported between diagnosis and treatment) ECOG PS in a real-world database. We used stepwise multivariable logistic regression to model associations between baseline ECOG PS good (

Background: Post-transplant lymphoproliferative disease (PTLD) occurs following allogeneic hematopoietic stem cell transplantation (HCT) as a consequence of immunosuppression. In most cases following HCT, PTLD is associated with Epstein-Barr Virus (EBV) infection of B cells, either due to reactivation, or from primary EBV infection (Styczynski J, Haematol. 2016; Allen UD, Am J Transplant, 2019; Nijand M, Transplant Direct, 2016). Clinical practice treatment guidelines recommend rituximab as preemptive therapy for EBV reactivation (based on EBV virus load) and for treatment of EBV-driven (EBV +) PTLD following HCT. However, EBV + PTLD patients (pts) who fail rituximab have very poor outcomes with limited treatment options. There are ongoing clinical studies investigating innovative therapies to address unmet needs in these pts. Published evidence on the clinical outcomes of these pts who fail rituximab is also limited. We aimed to describe the outcomes for pts diagnosed with EBV + PTLD following HCT who fail rituximab in a multinational real-world setting. Methods: We conducted a large multinational, multicenter retrospective chart review study of EBV + PTLD pts following HCT or solid organ transplantation who received rituximab or rituximab plus chemotherapy (CT) between January 2000-December 2018 and were refractory (failed to achieve complete response [CR] or partial response [PR]) or relapsed at any point after such therapy. Treatment response was assessed by either clinical diagnosis, radiographic/imaging, biopsy/cytology, or a combination of such assessments. Data was collected from 29 centers across North America (United States and Canada) and the European Union. The study population was aligned with the ongoing investigational trial (Clinicaltrials.gov Identifier: NCT03394365). This analysis includes pts with EBV + PTLD following HCT who were refractory or relapsed after rituximab ± CT as first line of therapy. The Kaplan-Meier (KM) method was used to estimate the overall survival (OS). Rituximab failure date was defined as the earliest date when pts became refractory or relapsed following rituximab ± CT. Results: A total of 81 pts with EBV + PTLD following HCT who failed rituximab ± CT were included in the analysis. Median age at PTLD diagnosis was 49 years (interquartile range [IQR]: 33‒57) and median time to PTLD onset from transplant was 3 months (IQR: 1.9‒4.2). Median follow-up time was 1.7 months (IQR: 0.6‒3.4) from the date of PTLD diagnosis. Of all the PTLDs, 52 (64.2%) were monomorphic, 18 (22.2%) polymorphic, 2 (2.5%) early lesions, and 9 (11.1%) were unknown. The most common PTLD subtype was diffuse large B-cell lymphoma (DLBCL) (46, 56.8%). Sixty-eight (84%) pts received rituximab monotherapy and 13 (16%) pts received rituximab plus CT as first line of therapy. Seven out of 13 pts who received rituximab plus CT had received preemptive rituximab treatment for EBV viremia prior to PTLD treatment. Median OS was 0.7 months (95% CI: 0.3‒1; IQR: 0.1‒2.7) for 81 pts who failed first line rituximab ± CT (Figure 1). Median OS from PTLD diagnosis was 1.7 months (95% CI: 1.1‒2.3; IQR: 0.6‒3.4). Seventy-four (91.4%) out of the 81 pts ultimately died. Causes of death comprised 50 (67.6%) related to PTLD and therapy, 10 (13.5%) graft-versus-host disease (GvHD), 5 (6.8%) from sepsis/infection, 3 (4.1%) due to primary disease leading to HCT, 2 (2.7%) organ failure, 1 (1.4%) graft failure, 1 (1.4%) from hepatic failure, and 2 (2.7%) unknown. Conclusions: The prognosis of EBV + PTLD pts following HCT who fail rituximab ± CT remains very poor with an estimated median OS of less than 1 month, highlighting the significant unmet need in this population. Figure 1 Figure 1. Disclosures Storek: Atara Biotherapeutics: Other: Site PI, Research Funding. Socié: Alexion: Research Funding. Thirumalai: Atara Biotherapeutics: Current Employment. Guzman-Becerra: Atara Biotherapeutics: Current Employment. Xun: Atara Biotherapeutics: Current Employment. Kumar: Roche: Research Funding; GSK: Research Funding; Amplyx: Research Funding; Merck: Research Funding; Takeda & Atara: Research Funding. Sadetsky: Atara Biotherapeutics: Current Employment. Dierickx: Sandoz: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Roche: Consultancy, Research Funding; Takeda, Incyte, Atara: Consultancy. Reitan: Atara, Kite, Janssen: Research Funding. Barlev: Atara Biotherapeutics: Current Employment. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a rare and often aggressive disease in the setting of immunosuppression following solid organ transplant (SOT). Epstein-Barr virus (EBV) infection of B cells is responsible for about 50% of cases, either due to reactivation of the virus after transplantation or primary EBV infection. Although there is no approved therapy for patients (pts) with PTLD, guidelines include reduction of immunosuppression (RIS) as a part of initial treatment and may be sufficient for pts with early lesions. Rituximab, either as monotherapy or in combination with chemotherapy (CT), is used in addition to RIS as initial treatment. Pts with EBV + PTLD following SOT who fail rituximab plus CT have poor outcomes with limited treatment options. There are ongoing clinical studies investigating innovative therapies to address unmet needs in these pts. Published data on clinical outcomes of these pts remain limited and not well documented. We aimed to characterize the outcomes for pts diagnosed with EBV + PTLD following SOT who fail initial rituximab plus CT in a multi-national real-world setting. Methods: We conducted a large multinational, multicenter, retrospective chart review study of pts with EBV + PTLD following allogeneic hematopoietic cell transplantation (HCT) or SOT who received rituximab or rituximab plus CT between January 2000‒December 2018 and were refractory (failed to achieve complete response [CR] or partial response [PR]) or relapsed at any point after such therapy. Treatment response was assessed either by clinical diagnosis, radiographic/imaging, biopsy/cytology, or a combination of such assessments. Data were collected from 29 centers across North America (United States and Canada) and the European Union. Study population was aligned to the ongoing investigational trial (Clinicaltrials.gov Identifier: NCT03394365). This analysis includes pts with EBV + PTLD following SOT who were refractory/relapsed to rituximab plus CT. The Kaplan-Meier method was utilized to estimate the overall survival (OS). Results: A total of 86 pts with EBV + PTLD following SOT who failed rituximab plus CT were included in the analysis; 65 (75.6%) pts were refractory while 21 (24.4%) relapsed after initial response of CR or PR. Median age at PTLD diagnosis was 43 years (range 1‒78) and median time to PTLD onset from transplant was 1.7 years (range 0.1‒27.9). Median follow up time was 12.9 months from the date of PTLD diagnosis. PTLD histological subtypes were 66 (76.7%) monomorphic, 18 (20.9%) polymorphic, and 2 (2.3%) early lesions. The most common PTLD subtype was diffuse large B-cell lymphoma (DLBCL) (58, 67.4%). Of the 86 pts, 49 (57%) received CT following rituximab monotherapy while 37 (43%) pts received CT concurrently with rituximab. Overall, 63 (73.3%) pts died. PTLD-specific mortality was observed in 41 (65.1%) pts, treatment-related mortality in 10 (15.9%) pts, mortality due to organ rejection/failure in 2 (3.2%) pts, mortality due to other causes in 7 (11.1%) pts, and mortality due to unknown causes in 3 (4.8%) pts. Median OS was 15.5 months (95% confidence interval [CI]: 8.3‒22.9) from PTLD diagnosis, and was 4.1 months (95%CI: 1.9‒8.5) from the earliest date when pts became refractory or relapsed following rituximab plus CT. Conclusions: The prognosis for pts with EBV + PTLD following SOT who fail rituximab plus CT remains poor, with an estimated median OS of about 4 months and a majority of pts dying from PTLD and related treatment. In this specific population, there remains a significant unmet medical need for effective and well-tolerated therapies. Figure 1 Figure 1. Disclosures Dharnidharka: Merck, Pfizer, Medronic, Cardinal Health: Current holder of stock options in a privately-held company; CareDx: Honoraria, Research Funding; Atara Bio, MedinCell: Consultancy. Thirumalai: Atara Biotherapeutics: Current Employment. Jaeger: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zhao: Atara Biotherapeutics: Current Employment. Dierickx: Roche: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Sandoz: Consultancy; Takeda, Incyte, Atara: Consultancy. Xun: Atara Biotherapeutics: Current Employment. Sawas: Flat Iron Health: Current Employment; Roche: Current holder of stock options in a privately-held company; Seattle Genetics, Acrotech: Consultancy; Daiichi-Sankyo, Seattle Genetics, Gilead: Other: Travel, accommodation, expenses, Speakers Bureau; Affimed, Trillium: Research Funding. Sadetsky: Atara Biotherapeutics: Current Employment. Barlev: Atara Biotherapeutics: Current Employment. Zimmermann: Roche, Atara: Research Funding; Celgene, Roche, Atara, Jansen: Other: Travel accomodations. Trappe: Celgene: Other: Travel support; Roche: Other: Travel support; Atara Biotherapeutics: Consultancy, Other: Travel support, Research Funding; Jansen: Other: Travel support; GSK: Other: Travel support; AbbVie: Other: Travel support.

