Effect of Health Service Area on Primary Care Physician Provision of Low-Value Cancer Screening.

BACKGROUND: Using a health systems approach to investigate low-value care (LVC) may provide insights into structural drivers of this pervasive problem. OBJECTIVE: To evaluate the influence of service area practice patterns on low-value mammography and prostate-specific antigen (PSA) testing. DESIGN: Retrospective study analyzing LVC rates between 2008 and 2018, leveraging physician relocation in 3-year intervals of matched physician and patient groups. SETTING: U.S. Medicare claims data. PARTICIPANTS: 8254 physicians and 56 467 patients aged 75 years or older. MEASUREMENTS: LVC rates for physicians staying in their original service area and those relocating to new areas. RESULTS: Physicians relocating from higher-LVC areas to low-LVC areas were more likely to provide lower rates of LVC. For mammography, physicians staying in high-LVC areas (LVC rate, 10.1% [95% CI, 8.8% to 12.2%]) or medium-LVC areas (LVC rate, 10.3% [CI, 9.0% to 12.4%]) provided LVC at a higher rate than physicians relocating from those areas to low-LVC areas (LVC rates, 6.0% [CI, 4.4% to 7.5%] [difference, -4.1 percentage points {CI, -6.7 to -2.3 percentage points}] and 5.9% [CI, 4.6% to 7.8%] [difference, -4.4 percentage points {CI, -6.7 to -2.4 percentage points}], respectively). For PSA testing, physicians staying in high- or moderate-LVC service areas provided LVC at a rate of 17.5% (CI, 14.9% to 20.7%) or 10.6% (CI, 9.6% to 13.2%), respectively, compared with those relocating from those areas to low-LVC areas (LVC rates, 9.9% [CI, 7.5% to 13.2%] [difference, -7.6 percentage points {CI, -10.9 to -3.8 percentage points}] and 6.2% [CI, 3.5% to 9.8%] [difference, -4.4 percentage points {CI, -7.6 to -2.2 percentage points}], respectively). Physicians relocating from lower- to higher-LVC service areas were not more likely to provide LVC at a higher rate. LIMITATION: Use of retrospective observational data, possible unmeasured confounding, and potential for relocating physicians to practice differently from those who stay. CONCLUSION: Physicians relocating to service areas with lower rates of LVC provided less LVC than physicians who stayed in areas with higher rates of LVC. Systemic structures may contribute to LVC. Understanding which factors are contributing may present opportunities for policy and interventions to broadly improve care. PRIMARY FUNDING SOURCE: National Cancer Institute of the National Institutes of Health.

Clinical Impact of Multiplex Molecular Diagnostic Testing in Children With Acute Gastroenteritis Presenting to an Emergency Department: A Multicenter Prospective Study.

BACKGROUND: Multiplex molecular diagnostic panels have greatly enhanced detection of gastrointestinal pathogens. However, data on the impact of these tests on clinical and patient-centered outcomes are limited. METHODS: We conducted a prospective, multicenter, stepped-wedge trial to determine the impact of multiplex molecular testing at 5 academic children's hospitals on children presenting to the emergency department with acute gastroenteritis. Caregivers were interviewed on enrollment and 7-10 days after enrollment to determine symptoms, risk factors, subsequent medical visits, and impact on family members. During the pre-intervention period, diagnostic testing was performed at the clinician's discretion . During the intervention period, multiplex molecular testing was performed on all children, with results available to clinicians. The primary outcome was return visits to a healthcare provider within 10 days of enrollment. RESULTS: Potential pathogens were identified by clinician-ordered tests in 19 of 571 (3.3%) in the pre-intervention period compared with 434 of 586 (74%) in the intervention period; clinically relevant pathogens were detected in 2.1% and 15%, respectively. In the multivariate model, the intervention was associated with a 21% reduction in the odds of any return visit (odds ratio, 0.79; 95% confidence interval, .70-.90) after adjusting for potential confounders. Appropriate treatment was prescribed in 11.3% compared with 19.6% during the intervention period (P = .22). CONCLUSIONS: Routine molecular multiplex testing for all children who presented to the ED with acute gastroenteritis detected more clinically relevant pathogens and led to a 21% decrease in return visits. Additional research is needed to define patients most likely to benefit from testing. Clinical Trials Registration. NCT02248285.