Introduction: Post-transplant lymphoproliferative disease (PTLD) is an ultra-rare lymphoma following allogeneic hematopoietic stem cell transplant (HCT) or solid organ transplant (SOT). Incidence of PTLD varies over time after transplant with majority of cases occurring within the first year (yr) after HCT (Garcia-Cadenas, Eur J Haematol. 2019). In the SOT setting, PTLD can occur up to 30 yrs post-transplant and is largely dependent on the transplanted organ, the type and degree of immunosuppression, and transplant recipient characteristics (Dierickx, N Eng J Med. 2018; Trappe, J Clin Oncol. 2017). Published literature reports wide ranges of epidemiological estimates due to variation in the follow-up time, transplant type and sample size. We conducted a systematic literature review (SLR) to summarize the incidence of PTLD to better understand the reasons for such variation. Methods: A SLR on the burden of PTLD was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines with the scope defined in terms of Population, Intervention Comparators, Outcomes and Study design (PICOS) criteria. Pertinent literature on epidemiology of PTLD published between January 2010 to February 2020 and relevant conference abstracts published between January 2018 to February 2020 were identified. Comprehensive literature searches were performed using the Ovid platform to identify articles indexed in PubMed, Embase, PsycINFO, and the National Health Service Economic Evaluation Database. Study designs were limited to population/registry-based studies, observational cohort studies (prospective/retrospective), and cross-sectional studies. Studies reporting incidence of PTLD were limited to those with at least 1000 total transplant recipients. All titles and abstracts were reviewed by two independent researchers with any discrepancies resolved by a third researcher. Incidence estimates were calculated by data extractors when it was not directly reported in the literature. Results: A total of 177 studies reporting epidemiological data on PTLD were identified using pre-specified SLR criteria. Most of the studies (n=150) were retrospective in design. Incidence was reported in 114 studies. Majority of the studies reported cumulative incidence (CI) over specified times such as 5-yr or 10-yr incidence or proportion of patients (pts) with PTLD out of a sample of transplanted pts. In the HCT setting, only CI was reported; twelve studies reported CI ranging from 0.1% among 15094 pts receiving autologous HCT over a 19-yr period to 4% in a cohort of 1021 pts receiving allogeneic HCT over a 16-yr period. A total of 100 studies reported incidence of PTLD in SOT pts which was highly influenced by the study population, EBV status at the time of transplant and follow-up time. Of these, 12 reported incidence rates ranging from 24 EBV negative PTLD cases per 100,000 person-years (PY) within 1-5 yrs post-transplant to 3460 PTLD cases per 100,000 PY at 20 yrs post-transplant. Eighty studies reported CI, 19 of which reported CI for various timepoints. In a group of 23171 heart transplant pts CI was 1% during a median follow-up of 4.3 yrs, while in a subgroup of four pediatric multi-organ transplant recipients followed from 2003 to 2011 CI was 25%. Across studies, CI at 1-yr post-transplant ranged from 0.1% to 4.9% and 5-yr CI ranged from 0.7% to 12.1% in select group of transplant pts. Twenty-four studies reported CI by transplant organ type ranging from 0.2% in kidney transplant pts within the first year to 12.1% in lung transplant pts over 7.5 yrs, with higher estimates reported in studies with smaller sample sizes. Conclusions: Our SLR shows large variation in the reported incidence of PTLD due to heterogeneity in the methodology and the study populations in both HCT and SOT settings. Published literature lacks the granularity to correctly interpret the incidence of PTLD in the general transplant population. Thus, additional methods and data considerations such as population type (HCT/SOT transplants, adult/pediatric pts, etc.), representativeness (single institutional data/multi-center/country level registry), unit of measurement of risk (CI/incidence rate, etc.), type of study (retrospective/prospective), length of follow-up, sample size, trends in transplant and treatment landscape over time are needed to ensure accuracy in the estimation of incidence of PTLD. Disclosures Thirumalai: Atara Biotherapeutics: Current Employment. Watson: Atara Biotherapeutics: Current Employment, Current holder of individual stocks in a privately-held company. Xun: Atara Biotherapeutics: Current Employment. Sadetsky: Atara Biotherapeutics: Current Employment. Schaible: Evidera: Current Employment. Barlev: Atara Biotherapeutics: Current Employment.

Background: The higher cost of confirmatory trials and ethical considerations for patients with the existing treatment options led to the investigation of new trial designs. There have been multiple efforts to develop statistical methodologies to evaluate the impact of borrowing external and historical randomized clinical trials (RCT) data sources in a hybrid control design setting. However, few studies used real-world data and historical RCT while comparing Bayesian and frequentist approaches under similar conditions. We evaluated Bayesian (commensurate prior model) and frequentist (Frailty Cox model) hierarchical methods in hybrid control simulation. In addition, dynamic borrowing between the control arms of two historical RCTs in previously treated non-small cell lung cancer (NSCLC) was tested. Methods: Bayesian and frequentist models were carried out and evaluated through computational simulations to mimic 300 repeated clinical trial experiments. Estimation of bias, power, and type I error was conducted. The critical value for testing of 5% (two-sided type I error) was used. Half-Cauchy hyperprior was chosen for the Bayesian commensurate approach. Normal prior for heterogeneity between RCT and the external data was used for Bayesian commensurate prior and Frailty Cox model. Results: Model performance, in terms of estimator bias, power, and Type I error, was similar between Bayesian and frequentist approaches. Estimator bias of the two models was within 0.07 (Log(HR), |β^-β|). Type I errors estimated by the two methods ranged from 3% and 10%. Slight type I error inflation was observed when there were differences between data sources. Power to detect treatment effect using various scenarios ranged from 60% to 85%. Power gain was demonstrated with sufficient commensurability between RCT and external control (81% to 82% compared to 75% without borrowing) and potential power loss observed with more differences between data sources (58%-66% compared to 75% without borrowing). When applying this methodology with historical RCTs, results were consistent with simulation scenarios. Conclusions: We demonstrated similar model performance for Bayesian and Frailty Cox models in estimating treatment effects in hybrid control simulation and existing RCT. While some differences in models’ setup, availability of standard software, and flexibility exists, a successful construct of hybrid control can lead to accelerated internal decision making and streamlined clinical trial design. However, many factors can affect treatment effect estimates and careful consideration of the differences between data sources, distribution of estimates, and direction of the bias has to be taken before implementing this approach in a clinical trial setting. Citation Format: Fu-Chi Hsieh, Natalia Sadetsky, Xiao Li, Ruilin Li, Jiawen Zhu. Real-world data in hybrid clinical trial design: Considerations and impact on treatment effect [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 05.

Background Distinctive genomic subtypes (BRAF-mutated [BRAFmut], NRASmut, NF1mut, and triple wild type [wt]) have been identified in melanoma, but little is known about their distribution and association with outcomes outside of clinical trials. By linking longitudinal electronic health records (EHR) and comprehensive genomic profiling we aim to describe characteristics and outcomes among CIT-treated pts in a real-world setting. Methods Metastatic melanoma pts in the de-identified Flatiron Health (FH)-Foundation Medicine (FMI) Clinico-Genomic Database (CGDB), in which EHR-derived data from FH are linked to genomic data from FMI, who received first-line pembrolizumab (pembro), nivolumab (nivo), ipilimumab (ipi), or ipi + nivo between Jan 1, 2011, and Nov 30, 2018, were analyzed. Median OS was calculated from the start of first-line therapy and was evaluated according to BRAF status and genomic subtypes. Results Of 656 melanoma pts in CGDB, 236 received first-line CIT. The majority of pts (69%, n = 165) were BRAFwt and the rest (31%, n = 71) were BRAFmut. Median age was 62.9 yrs (57.3 yrs for BRAFmut pts and 65.6 yrs for BRAFwt pts), 89% were white, and 97% were treated in community clinics. Among BRAFwt pts, 40% (n = 66) were NRASmut, 32% (n = 53) were NF1mut, and 28% (n = 46) were triple wt. Pembro was used in 36% of pts, followed by ipi + nivo (25%), nivo (20%), and ipi (18%). Almost half (47%) of the pts received subsequent therapy; of these pts, 53% (n = 59) received CIT, 23% (n = 26) received targeted therapy, and 24% (n = 27) received other therapies. Median OS for BRAFwt and BRAFmut pts after first-line CIT was 38.6 mo (95% CI 20.2–not estimable [NE]) and 28.9 mo (95% CI 23.3–NE), respectively. Among BRAFwt pts, median OS was 44.9 mo (95% CI 28.9–NE) for NRASmut pts, 27.1 mo (95% CI 19.4–NE) for NF1mut pts, and 19.8 mo (95% CI 11.8-NE) for triple wt pts. Conclusions Our study demonstrated that outcomes among melanoma pts receiving first-line CIT in real-world setting vary based on genomic subtypes and revealed, for the first time, differences in outcomes of major genomic subtypes in BRAFwt pts. Continued investigation of the association between specific genomic subtypes and survival in a real-world setting is needed. Editorial acknowledgement Melanie Sweetlove, MSc (ApotheCom, Yardley, PA, USA). Legal entity responsible for the study Genentech, a member of the Roche Group. Funding Genentech, a member of the Roche Group. Disclosure N. Sadetsky: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech, a member of the Roche Group. P. Lambert: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech, a member of the Roche Group. C. Julian: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech, a member of the Roche Group. J. Chen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech, a member of the Roche Group. Y. Yan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech, a member of the Roche Group.

e18194 Background: Performance status measured by ECOG PS (ECOG) predicts therapy choice, and overall survival (OS), but often not reported in routine care. EHR data include rich clinical information which Methods: In this retrospective analysis using Flatiron Health EHR-derived database we selected patients diagnosed from 2011-2018 with aNSCLC, aBCa, and aMM and ECOG reported between diagnosis and 1) therapy start, or 2) within 90 days. We used multivariable logistic regressions in a 75% development sample to model associations between selected sociodemographic, clinical and laboratory measures and poor ECOG (2+ vs 0-1) for each cancer. Predictive accuracy was assessed in 25% validation datasets. Kaplan-Meier analysis tested the associations between observed and predicted poor ECOG with OS. Results: The non-missing ECOG samples were 20,697 aNSCLC, 2627 aBCa, and 2558 aMM (out of 50,876, 6955, and 7917 respectively). The proportion of patients with ECOG 2+ ranged from 28.5% for aNSCLC to 15% for aMM. Higher number of comorbid conditions, older age, lowest BMI, higher number of metastases, abnormal albumin and hemoglobin and public insurance were associated with poor ECOG status. Predictive accuracy for poor baseline ECOG was 71.8% for NSLCL, 73.8% for aBca, and 85.4% for aMM). There was a consistent association between OS and observed and predicted baseline ECOG (Table 1). Conclusions: In a large cohort of cancer patients, routinely collected EHR data were used to predict baseline ECOG PS status. Complete ECOG status results may enhance evaluation of cancer treatment patterns and outcomes in EHR data. [Table: see text]

OBJECTIVE To determine whether the current definition of potency, inclusive of phosphodiesterase inhibitor (PDEi) use, is valid with respect to sexual bother (SB). This will be assessed by characterizing the effect of PDEi use on SB scores in men who are potent post radical prostatectomy. PATIENTS AND METHODS The study population consisted of patients who were potent both before and after radical prostatectomy, with at least 2 years of follow-up. Disease-specific quality of life data were evaluated by the University of California, Los Angeles, Prostate Cancer Index (PCI) survey. The relationships between changes in sexual function (SF) and SB and use of PDEi over time were evaluated by mixed model analysis controlling for age, clinical risk group, marital status, and time of PCI assessment. RESULTS Of the 246 patients who met the study criteria, 39% reported PDEi use at some point after treatment. PDEi use was not associated with improved SF (P = 0.81). Furthermore, PDEi use was not associated with a change in SB (P = 0.36). Both SF and SB were significantly associated with time of assessment and age, and SF and SB each improved over time. In addition, SB was significantly associated with marital status. CONCLUSION In this analysis, there was no difference in SF scores between men who were potent with or without the use of PDEi. Furthermore, there was no difference in SB scores between men who were potent with or without the use of PDEi. This suggests that the current, inclusive, definition of potency is valid with respect to SB. Keywords: radical prostatectomy, phosphodiesterase inhibitors, sexual bother, CaPSURE INTRODUCTION For men with localized prostate cancer, radical prostatectomy achieves excellent cancer control [1,2]. However, surgery is known to impact sexual function (SF) and sexual bother (SB) [3–6]. The use of phosphodiesterase inhibitors (PDEi) improves SF – specifically erectile function – in patients after surgery for prostate cancer [7,8]. Potency following surgery is most commonly defined as having erections sufficient for intercourse with or without the use of PDEi [9]. However, this definition – inclusive of medication use – does not consider the extent to which men who are potent after surgery with the use of PDEi may be bothered by having to take a medication. Previous studies have suggested a complex relationship between SF and SB, with findings of inconsistent correlation between the two domains [10–12]. For example, a recent study showed that even men with good erectile function post surgery were troubled by their broader sexual outcomes, resulting in worsening SB and quality of life [11]. Therefore, it may not be sufficient to assume patients with good erections post radical prostatectomy have no SB. More than half of patients typically use PDEi to improve their SF post surgery [13–15]. However, no study has assessed whether the use of PDEi in potent men affects SB. Without knowing the impact of PDEi use on SB in potent men, we cannot assume that the current definition of potency, inclusive of PDEi use, is valid with respect to SB. Therefore, this study aimed to characterize the effect of PDEi use on SF and SB scores in men who were potent before and following prostatectomy in a large national prostate cancer registry.

Purpose The potential association between androgen deprivation therapy (ADT) and cardiovascular mortality (CVM) remains controversial. This study assessed mortality outcomes in a large national registry to further elucidate the association between treatment selection and cause of mortality. Patients and Methods A total of 7,248 men in the CaPSURE registry were analyzed. Treatment was categorized as local only, primary ADT monotherapy, local treatment plus ADT, and watchful waiting/active surveillance (WW/AS). Competing hazards survival analysis was performed for prostate cancer–specific mortality (PCSM), CVM, and all-cause mortality. A propensity score–adjusted and a propensity-matched analysis were undertaken to adjust for imbalances in covariates among men receiving various treatments. Results Patients treated with ADT or WW/AS had a higher likelihood of PCSM than those treated with local therapy alone. Patients treated with primary ADT had an almost two-fold greater likelihood of CVM (HR, 1.94; 95% CI, 1.29 to 2.97) than those treated with local therapy alone; however, patients treated with WW/AS had a greater than two-fold increased risk of CVM (HR, 2.46; 95% CI, 1.53 to 3.95). A propensity-matching algorithm in a subset of 1,391 patients was unable to find a significant difference in CVM between those who did or did not receive ADT. Conclusion Patients matched on propensity to receive ADT did not show an association between ADT and CVM. This suggests that potential unmeasured variables affecting treatment selection may confound the relationship between ADT use and cardiovascular risk. However, an association may yet exist, because the propensity score could not include all known risk factors for CVM.

BACKGROUND: As androgen deprivation therapy (ADT) becomes a standard of treatment for men with recurrent or metastatic prostate cancer, evaluation of adverse effects associated with this treatment is needed. In this study, the authors evaluated the effect of ADT administered as monotherapy and in combination with local treatment on physical well-being in a longitudinal sample of men with prostate cancer. METHODS: Exposure to ADT was defined by 3 groups: local (local treatment only), combination (local treatment with adjuvant and/or neoadjuvant ADT), and primary ADT. Associations between exposure to ADT and physical well-being measured by self-reported health-related quality of life outcomes over time were evaluated by repeated measures analysis using mixed modeling. Estimates adjusted for various clinical and demographic variables are reported. RESULTS: A total of 2922 men, who completed both pretreatment and follow-up health-related quality of life assessment, were identified from the CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) registry. During 24 months of follow-up, exposure to ADT was associated with worse physical well-being compared with local treatment at all time points (P < .001). Being exposed to ADT as primary therapy was associated with more severe declines compared with combination therapy. CONCLUSIONS: The potential consequence of decline in physical well-being in patients exposed to ADT has to be included in treatment decision making. Cancer 2011;. © 2011 American Cancer Society.