Comparing Bayesian hierarchical meta-regression methods and evaluating the influence of priors for evaluations of surrogate endpoints on heterogeneous collections of clinical trials.

BACKGROUND: Surrogate endpoints, such as those of interest in chronic kidney disease (CKD), are often evaluated using Bayesian meta-regression. Trials used for the analysis can evaluate a variety of interventions for different sub-classifications of disease, which can introduce two additional goals in the analysis. The first is to infer the quality of the surrogate within specific trial subgroups defined by disease or intervention classes. The second is to generate more targeted subgroup-specific predictions of treatment effects on the clinical endpoint. METHODS: Using real data from a collection of CKD trials and a simulation study, we contrasted surrogate endpoint evaluations under different hierarchical Bayesian approaches. Each approach we considered induces different assumptions regarding the relatedness (exchangeability) of trials within and between subgroups. These include partial-pooling approaches, which allow subgroup-specific meta-regressions and, yet, facilitate data adaptive information sharing across subgroups to potentially improve inferential precision. Because partial-pooling models come with additional parameters relative to a standard approach assuming one meta-regression for the entire set of studies, we performed analyses to understand the impact of the parameterization and priors with the overall goals of comparing precision in estimates of subgroup-specific meta-regression parameters and predictive performance. RESULTS: In the analyses considered, partial-pooling approaches to surrogate endpoint evaluation improved accuracy of estimation of subgroup-specific meta-regression parameters relative to fitting separate models within subgroups. A random rather than fixed effects approach led to reduced bias in estimation of meta-regression parameters and in prediction in subgroups where the surrogate was strong. Finally, we found that subgroup-specific meta-regression posteriors were robust to use of constrained priors under the partial-pooling approach, and that use of constrained priors could facilitate more precise prediction for clinical effects in trials of a subgroup not available for the initial surrogacy evaluation. CONCLUSION: Partial-pooling modeling strategies should be considered for surrogate endpoint evaluation on collections of heterogeneous studies. Fitting these models comes with additional complexity related to choosing priors. Constrained priors should be considered when using partial-pooling models when the goal is to predict the treatment effect on the clinical endpoint.

Change in Albuminuria and GFR Slope as Joint Surrogate End Points for Kidney Failure: Implications for Phase 2 Clinical Trials in CKD.

SIGNIFICANCE STATEMENT: Changes in albuminuria and GFR slope are individually used as surrogate end points in clinical trials of CKD progression, and studies have demonstrated that each is associated with treatment effects on clinical end points. In this study, the authors sought to develop a conceptual framework that combines both surrogate end points to better predict treatment effects on clinical end points in Phase 2 trials. The results demonstrate that information from the combined treatment effects on albuminuria and GFR slope improves the prediction of treatment effects on the clinical end point for Phase 2 trials with sample sizes between 100 and 200 patients and duration of follow-up ranging from 1 to 2 years. These findings may help inform design of clinical trials for interventions aimed at slowing CKD progression. BACKGROUND: Changes in log urinary albumin-to-creatinine ratio (UACR) and GFR slope are individually used as surrogate end points in clinical trials of CKD progression. Whether combining these surrogate end points might strengthen inferences about clinical benefit is unknown. METHODS: Using Bayesian meta-regressions across 41 randomized trials of CKD progression, we characterized the combined relationship between the treatment effects on the clinical end point (sustained doubling of serum creatinine, GFR <15 ml/min per 1.73 m 2 , or kidney failure) and treatment effects on UACR change and chronic GFR slope after 3 months. We applied the results to the design of Phase 2 trials on the basis of UACR change and chronic GFR slope in combination. RESULTS: Treatment effects on the clinical end point were strongly associated with the combination of treatment effects on UACR change and chronic slope. The posterior median meta-regression coefficients for treatment effects were -0.41 (95% Bayesian Credible Interval, -0.64 to -0.17) per 1 ml/min per 1.73 m 2 per year for the treatment effect on GFR slope and -0.06 (95% Bayesian Credible Interval, -0.90 to 0.77) for the treatment effect on UACR change. The predicted probability of clinical benefit when considering both surrogates was determined primarily by estimated treatment effects on UACR when sample size was small (approximately 60 patients per treatment arm) and follow-up brief (approximately 1 year), with the importance of GFR slope increasing for larger sample sizes and longer follow-up. CONCLUSIONS: In Phase 2 trials of CKD with sample sizes of 100-200 patients per arm and follow-up between 1 and 2 years, combining information from treatment effects on UACR change and GFR slope improved the prediction of treatment effects on clinical end points.