Purpose: Recent reports suggest that nephrolithiasis and atherosclerosis share a number of risk factors. To our knowledge there has been no previous examination of the relationship between kidney stones and subclinical atherosclerotic disease. We studied the relationship between nephrolithiasis, and carotid wall thickness and carotid stenosis assessed by B-mode ultrasound in the general community using data from the CARDIA study.Materials and Methods: The CARDIA study is a United States, population based, observational study of 5,115 white and African-American men and women between the ages of 18 and 30 years at recruitment in 1985 to 1986.Results: By the year 20 examination 200 (3.9%) CARDIA participants had reported ever having kidney stones. Symptomatic kidney stones were associated with greater carotid wall thickness measured at the year 20 examination, particularly of the internal carotid/bulb region. Using a composite dichotomous end point of carotid stenosis and/or the upper quartile of internal ca...

Objective To determine the relationship between number of fertility treatment cycles and pregnancy rates. Design Prospective cohort study. Setting Eight community and academic infertility practices. Patient(s) Four hundred eight (408) couples presenting for an infertility evaluation. Intervention(s) Face-to-face and telephone interviews and questionnaires. Main Outcome Measure(s) Incidence of pregnancy. Cox regression analysis compared the efficacy of cycle-based fertility treatments with no cycle-based fertility treatment after multivariable adjustment. Result(s) Couples using one to two medications-only cycles had a significantly higher pregnancy rate (hazard ratio [HR] 4.7 [95% confidence interval 1.3–16.6]), a benefit that did not persist after three or more cycles (HR 0.6 [0.1–3.2]). Couples using IUI for one (HR 2.9 [1.4–5.8]), two (HR 2.0 [0.9–4.5]), and three cycles (HR 4.5 [1.8–10.9]) were more likely to achieve a pregnancy. No additional benefit was seen for couples using four or more IUI cycles (HR 1.0 [0.4–2.6]). In vitro fertilization was associated with significant benefit for couples using one (HR 2.8 [1.5–5.2]) and two cycles (HR 2.2 [1.2–4.1]). Couples using three or more IVF cycles had a non–statistically significant higher likelihood of pregnancy (HR 1.3 [0.7–2.4]). Conclusion(s) Cycle-based fertility treatments may offer a point of diminishing returns for infertile couples: two cycles of medications only, three cycles of IUI, and two cycles of IVF.

Commonly used measures of comorbidity assess comorbidity number and type but not severity. We sought to evaluate the impact of comorbidity severity on longitudinal health-related quality of life (HRQOL) in men treated with radical prostatectomy (RP) or radiation therapy (RT) using the Total Illness Burden Index for prostate cancer (TIBI-CaP). We sampled 738 men with non-metastatic prostate cancer treated with RP or RT from the Cancer of the Prostate Strategic Urologic Research Endeavor registry. We examined the impact of comorbidity severity on generic and disease-specific HRQOL at baseline and at 6, 12, 18 and 24 months post-treatment. Men with worse TIBI-CaP comorbidity had significantly lower baseline and post-treatment HRQOL in all domains at all time points. In a multivariate model, men with moderate or severe TIBI-CaP comorbidity had significantly worse HRQOL scores at 12 and 24 months after treatment in all domains except sexual and urinary function (P

Study Type – Therapy (outcomes research) Level of Evidence 2c OBJECTIVE To quantitatively assess the effect of radical prostatectomy (RP) on the specific domains that comprise overall sexual function (SF), focusing on the relationships among these domains and overall SF, and to identify predictors for recovery of SF over time, as a decline in SF and sexual bother (SB) are known potential complications of treatment for prostate cancer. PATIENTS AND METHODS Within the Cancer of the Prostate Strategic Urologic Research Endeavor database, we identified men diagnosed between 1995 and 2001 with localized prostate cancer treated with RP. SF and SB outcomes, measured using the University of California Los Angeles Prostate Cancer Index, were assessed at 6-month intervals for 4 years after RP. RESULTS In all, 620 men met the study criteria; at 6 months after RP, overall and all the specific domains of SF declined, with improvement in most specific domains by 2 years after RP. The greatest declines were in the ability to achieve erections, high-quality erections, and frequent erections; these domains were also most strongly correlated with overall SF. Sexual desire was relatively preserved, and there was a weak correlation between overall SF and sexual desire after RP, when there was the greatest discrepancy between sexual desire and other domains of function. SB showed continued improvement over time to 4 years but was not well correlated with any measurements of SF assessed. Younger age, college education, sexual aid and medication use, the absence of comorbid conditions, and nerve-sparing surgery were predictive of significant recovery of function in several specific domains of SF. CONCLUSIONS RP affects specific domains of SF to differing degrees. Compromised erectile function is most commonly reported among these specific domains and seems to play a more dominant role in determining overall SF, but notably none of the domains of function were closely linked to SB. Because education is protective in the perception of bother, appropriate counselling and the setting of expectations for outcomes in overall and specific domains of SF might lead to improved quality of life after treatment for prostate cancer.

Men who undergo primary treatment for prostate cancer can expect changes in health related quality of life. Long-term changes after treatment are not yet fully understood. We characterized health related quality of life evolution from baseline to 4 years after treatment.We identified 1,269 men in CaPSURE who underwent primary treatment for clinically localized prostate cancer and completed followup health related quality of life questionnaires for at least 4 years. The men underwent radical prostatectomy, external beam radiotherapy, brachytherapy, combined external beam radiotherapy/brachytherapy or androgen deprivation therapy. Health related quality of life was measured using patient reported questionnaires. Effects of select covariates on quality of life were measured with a multivariate mixed model.Age at diagnosis, time from treatment and primary treatment were significant predictors of health related quality of life in all domains (p0.05) except primary treatment on sexual bother. Men who underwent radical prostatectomy experienced the most pronounced worsening urinary function but also had the greatest recovery. All treatments worsened urinary bother, and sexual function and bother. All forms of radiotherapy moderately worsened bowel function and bother after treatment but eventual recovery to baseline was noted.Age at diagnosis, time from treatment and primary treatment type affect health related quality of life. Treatment has a greater impact on disease specific than general health related quality of life. All treatments adversely affect urinary and sexual function. Most adverse changes develop immediately after treatment. Recovery occurs mostly within 2 years after treatment with little change beyond 3 years.

6578Background: Overall response rate (ORR) based on Response Evaluation Criteria in Solid Tumors (RECIST) is an established early efficacy endpoint used in clinical trials. Comparison of real worl...

We examined whether maximum androgen blockade (MAB) is associated with a decreased recurrence risk vs. single-agent androgen suppression (monotherapy) for men undergoing brachytherapy (BT) for localized prostate cancer.Data from 223 men in the Cancer of the Prostate Strategic Urologic Research Endeavor database who received androgen deprivation therapy (ADT) concurrent with BT for intermediate- or high-risk prostatic adenocarcinoma were included; 159 (71%) received MAB, and 64 (29%) monotherapy (luteinizing hormone-releasing hormone agonist or anti-androgen alone). Cox regression analysis was performed to assess whether the choice of ADT was associated with disease recurrence adjusting for known prognostic factors.Men who received MAB had similar Gleason scores, T categories, and pretreatment prostate-specific antigen as those who received monotherapy. After a median follow-up of 49 months, the use of MAB was not associated with a decrease in the risk recurrence (p = 0.72), after adjusting for known prognostic factors. A higher PSA at diagnosis (p = 0.03) and younger age at diagnosis (p0.01) were associated with increased recurrence risk. The 3-year recurrence free survival was 76% for patients in both monotherapy and MAB groups.There are varied practice patterns in physicians' choice of the extent of concurrent ADT when used with brachytherapy for men with intermediate- or high-risk prostate cancer. Given a lack of demonstrated superiority from either ADT choice, both appear to be reasonable options.