A Real-World Comparison of Regorafenib and Trifluridine/Tipiracil in Refractory Metastatic Colorectal Cancer in the United States.

BACKGROUND: Trifluridine/Tipiracil (TAS-102) and regorafenib are FDA-approved in the United States for treatment of refractory metastatic colorectal cancer (mCRC). FDA approvals of these agents were based on modest improvements in overall survival (OS) compared with best supportive care + placebo in the RECOURSE and CORRECT trials, respectively. This study compared real-world clinical outcomes with the use of these agents. METHODS: A nationwide deidentified electronic health record-derived database was reviewed for patients diagnosed with mCRC between 2015 and 2020. Patients who received at least 2 lines of standard systemic therapy followed by treatment with either TAS-102 or regorafenib were included for analysis. Kaplan-Meier and propensity score-weighted proportional hazards models were used to compare survival outcomes between groups. RESULTS: The records of 22,078 patients with mCRC were reviewed. Of these, 1,937 patients received at least 2 lines of standard therapy followed by regorafenib and/or TAS-102. Median OS for the TAS-102 alone or prior regorafenib group (n=1,016) was 6.66 months (95% CI, 6.16-7.18 months) compared with 6.30 months (95% CI, 5.80-6.79 months) for regorafenib alone or prior to TAS-102 (n=921; P=.36). A propensity score-weighted analysis controlling for potential confounders did not demonstrate a significant difference in survival between groups (hazard ratio, 0.99; 95% CI, 0.90-1.09; P=.82). A subgroup analysis did not identify any significant differences in outcomes regarding age, performance status, tumor sidedness, microsatellite instability status, or RAS/RAF status. CONCLUSIONS: This analysis of real-world data found that OS was similar for patients with mCRC who were treated with TAS-102 compared with regorafenib. Median OS with both agents in a real-world setting was similar to that shown in the clinical trials that led to their approvals. A prospective trial comparing TAS-102 and regorafenib would unlikely change current management of patients with refractory mCRC.

Handling missing within-study correlations in the evaluation of surrogate endpoints.

Rigorous evaluation of surrogate endpoints is performed in a trial-level analysis in which the strength of the association between treatment effects on the clinical and surrogate endpoints is quantified across a collection of previously conducted trials. To reduce bias in measures of the performance of the surrogate, the statistical model must account for the sampling error in each trial's estimated treatment effects and their potential correlation. Unfortunately, these within-study correlations can be difficult to obtain, especially for meta-analysis of published trial results where individual patient data is not available. As such, these terms are frequently partially or completely missing in the analysis. We show that improper handling of these missing terms can meaningfully alter the perceived quality of the surrogate and we introduce novel strategies to handle the missingness.

Impact of academic medical center access on outcomes in multiple myeloma.

Treatment at academic cancer centers (ACs) is associated with improved survival across hematologic malignancies, though the benefit in multiple myeloma (MM) has not been examined. This study aims to evaluate survival outcomes at Commission on Cancer accredited ACs compared to non-academic centers (NACs) for patients receiving MM-directed therapy. The National Cancer Database (NCDB) was used to identify demographics and overall survival (OS) of MM patients diagnosed from 2004 to 2017 and to compare outcomes by facility type. Survival analysis was repeated in a propensity score matched cohort, with NACs matched 1:1 to ACs by age, race, comorbidity score, insurance, year of diagnosis, distance traveled, and income. Of 163 375 MM patients, 44.5% were treated at ACs. Patients at ACs were more likely to receive MM-directed therapy compared to NACs (81% vs. 73%, p < .001). For patients receiving treatment, median OS at ACs was 71.3 months versus 41.2 months at NACs (p < .001). When adjusted for baseline demographics, patients treated at ACs had reduced mortality; hazard ratio (HR) 0.79 (95% CI 0.78-0.81, p < .001). The propensity score matched cohort maintained this survival benefit with a median OS of 59.9 months at ACs versus 37.0 months at NACs (p < .001), HR of 0.66 (95% CI 0.64-0.67, p < .001). ACs treated younger patients with fewer comorbidities and were more likely to treat racial minorities and patients with Medicaid or private insurance, and the uninsured. In this analysis, MM patients treated at ACs have significantly improved survival. While potentially related to access to specialized care, socioeconomic factors that drive facility selection may also contribute.

Increasing Skin Cancer Prevention in Young Adults: the Cumulative Impact of Personalized UV Photography and MC1R Genetic Testing.

Skin cancer has become increasingly common among young adults; however, this population does not consistently adhere to recommended methods for preventing the disease. Interventions in college settings have relied on appearance-focused appeals and have not been able to examine the cumulative effect of multiple behavior change and skin cancer risk communication strategies. The goal of the current study was to examine the unique and combined impacts of personalized ultraviolet (UV) radiation photographs, genetic testing for skin cancer risk, and general skin cancer prevention education. Participants were randomly assigned to one of four conditions: (1) skin cancer prevention education, (2) education + UV photo, (3) education + genetic testing, and (4) education + UV photo + genetic testing. Self-reported sun protection, tanning, and sunburn were assessed at baseline, immediately post-intervention, and 1 month post-intervention. The findings indicated benefits of the interventions to skin cancer prevention behaviors in the overall sample; however, the combined (UV photo + genetic testing) intervention had the most consistent positive effects on behaviors. Intervention effects were distinct across seasons. These results suggest that interventions containing multiple skin cancer risk communication strategies hold promise in benefitting health-promoting behavior changes in an at-risk, young adult population.Trial Registration Number: NCT03979872; Registered 6/5/2019.

Cardiovascular disease risk in long-term breast cancer survivors: A population-based cohort study.

BACKGROUND: Breast cancer survival is increasing, making late effects such as cardiovascular disease (CVD) more relevant. The purpose of this study was to evaluate incident CVD following breast cancer diagnosis among long-term survivors and to investigate possible risk factors for CVD. METHODS: A population-based cohort of 6641 breast cancer survivors diagnosed between 1997 and 2009 who survived at least 10 years was identified within the Utah Cancer Registry. In addition, 36,612 cancer-free women from the general population, matched by birth year and state, were identified within the Utah Population Database. Cox proportional hazards models were used to calculate CVD hazard ratios (HRs) for >10 to 15 and >15 years. RESULTS: Long-term breast cancer survivors had an increased risk of newly diagnosed diseases of the circulatory system (HR, 1.32; 99% confidence interval [CI], 1.00-1.75) from 10 to 15 years following cancer diagnosis compared with the general population. No increased CVD risks were observed after 15 years. Breast cancer survivors with Charlson Comorbidity Index score ≥2 had a significantly higher risk of diseases of the circulatory system (HR, 2.64; 95% CI, 1.08-6.45) beyond 10 years following breast cancer diagnosis. Similarly, older age, obesity, lower education, and family history of CVD and breast cancer were risk factors for heart and circulatory system diseases among long-term breast cancer survivors. CONCLUSION: Risk of CVD compared to the general population was moderate among this cohort of long-term breast cancer survivors between 10 to 15 years since cancer diagnosis. Awareness of CVD risks is important for breast cancer survivors.

Treatment outcomes in recurrent versus de novo metastatic pancreatic adenocarcinoma: a real world study.