We examined the impact of obesity on disease specific and overall survival in patients with prostate cancer.We identified 7,274 men from the Cancer of the Prostate Strategic Urological Research Endeavor database with clinically localized prostate cancer, known body mass index and clinicopathological disease characteristics. Patients were classified by body mass index as normal (less than 25 kg/m(2)), overweight (25 to 29.9 kg/m(2)), obese (30 to 34.9 kg/m(2)) and severely obese (35 kg/m(2) or greater). Associations between body mass index and need for secondary treatment, disease specific survival and overall survival were analyzed using univariate and multivariate models.Patients were classified by body mass index category as normal (28.8%), overweight (50%), obese (16.4%) and very obese (4.8%). Mean followup was 51.3 +/- 38.5 months. During followup there were 1,044 deaths with 220 (21.1%) from prostate cancer. Stratified by body mass index category the groups differed with regard to the need for secondary treatment (p = 0.05) and overall mortality (p0.01) but there were no significant differences with regard to disease specific survival (p = 0.09). On multivariate analysis age 65 to 74 years (HR 2.4, p = 0.002), age older than 75 years (HR 3.2, p = 0.0001), high risk disease (HR 1.6, p0.0001), conservative treatment (HR 1.2, p0.0001) and presence of diabetes (HR 1.6, p0.0001) were associated with decreased overall survival. Only conservative treatment (HR 1.4, p0.0001), high risk disease (HR 8.4, p0.0001) and intermediate risk disease (HR 2.5, p = 0.004) were associated with decreased disease specific survival.In a prospective, community based cohort we were unable to establish a relationship between body mass index and prostate cancer disease specific survival or overall survival.

We present longitudinal quality of life outcomes in a national observational cohort of men with locally advanced prostate adenocarcinoma.The CaPSURE registry was used to evaluate quality of life in men with clinical T3 or T4 prostate adenocarcinoma who underwent primary treatment and had a minimum followup of 2 years. Records were reviewed for treatment, patient age, T stage, prostate specific antigen at diagnosis, body mass index, and initial and posttreatment quality of life using the SF-36 and UCLA-PCI questionnaires, which can each be scored from 0 to 100 with higher scores indicating better outcomes. The association of treatment type and quality of life changes after treatment were evaluated with multivariate mixed model analysis, adjusting for age, time of quality of life assessment, and interaction between treatment and time.Of the 13,740 men enrolled in CaPSURE 608 (4.42%) presented with T3 or T4 tumors. In this subgroup 151 men completed baseline and a minimum of 2 years of followup with quality of life data available. These men underwent primary treatment with radical prostatectomy (21%), cryotherapy (8%), brachytherapy (17%) or hormonal ablation (54%). The treatment cohort demonstrated significant decreases in quality of life, most profoundly in urinary and sexual function. Mean urinary function was 91 at baseline, which decreased to 82, 83 and 82 at 1, 2 and 3 years after treatment, respectively (p = 0.04). Mean sexual function was 38 at baseline, which decreased to 15, 16 and 14 at 1, 2 and 3 years after treatment, respectively (p0.01). On multivariate analysis quality of life varied significantly by treatment type (p0.01).Treatment for locally advanced prostate adenocarcinoma is associated with a significant burden in patients, notably decrements in urinary and sexual function. Clinicians should consider the impact that treatment imparts on quality of life when counseling patients with locally advanced disease.

Objectives Obese patients with prostate cancer have more aggressive tumors and, in some studies, more prostate cancer-specific deaths. This study was designed to assess the relationship between body mass index (BMI) and treatment patterns of prostate cancer patients. Methods We identified 5041 men with clinically localized prostate cancer (T1-3a, N0M0) who received their first treatment between 1995 and 2006. We derived the odds ratios (OR) for the likelihood of receiving each type of therapy compared with radical prostatectomy by BMI categories using multinomial logistic regression. In our analysis we controlled for age at diagnosis, race/ethnicity, education level, clinical risk category, and number of co-morbidities. Results A total of 28.1% of patients were classified as normal BMI, 50.5% were overweight, 16.5% were obese, and 4.8% were very obese. The adjusted OR of receiving nonsurgical therapies (brachytherapy, external radiation, primary androgen deprivation, and active surveillance) increased relative to radical prostatectomy for increasing obesity (P = 0.003). Compared with the patients with normal BMI, very obese patients were more likely to receive brachytherapy (OR 1.59, 95% confidence interval [CI] 1.01 to 2.52), external radiation (OR 1.29, 95% CI 0.73 to 2.26), primary androgen therapy only (OR 1.77, 95% CI 1.12 to 2.81), and active surveillance (OR 1.06, 95% CI 0.52 to 2.17) compared with radical prostatectomy. Conclusions In a large cohort of American prostate cancer patients, a significant trend toward nonsurgical treatment modalities was apparent with increasing BMI.

Objective To evaluate the influence of comorbid cardiovascular disease severity on health-related quality of life (HRQL) in men treated with radical prostatectomy (RP) or radiotherapy (RT) for early stage prostate cancer. Methods Subjects (n = 830) with non-metastatic disease who had been diagnosed in 2000–2002 were drawn from Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE). We evaluated the influence of cardiovascular disease (CVD) severity on generic and disease-specific HRQL before and 6, 12, 18, and 24 months after treatment with RP or RT. HRQL was measured with the SF-36 and the UCLA Prostate Cancer Index. Results Men with moderate (n = 193) or severe (n = 51) cardiovascular disease had worse pre-treatment HRQL than did men without CVD (n = 293) (P

We determined whether the impact of phosphodiesterase inhibitors on sexual function and sexual bother is different after radical prostatectomy vs radiation therapy for localized prostate cancer.We analyzed data from 1,087 men treated for localized prostate cancer with radical prostatectomy or radiation therapy, who had at least 2 years of health related quality of life followup and who reported using a phosphodiesterase type 5 inhibitor after prostate cancer treatment. Sexual function and bother were assessed over time using the UCLA Prostate Cancer Index. Mixed model analysis was used to examine sexual function and sexual bother over time after initiation of treatment with a phosphodiesterase type 5 inhibitor. Response rates were then determined using the criterion of an increase in score of at least half the standard deviation in baseline scores, and multivariate logistic regression was used to identify predictors of improved sexual function and sexual bother in response to phosphodiesterase type 5 inhibitor use.Patients treated with radical prostatectomy and those who received radiation therapy had an improvement in sexual function and sexual bother after initiating phosphodiesterase type 5 inhibitor use. Response rates were similar for both types of treatment, and the only significant predictors of response to phosphodiesterase type 5 inhibitors were higher baseline (pretreatment) sexual function score and lower sexual function before phosphodiesterase type 5 inhibitor use. There was no significant change in response to phosphodiesterase type 5 inhibitors over time.Analysis of these data suggests that choice of treatment for localized prostate cancer is unlikely to have a significant impact on response to phosphodiesterase type 5 inhibitors should they be needed after treatment. However, patients with better pretreatment sexual function are more likely to respond to phosphodiesterase type 5 inhibitors.

BACKGROUND. The authors report the likelihood of treatment failure and the outcomes after salvage therapy among men with prostate cancer who initially either received external-beam radiation therapy (EBRT) or underwent radical prostatectomy (RP). METHODS. Using a national disease registry, the Cancer of the Prostate Strategic Urological Research Endeavor (CaPSURE) database, 5277 men with prostate cancer were identified who initially either underwent RP (4342 men) or received EBRT (935 men). Outcomes after disease recurrence and subsequent salvage therapy were assessed. RESULTS. Recurrent disease developed in 1590 men (30%), including 1003 patients (23%) in the RP group and 587 patients (63%) in the EBRT group, at a mean of 34 months and 38 months, respectively (P = .003). Patients who had recurrent disease had greater rates of overall death (19% vs 3%; P < .01) and bone metastases (15% vs 1%; P < .01). Data after salvage therapy were available for 1050 patients (620 men in the RP group and 430 men in the EBRT group). Androgen-deprivation therapy (ADT) was the most common salvage treatment in both groups. Overall, 420 men in the RP group (68%) and 319 men in the EBRT group (74%) failed salvage therapy at mean of 43.6 months and 43.8 months, respectively (P = .95). These patients had a greater overall death rate than the 311 patients who did not fail salvage therapy (24.8% vs 6.9%, respectively; P < .001). No survival benefit in terms of prostate cancer-related death (P = .91) was identified with any particular combination of primary and salvage therapy. CONCLUSIONS. Disease recurrence developed in 30% of patients who were treated for prostate cancer, and ADT was the most common salvage therapy used. Patients who failed salvage therapy had worse overall survival, and no survival benefit was noted for any particular combination of primary and salvage therapy. Cancer 2008. © 2007 American Cancer Society.

Background We investigated whether androgen deprivation therapy (ADT) use is associated with an increased risk of death from cardiovascular causes in patients treated for localized prostate cancer. Methods From the Cancer of the Prostate Strategic Urologic Research Endeavor database, data on 3262 patients treated with radical prostatectomy and 1630 patients treated with external beam radiation therapy, brachytherapy, or cryotherapy for localized prostate cancer were included in this analysis. Competing risks regression analyses were performed to assess whether use of ADT was associated with a shorter time to death from cardiovascular causes after controlling for age (as a continuous variable) and the presence of baseline cardiovascular disease risk factors. All tests for statistical significance were two-sided. Results The median follow-up time was 3.8 years (range = 0.1-11.3 years). Among the 1015 patients who received ADT, the median duration of ADT use was 4.1 months (range = 1.0-32.9 months). In a competing risks regression analysis that controlled for age and risk factors for cardiovascular disease, both ADT use (adjusted hazard ratio [HR] = 2.6; 95% confidence interval [CI] = 1.4 to 4.7; P = .002) and age (adjusted HR = 1.07; 95% CI = 1.02 to 1.1; P = .003) were associated with statistically significantly increased risks of death from cardiovascular causes in patients treated with radical prostatectomy. Among patients 65 years or older treated with radical prostatectomy, the 5-year cumulative incidence of cardiovascular death was 5.5% (95% CI = 1.2% to 9.8%) in those who received ADT and 2.0% (95% CI = 1.1% to 3.0%) in those who did not. Among patients 65 years or older treated with external beam radiation therapy, brachytherapy, or cryotherapy, ADT use was associated with a higher cumulative incidence of death from cardiovascular causes, but the difference did not reach statistical significance. Conclusions The use of ADT appears to be associated with an increased risk of death from cardiovascular causes in patients undergoing radical prostatectomy for localized prostate cancer.

With growing number of older adults in the United States and complexity of issues related to Medicare and other insurances more research is needed to evaluate an effectiveness of the different insurance types in prevention, screening and treatment of cancer. With prostate cancer being highly prevalent disease in older men, the importance of appropriate treatment and favorable outcomes is imperative. In this study we examine whether prostate cancer outcomes, such as risk category at diagnosis, treatment and survival differ in relationship to insurance status in older patients in CaPSURE. Data were abstracted from CaPSURE, a longitudinal observational database of 13 124 men with prostate cancer. Men were selected for the study if they were older than 65 years old at diagnosis, newly diagnosed between 1995 and 2005 at entry to CaPSURE with localized disease and received radical prostatectomy (RP), external beam radiation (EBRT), brachytherapy (BT), hormonal therapy or expectant management (EM). Insurance status was summarized by eight categories: Medicare only, Medicare+supplement, Medicare+HMO, Medicare+PPO, Medicare+FFS, health maintenance organization (HMO), preferred provider organization (PPO) and Veteran's Administration (VA). A total of 2983 men met the inclusion criteria. Odds ratios (OR) for the likelihood of receiving each type of therapy compared to RP by insurance status and likelihood of presenting with high-risk classification at diagnosis were derived using multinomial logistic regression, adjusting for clinical and demographic characteristics. Difference in survival between insurance groups was evaluated by Cox's multivariate regression. Multivariate analysis demonstrated a strong association between initial treatment and insurance status. Compared to Medicare patients, men in the CaPSURE database treated at HMO, PPO and VA systems were more likely to receive BT than RP (OR, 1.71-1.92) and less likely to receive this treatment if they were in Medicare+FFS and Medicare+PPO (OR, 0.18-0.38). Hormonal treatment demonstrated similar pattern, however OR did not reached statistical significance for HMO and PPO. Use of EM was much more predominant for patients in VA system (OR, 4.74; 95% CI, 1.94-11.55). Use of EBRT was significantly associated with type of insurance. Men with VA, Medicare+FFS and Medicare+PPO insurance were less likely to receive this treatment compared to RP. Survival and clinical risk at diagnosis was associated with insurance status in univariate analysis but this association diminished after adjusting for possible covariates. This study provides important information on relationship between insurance status and several outcomes in patients with prostate cancer. Even after controlling for important clinical and sociodemographic factors we found marked differences in prostate cancer treatment according to type of insurance. Future explorations of associations between health care delivery system, cancer care and outcomes are needed.

We assessed the impact of second treatment on health related quality of life for men with prostate cancer. This issue is important because second treatment resulting from prostate specific antigen recurrence has the potential to further negatively impact health related quality of life and affect the overall value of treatment. We compared differences in health related quality of life before and after second treatment for men who had asymptomatic prostate specific antigen recurrence with those who did not have biochemical failure.Men in this analysis (897) had localized disease, initially underwent radical prostatectomy monotherapy, and completed at least 1 health related quality of life questionnaire before and after radical prostatectomy. In this cohort 175 men underwent second treatment (nonadjuvant). The Medical Outcomes Survey Short Form-36 and UCLA Prostate Cancer Index were used to measure health related quality of life. Associations between patient groups and time on health related quality of life were analyzed using repeated measures.Men who received a second treatment presented with more severe disease before radical prostatectomy and had worse general health related quality of life. Although health related quality of life differed significantly with time for the 2 groups, most domains for the second treatment group improved or remained stable until 15 months before second treatment, at which point they declined. Scores in the sexual functioning and role-physical domains showed clinically and statistically significant patterns of decreasing with time.Health related quality of life is affected following second treatment but starts to decline approximately 1 year before second treatment. Not all aspects of health related quality of life decreased at the same rate, so patients should be counseled that certain domains may be affected more by additional treatment.

Widespread screening for prostate cancer in the United States has resulted in earlier tumor identification at lower stages. The fewer number of men with lymph node metastases at initial presentation has altered patterns of pelvic lymphadenectomy before definitive treatment. We characterized patterns of pelvic lymphadenectomy in conjunction with radical prostatectomy in a community based cohort.In the CaPSURE database we identified men undergoing radical prostatectomy. Patients were stratified into 3 clinical risk groups based on serum prostate specific antigen, T stage and pathological grade. We examined temporal trends of pelvic lymphadenectomy and predictors of pelvic lymphadenectomy.From 1992 to 2004 the proportion of men undergoing pelvic lymphadenectomy in conjunction with radical prostatectomy decreased from 94% to 80%. Overall positive lymph nodes were identified in 0.87%, 2.0% and 7.1% of men in the low, intermediate and high risk groups, respectively. While men with high risk disease continued to undergo pelvic lymphadenectomy at a high rate (greater than 90%), the fraction of men at low and intermediate risk undergoing pelvic lymphadenectomy steadily decreased. Prostate specific antigen, Gleason sum, clinical stage and income were factors associated with pelvic lymphadenectomy. A mean of 5.7 lymph nodes (median 5.0) were removed.The performance of pelvic lymphadenectomy has decreased in patients at low and intermediate risk, and remained stable in patients at high risk. Further investigation of the role of extended pelvic lymphadenectomy and the potential therapeutic benefits of pelvic lymphadenectomy would better define the contemporary role of pelvic lymphadenectomy and identify appropriate candidates.

Objectives. To determine the association between obesity and prostate cancer recurrence after primary treatment with radical prostatectomy. Methods. Data were abstracted from CaPSURE, a disease registry of 10,018 men with prostate cancer. We included 2131 men who had undergone radical prostatectomy between 1989 and 2003 and had body mass index (BMI) information available. Recurrence was defined as two consecutive prostate-specific antigen (PSA) levels of 0.2 ng/mL or greater or any second treatment. Patients were risk stratified using the PSA level, Gleason grade, and clinical T stage. Results. Patients were followed up for a median of 23 months. Of the 2131 patients, 251 (12%) developed recurrence at a median of 13 months (range 1 to 107); 183 (9%) of these men had PSA failure and 68 (3%) received a second treatment. After adjusting for risk group, ethnicity, age, and comorbidities, a significant association was found between an increasing BMI and disease recurrence (P 0.028). Very obese patients (BMI 35 kg/m 2 or more) were 1.69 times more likely to have recurrence relative to men of normal weight (BMI less than 25.0 kg/m 2 ; 95% confidence interval [CI] 1.01 to 2.84). An increasing PSA level (P 0.0001) and Gleason grade (P 0.0001) were also associated with recurrence. Ethnicity was not significantly associated with either BMI or PSA recurrence (P 0.685 and P 0.068, respectively). Conclusions. The results of our study have shown that obesity is an independent predictor of prostate cancer recurrence. Because of the increased comorbidities and greater rates of recurrence, obese individuals undergoing radical prostatectomy need vigilant follow-up care. UROLOGY 66: 1060‐1065, 2005. © 2005 Elsevier Inc.