BACKGROUND: A majority of patients undergoing curative intent surgery for pancreatic ductal adenocarcinoma (PDAC) will unfortunately develop recurrent disease. Treatment outcomes for patients with metastatic disease remain suboptimal. In this study, we evaluated clinical outcomes of patients with recurrent PDAC who received systemic therapy and compared outcomes to patients with de novo metastatic PDAC undergoing systemic therapy. METHODS: Patients diagnosed with metastatic PDAC between 2014 and 2019 were included using a real-world database. Patients were characterized as either de novo or recurrent based on the date of metastatic diagnosis and history of surgical resection. Overall survival (OS) was summarized within groups via Kaplan-Meier survival estimates and compared using Cox proportional hazards models. RESULTS: We included 5170 patients with metastatic PDAC, of which 1101 (21.3%) were classified as having recurrent disease. Median OS for the recurrent group was significantly greater at 10.8 m (95% CI 9.9-11.7) than in the de novo group at 7.3 m (95% CI 7.0-7.7, p < 0.001). We did not observe a significant difference in OS based on when patients recurred after surgery: 10.0 m (95% CI 8.7-11) within six months of surgery versus 11.6 m (95% CI 10-12, p = 0.256) greater than six months from surgery. CONCLUSIONS: These data support the inclusion of patients with recurrent PDAC in clinical trials for advanced disease, including those who develop recurrent disease within six months of surgery. Due to observed differences in survival, randomization should be stratified by disease presentation (recurrent vs de novo).

Real-World Outcomes of Patients With BRAF-Mutated Metastatic Colorectal Cancer Treated in the United States.

BACKGROUND: BRAF mutations portend a poor prognosis in metastatic colorectal cancer (mCRC). Whether these patients may benefit from more aggressive frontline chemotherapy with a triplet regimen such as FOLFOXIRI remains unclear. We used real-world data from a cohort of patients in the United States to assess the BRAF testing rate, determine the prevalence of FOLFOXIRI use, and compare survival outcomes in mCRC, stratified by BRAF mutation status and first-line therapy. METHODS: A nationwide electronic health record-derived deidentified database was reviewed for patients diagnosed with mCRC between 2013 and 2018. Those with documented BRAF mutation testing who received standard first-line therapy were included. Kaplan-Meier estimates with corresponding log-rank tests and Cox proportional hazards modeling compared survival outcomes stratified by BRAF status and first-line therapy. RESULTS: Of 4,457 included patients, 3,991 (89.5%) had BRAF wild-type (BRAFwt) and 466 (10.5%) had BRAF-mutated (BRAFmt) mCRC. Median overall survival (OS) was 15.4 months in the BRAFmt group versus 28.1 months in the BRAFwt group (hazard ratio [HR], 0.48; 95% CI, 0.41-0.56; P<.001). Only 3% of patients with BRAF mutations received first-line FOLFOXIRI ± bevacizumab, with a median OS of 13.8 months compared with 15.5 months in those treated with doublet chemotherapy ± bevacizumab (P=.38). In patients with BRAF mutations, propensity-weighted analysis did not detect a significant improvement in OS with FOLFIRI + bevacizumab (HR, 0.90; 95% CI, 0.58-1.39; P=.63) or FOLFOX/CAPEOX + bevacizumab (HR, 0.81; 95% CI, 0.52-1.26; P=.35) versus doublet chemotherapy alone. In 2018, only 56% of patients diagnosed with mCRC had documented BRAF testing at any time. CONCLUSIONS: This real-world data analysis confirms the negative prognostic impact of BRAF mutations in mCRC and suggests that FOLFOXIRI has not been widely adopted in the United States. The proportion of patients with documented BRAF testing in this real-world population was low at 56%. We were unable to show any significant difference in OS of patients with BRAFmt mCRC based on the first-line therapy received.

Treatment Trends and Clinical Outcomes of Left-Sided RAS/RAF Wild-Type Metastatic Colorectal Cancer in the United States.