Purpose: Health related quality of life (HRQOL) is an important measure of outcomes among patients with prostate cancer due to disease related and treatment related effects on physical and emotional health. We determined if there are differences in the HRQOL of obese men at diagnosis and after radical prostatectomy compared to the HRQOL of men with normal body mass index (BMI). Materials and Methods: Data were abstracted from Cancer of the Prostate Strategic Urological Research Endeavor (CaPSURE), a disease registry of 10,018 men with prostate cancer. A total of 1,884 men were included in study who were treated with radical prostatectomy between 1989 and 2002, had BMI information available and had completed 1 initial HRQOL questionnaire. Of these men 672 who completed at least 2 followup questionnaires were assessed further. Results: The BMI (kg/m2) distributions were 24% normal (less than 24.9 kg/m2), 56% overweight (25 to 29.9), 16% obese (30 to 34.9) and 4% very obese (greater than 35 kg/m2). Higher BMI was associated with worse physical function, bodily pain, general health, vitality and role physical, but better bowel bother at diagnosis independent of race. Higher BMI was also associated with worse HRQOL after radical prostatectomy for physical function, general health and vitality, but better bowel bother. HRQOL differences between BMI groups were similar among times for all measured variables. Compared to the normal group, the higher BMI groups had similar HRQOL after radical prostatectomy. Conclusions: In the majority of domains men with higher BMI had lower HRQOL at diagnosis than men of normal BMI. Obese men have a similar recovery pattern of HRQOL after radical prostatectomy, with minimal additive long-term impairment in HRQOL relative to men of normal weight. Copyright © 2005 by American Urological Association.

Purpose: We investigated the association of obesity with prostate cancer case demographics and clinical disease features at presentation. Materials and Methods: Data were abstracted from CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor), a disease registry of 10,018 men with prostate cancer. A total of 2,952 men were included who were treated between 1989 and 2002, and had complete body mass index (BMI) information. BMI classes were defined as normal (less than 25 kg/m 2 ), overweight (25 to 29.9 kg/m 2 ), obese (30 to 34.9 kg/m 2 ) or very obese (35 kg/m 2 or greater). Patients were categorized as having low, intermediate or high risk disease based on the D'Amico classification. Associations among BMI, risk and demographics were analyzed using univariate and multivariate models. Results: Of the patients 29% had a normal BMI, 51% were overweight, 16% were obese and 5% were very obese. Patients who were overweight or obese were more likely to be young, have hypertension and diabetes, and have a lower education level. The overweight group had a lower serum prostate specific antigen (p = 0.010) and lower stage disease (p = 0.030) at diagnosis, but there was no association between Gleason score and obesity (p = 0.57). However, among men with a BMI of 25 kg/m 2 or greater there was a positive correlation between increasing BMI and risk of being in a worse prognostic group at diagnosis (p = 0.018). Conclusions: Overweight and obese patients are more likely to be young at diagnosis and have multiple comorbidities. Men in the overweight and obese groups presented with lower risk prostate cancer at diagnosis. This may be due to earlier disease detection secondary to more frequent interaction with the medical community. Among overweight and obese patients increased obesity is associated with a slightly increased chance of having high risk prostate cancer at diagnosis.

We measured the impact brachytherapy monotherapy (BMT) has on general and disease specific health related quality of life (HRQOL) compared to patients treated with radical prostatectomy (RP).We studied 419 men with newly diagnosed prostate cancer who enrolled in CaPSURE (Cancer of the Prostate Strategic Urological Research Endeavor) data base whose primary treatment was brachytherapy monotherapy (92) or radical prostatectomy (327). The validated RAND 36-Item Health Survey and the UCLA Prostate Cancer Index were used to measure HRQOL before treatment and at 6-month intervals during the first 2 years after treatment.Patients treated with BMT or RP did not differ greatly in general HRQOL after treatment. Both treatment groups showed early functional impairment in most general domains with scores returning to or approaching baseline in most domains 18 to 24 months after treatment. Patients treated with BMT had significantly higher urinary function scores at 0 to 6 months after treatment (84.5, SD 18.7) than patients treated with RP (63.3, SD 26.6). Urinary bother scores at 0 to 6 months after treatment were not significantly different between patients treated with BMT (67.7, SD 31.2) and those treated with RP (67.4, SD 29.1). Both treatment groups had decreases in sexual function that did not return to pretreatment levels.Overall BMT and RP are well tolerated procedures that cause mild changes in general HRQOL. Disease specific HRQOL patterns are different in patients treated with BMT or RP. Baseline and serial HRQOL measurements after treatment can provide valuable information regarding expected quality of life outcome after treatment for localized prostate cancer.

PurposeA randomized, placebo controlled clinical trial of folic acid supplementation for the chemoprevention of colorectal adenoma revealed an increased incidence of prostate cancer in the treatment group. Limited data exist on postdiagnostic folate/folic acid intake and the risk of prostate cancer progression. We prospectively examined the association between postdiagnostic folate consumption and the risk of prostate cancer recurrence after radical prostatectomy, external beam radiation therapy and brachytherapy.Materials and methodsThis study was done in 1,153 men treated with radical prostatectomy, external beam radiation therapy and brachytherapy who had clinical stage T1-T2c prostate adenocarcinoma and participated in the CaPSURE Diet and Lifestyle substudy by completing the semiquantitative Food Frequency Questionnaire in 2004 to 2005. We used Cox proportional hazards regression to analyze the association between folate intake and prostate cancer progression.ResultsProstate cancer progressed in 101 men (8.76%) during a mean 34-month followup. After multivariate adjustment we observed no evidence of an association of the intake of total folate, dietary folate or dietary folate equivalents with prostate cancer recurrence. On secondary analysis by treatment after radical prostatectomy patients in the lowest decile of dietary folate intake had a 2.6-fold increase in the risk of recurrence (HR 2.56, 95% CI 1.23-5.29, p = 0.01). In patients treated with external beam radiation and brachytherapy we observed no evidence of an association between prostate cancer progression and increased folate intake.ConclusionsResults suggest that the consumption of foods and multivitamins that contain folate is not associated with prostate cancer progression after definitive treatment.

PurposeIntestinal calcium absorption is thought to have a critical role in nephrolithiasis. However, to our knowledge no study has directly assessed this association. Therefore, we explored the relationship among intestinal fractional calcium absorption, calcium intake and nephrolithiasis.Materials and methodsThe Study of Osteoporotic Fractures is a prospective cohort of 9,704 postmenopausal women recruited from population based listings in 1986 and followed for more than 20 years. Secondary analyses were performed of 7,982 women who reported their history of nephrolithiasis, of which 5,452 (68%) underwent an oral radioactive calcium assay (45Ca). The impact of dietary and supplemental calcium on intestinal fractional calcium absorption was evaluated, and factors independently associated with nephrolithiasis were determined.ResultsFractional calcium absorption decreased with increased calcium intake, with no difference between dietary and supplemental calcium. Fractional calcium absorption was higher in women with a nephrolithiasis history among all calcium intake groups. Increased dietary calcium intake reduced the likelihood of nephrolithiasis by 45% to 54% (p=0.03). Women with a history of nephrolithiasis were less likely to supplement calcium (p

Increased fluid intake, and decreased dietary sodium and animal protein intake are thought to reduce the risk of kidney stones but the role of calcium intake is controversial. We evaluated the relationship between dietary factors and incident kidney stone formation.Secondary analysis was done of 78,293 women from the prospective WHI OS (Women's Health Initiative Observational Study) with no history of nephrolithiasis who completed the validated food frequency questionnaire. Multivariate logistic regression was used to determine demographic and dietary factors, and supplement use independently associated with incident kidney stones.Overall 1,952 women (2.5%) reported an incident kidney stone in 573,575 person-years of followup. The risk of incident kidney stones was decreased by 5% to 28% (p = 0.01) with higher dietary calcium intake and by 13% to 31% (p = 0.002) with higher water intake after adjusting for nephrolithiasis risk factors. Conversely higher dietary sodium intake increased the risk of nephrolithiasis by 11% to 61% (p0.001) after adjustment with the most pronounced effect in women with the highest intake. Higher body mass index independently increased the risk of incident nephrolithiasis (adjusted OR 1.19-2.01, p0.001). Animal protein intake was not associated with nephrolithiasis on multivariate analysis.This study adds to the growing evidence underscoring the importance of maintaining adequate fluid and dietary calcium intake. Greater dietary calcium intake significantly decreased the risk of incident kidney stones. In contrast, excess sodium intake increased the risk of incident nephrolithiasis, especially in women with the highest intake. Animal protein intake was not independently associated with nephrolithiasis.