BACKGROUND: Post hoc analysis of the CALGB/SWOG 80405 trial suggests that anti-EGFR therapy may be superior to bevacizumab when added to first-line chemotherapy in patients with metastatic colorectal cancer (mCRC) who have left-sided primary tumors. We evaluated trends in use of anti-EGFR agents in patients with left-sided RAS/RAF wild-type (WT) mCRC and compared clinical outcomes among the most commonly used treatment strategies. METHODS: A nationwide electronic health record (EHR)-derived deidentified database was reviewed for patients with left-sided RAS/RAF WT mCRC. Treatment trends over time were assessed by fitting a linear model to the percentage of patients receiving anti-EGFR therapy. A propensity score weighted Cox model was used to compare overall survival (OS) stratified by first-line targeted therapy received. RESULTS: A total of 1,607 patients with left-sided RAS/RAF WT mCRC received standard first-line chemotherapy. Of these, 965 (60%) received bevacizumab and 186 (12%) received an anti-EGFR agent. The percentage of patients receiving an anti-EGFR increased from 9% in 2013 to 16% in 2018. Median OS for patients treated with chemotherapy alone was 27.3 months (95% CI, 24.8-32.3), 27.5 months with bevacizumab (95% CI, 25.8-28.9; hazard ratio [HR], 0.88; P=.33), and 42.9 months with an anti-EGFR agent (95% CI, 36.0 to not reached; HR, 0.52; P=.005). CONCLUSIONS: This analysis suggests that chemotherapy with bevacizumab remained the most widely used first-line treatment strategy for patients with left-sided RAS/RAF WT mCRC in the United States in 2018. Despite this preference, treatment with an anti-EGFR agent was associated with improved OS.

Initial Derivation of a Predictive Model for Left Ventricular Longitudinal Strain (LS) in Early Sepsis.

Septic shock is a common deadly disease often associated with cardiovascular dysfunction. Left ventricular longitudinal strain (LV LS) has been proposed as a sensitive marker to measure cardiovascular function; however, it is not available universally in standard clinical echocardiograms. We sought to derive a predictive model for LV LS, using machine learning techniques with the hope that we may uncover surrogates for LV LS. We found that left ventricular ejection fraction, tricuspid annular plane systolic excursion, sepsis source, height, mitral valve Tei index, LV systolic dimension, aortic valve ejection time, and peak acceleration rate were all predictive of LV LS in this initial exploratory model. Future modeling work may uncover combinations of these variables which may be powerful surrogates for LV LS and cardiovascular function.

Impact of Implementation of the Core Elements of Outpatient Antibiotic Stewardship Within Veterans Health Administration Emergency Departments and Primary Care Clinics on Antibiotic Prescribing and Patient Outcomes.

BACKGROUND: The Core Elements of Outpatient Antibiotic Stewardship provide a framework to improve antibiotic use. We report the impact of core elements implementation within Veterans Health Administration sites. METHODS: In this quasiexperimental controlled study, effects of an intervention targeting antibiotic prescription for uncomplicated acute respiratory tract infections (ARIs) were assessed. Outcomes included per-visit antibiotic prescribing, treatment appropriateness, ARI revisits, hospitalization, and ARI diagnostic changes over a 3-year pre-implementation period and 1-year post-implementation period. Logistic regression adjusted for covariates (odds ratio [OR], 95% confidence interval [CI]) and a difference-in-differences analysis compared outcomes between intervention and control sites. RESULTS: From 2014-2019, there were 16 712 and 51 275 patient visits within 10 intervention and 40 control sites, respectively. Antibiotic prescribing rates pre- and post-implementation within intervention sites were 59.7% and 41.5%, compared to 73.5% and 67.2% within control sites, respectively (difference-in-differences, P < .001). Intervention site pre- and post-implementation OR to receive appropriate therapy increased (OR, 1.67; 95% CI, 1.31-2.14), which remained unchanged within control sites (OR,1.04; 95% CI, .91-1.19). ARI-related return visits post-implementation (-1.3% vs -2.0%; difference-in-differences P = .76) were not different, but all-cause hospitalization was lower within intervention sites (-0.5% vs -0.2%; difference-in-differences P = .02). The OR to diagnose non-specific ARI compared with non-ARI diagnoses increased post-implementation forintervention (OR, 1.27; 95% CI, 1.21 -1.34) but not control (OR, 0.97; 95% CI, .94-1.01) sites. CONCLUSIONS: Implementation of the core elements was associated with reduced antibiotic prescribing for RIs and a reduction in hospitalizations. Diagnostic coding changes were observed.