Background:Men with persistently elevated and/or rising PSA levels after negative prostate biopsy often undergo multiple repeat biopsies. Prostate cancer antigen 3 (PCA3) has emerged as a predictor of prostate cancer.Methods:We sought to define the utility of PCA3 in combination with other clinical data in predicting the risk of prostate cancer on repeat biopsy. We retrospectively obtained PCA3, PSA, PSA density (PSAD), digital rectal examination (DRE) and transrectal ultrasound (TRUS) findings from 103 patients at a single institution who had at least one prior negative prostate biopsy. The sensitivity and specificity of PCA3 in detecting prostate cancer was determined. Receiver operating characteristics curves were produced for each variable individually and in multivariable analysis, controlling for PCA3, PSAD, TRUS, PSA and DRE. A nomogram was created, internally validated and compared to another recently published nomogram.Results:Of the 103 patients, 37 (31%) had prostate cancer on repeat biopsy. The sensitivity and specificity of PCA3 (using a cut point of 25) was 0.67 and 0.64, respectively. In multivariable analyses, PCA3 was independently associated with prostate cancer (odds ratio: 1.02, 95% confidence interval: 1.01-1.04), with area under the curve (AUC) of 0.64. A multivariable model containing PCA3, PSAD, PSA, DRE and TRUS findings showed the most diagnostic accuracy (AUC: 0.82).Conclusions:In the setting of prior negative biopsies, PCA3 was independently associated with prostate cancer in a multivariable model. In combination with other clinical data, PCA3 is a valuable tool in assessing the risk of prostate cancer on repeat biopsy. © 2012 Macmillan Publishers Limited All rights reserved.

Context: Sexual function is the health-related quality of life (HRQOL) domain most commonly impaired after prostate cancer treatment; however, validated tools to enable personalized prediction of erectile dysfunction after prostate cancer treatment are lacking. Objective: To predict long-term erectile function following prostate cancer treatment based on individual patient and treatment characteristics. Design: Pretreatment patient characteristics, sexual HRQOL, and treatment details measured in a longitudinal academic multicenter cohort (Prostate Cancer Outcomes and Satisfaction With Treatment Quality Assessment; enrolled from 2003 through 2006), were used to develop models predicting erectile function 2 years after treatment. A community-based cohort (community-based Cancer of the Prostate Strategic Urologic Research Endeavor [CaPSURE]; enrolled 1995 through 2007) externally validated model performance. Patients in US academic and community-based practices whose HRQOL was measured pretreatment (N=1201) underwent follow-up after prostatectomy, external radiotherapy, or brachytherapy for prostate cancer. Sexual outcomes among men completing 2 years' follow-up (n=1027) were used to develop models predicting erectile function that were externally validated among 1913 patients in a community-based cohort. Main Outcome Measures: Patient-reported functional erections suitable for intercourse 2 years following prostate cancer treatment. Results: Two years after prostate cancer treatment, 368 (37% [95% CI, 34%-40%]) of all patients and 335 (48% [95% CI, 45%-52%]) of those with functional erections prior to treatment reported functional erections; 531 (53% [95% CI, 50%-56%]) of patients without penile prostheses reported use of medications or other devices for erectile dysfunction. Pretreatment sexualHRQOLscore, age, serum prostate-specific antigen level, race/ethnicity, body mass index, and intended treatment details were associated with functional erections 2 years after treatment. Multivariable logistic regression models predicting erectile function estimated 2-year function probabilities from as low as 10% or less to as high as 70% or greater depending on the individual's pretreatment patient characteristics and treatment details. The models performed well in predicting erections in external validation among CaPSURE cohort patients (areas under the receiver operating characteristic curve, 0.77 [95% CI, 0.74-0.80] for prostatectomy; 0.87 [95% CI, 0.80-0.94] for external radiotherapy; and 0.90 [95% CI, 0.85-0.95] for brachytherapy). Conclusion: Stratification by pretreatment patient characteristics and treatment details enables prediction of erectile function 2 years after prostatectomy, external radiotherapy, or brachytherapy for prostate cancer. ©2011 American Medical Association. All rights reserved.

INTRODUCTION AND OBJECTIVES: Intestinal absorption of calcium is known to play a critical role in hypercalciuric nephrolithiasis, a urinary metabolic defect present in up to 50% of calcium stone formers. A few small studies have used radioactive calcium to examine the association between intestinal calcium absorption and hypercalciuria, but no study has evaluated the association with nephrolithiasis. The purpose of this study was to evaluate the relationship between patient reported history of nephrolithiasis, fractional absorption of calcium, and the effect on bone mineral density (BMD). METHODS: The Study of Osteoporotic Fractures (SOF) is a cohort of 9704 older women enrolled in 1986 and followed prospectively for more than 20 years. We performed secondary analyses of 7982 women who reported their kidney stone history and then presented in 1992, where 5452 patients (82%) underwent oral radioactive calcium assay (45Ca). We evaluated the relationship between nephrolithiasis, fractional calcium absorption and BMD. RESULTS: Women with a history of nephrolithiasis had higher BMIs (p 0.01), and were less likely to currently use calcium supplements (p 0.02). For each 10% increase in fractional calcium absorption, there was a 30% (CI 12–51%, p 0.001) increased risk of nephrolithiasis. This risk was more pronounced (51%, CI 3–120%, p 0.03) among women that never supplemented calcium. Dietary calcium was not associated with nephrolithiasis. Among women that never used calcium supplements, there was a trend towards lower BMD in stone formers (p 0.07–0.13) at all sites except the spine. Women who used calcium supplements had similar BMD, regardless of nephrolithiasis history. After adjusting for age, BMI, health status, calcium supplementation and thiazide diuretic use, each 10% increase in fractional calcium absorption was associated with a 38% (CI 16–66%, p 0.001) increased risk of having a history of nephrolithiasis. CONCLUSIONS: These data provide direct evidence that elevated intestinal calcium absorption is associated with an increased likelihood of historic nephrolithiasis. Women that supplemented calcium were less likely to have a history of nephrolithiasis, and had lower calcium absorption which may have prevented some of the decreased BMD seen in those with a history of nephrolithiasis. Although the mechanism remains to be established, these findings provide further evidence that calcium supplementation reduces the risk of nephrolithiasis; interventions to reduce intestinal calcium absorption may reduce the likelihood of nephrolithiasis.

INTRODUCTION AND OBJECTIVES: Androgen deprivation therapy (ADT) is commonly used for prostate cancer as primary, neoadjuvant/adjuvant, and secondary. Several recent reports have drawn attention to important skeletal, metabolic, cardiovascular, and cognitive side effects of ADT. The association between ADT use and cardiovascular mortality (CVM), in particular, remains controversial. We analyzed mortality outcomes in a large national registry to elucidate the impact of treatment selection on mortality. METHODS: 8,095 men in the CaPSURE registry diagnosed between 1998 and 2005 were analyzed. Treatment was categorized as local alone, primary ADT (PADT), local treatment with adjuvant / neoadjuvant therapy (local ADT), and watchful waiting/active surveillance (WW). A competing hazards survival analysis was performed, including events defined as prostate cancer-specific mortality (CSM), CVM, and other. The model was adjusted for age, cardiovascular disease, other comorbidities, prostate cancer risk characteristics, and duration of ADT. A propensity score analysis was undertaken to adjust further for imbalances in covariate among men receiving various treatments. RESULTS: 4889 men (63.7%) received local treatment, 1044 (13.6%) PADT, 1248 (16.3%) local ADT, and 497 (6.5%) WW. 1104 (14.6%) received secondary therapy, which was ADT in 837 cases and local treatment in 267 cases. Overall, 2553 (32.2%) of men in the dataset received ADT at some point during treatment. 1068 (13.2%) men died of any cause: 132 (1.6%) with CSM, 251 (3.1%) with CVM, 593 (7.4%) of other causes, and 86 (1.1%) of unknown causes. On riskand comorbidity-adjusted survival analysis, the hazard ratios (HRs) for CSM relative to local treatment was 4.4 (2.7–7.4) for PADT, 2.8 (1.7–4.7) for local ADT, and 2.5 (1.6–3.9) for WW. For CVM, the HRs relative to local treatment were 2.1 (1.4–3.0) for PADT, 1.8 (1.0–3.2) for local ADT, and 2.5 (1.6–3.9) for WW. For overall mortality, the HRs relative to local treatment were 1.6 (1.3–2.0) for PADT, 1.3 (1.0–1.5) for local ADT, and 1.7 (1.3–2.1) for WW. In the propensity-matched analysis, receipt of ADT was associated with overall mortality, but not CVM. CONCLUSIONS: Men treated with ADT have higher likelihood of CSM, CVM, and overall mortality than those treated with local therapy onlyebut so do those managed with WW. With respect to CVM, therefore, despite adjustment for disease risk and major comorbidities, unmeasured variablesewhich influence treatment decision-making but are not recorded databaseselikely confound analyses of the impact of ADT on cardiac endpoints.