Decision fatigue in low-value prostate cancer screening.

BACKGROUND: Low-value prostate-specific antigen (PSA) testing is common yet contributes substantial waste and downstream patient harm. Decision fatigue may represent an actionable target to reduce low-value urologic care. The objective of this study was to determine whether low-value PSA testing patterns by outpatient clinicians are consistent with decision fatigue. METHODS: Outpatient appointments for adult men without prostate cancer were identified at a large academic health system from 2011 through 2018. The authors assessed the association of appointment time with the likelihood of PSA testing, stratified by patient age and appropriateness of testing based on clinical guidelines. Appointments included those scheduled between 8:00 am and 4:59 pm, with noon omitted. Urologists were examined separately from other clinicians. RESULTS: In 1,581,826 outpatient appointments identified, the median patient age was 54 years (interquartile range, 37-66 years), 1,256,152 participants (79.4%) were White, and 133,693 (8.5%) had family history of prostate cancer. PSA testing would have been appropriate in 36.8% of appointments. Clinicians ordered testing in 3.6% of appropriate appointments and in 1.8% of low-value appointments. Appropriate testing was most likely at 8:00 am (reference group). PSA testing declined through 11:00 am (odds ratio [OR], 0.57; 95% CI, 0.50-0.64) and remained depressed through 4:00 pm (P < .001). Low-value testing was overall less likely (P < .001) and followed a similar trend, declining steadily from 8:00 am (OR, 0.48; 95% CI, 0.42-0.56) through 4:00 pm (P < .001; OR, 0.23; 95% CI, 0.18-0.30). Testing patterns in urologists were noticeably different. CONCLUSIONS: Among most clinicians, outpatient PSA testing behaviors appear to be consistent with decision fatigue. These findings establish decision fatigue as a promising, actionable target for reducing wasteful and low-value practices in routine urologic care. LAY SUMMARY: Decision fatigue causes poorer choices to be made with repetitive decision making. This study used medical records to investigate whether decision fatigue influenced clinicians' likelihood of ordering a low-value screening test (prostate-specific antigen [PSA]) for prostate cancer. In more than 1.5 million outpatient appointments by adult men without prostate cancer, the chances of both appropriate and low-value PSA testing declined as the clinic day progressed, with a larger decline for appropriate testing. Testing patterns in urologists were different from those reported by other clinicians. The authors conclude that outpatient PSA testing behaviors appear to be consistent with decision fatigue among most clinicians, and interventions may reduce wasteful testing and downstream patient harms.

Radium-223 plus Enzalutamide Versus Enzalutamide in Metastatic Castration-Refractory Prostate Cancer: Final Safety and Efficacy Results.

LESSONS LEARNED: Long-term safety of radium-223 with enzalutamide was confirmed in this clinical trial. PSA-PFS2 was prolonged with the combination compared with enzalutamide alone. BACKGROUND: Previously, we showed the combination of radium-223 and enzalutamide to be safe and associated with improved efficacy based on a concomitant decline in serum bone metabolism markers compared with enzalutamide alone in a phase II trial of men with metastatic castration-resistant prostate cancer (mCRPC) [1]. METHODS: Secondary endpoints were not included in our initial report, and we include them herein, after a median follow-up of 22 months. These objectives included long-term safety, prostate-specific antigen (PSA)-progression-free survival (PFS), and radiographic progression-free survival; PSA-PFS2 (time from start of protocol therapy to PSA progression on subsequent therapy); time to next therapy (TTNT); and overall survival (OS). Survival analysis and log-rank tests were performed using the R statistical package v.4.0.2 (https://www.r-project.org). Statistical significance was defined as p < .05. RESULTS: Of 47 patients (median age, 68 years), 35 received the combination and 12 enzalutamide alone. After a median follow-up of 22 months, final safety results did not show any increase in fractures or other adverse events in the combination arm. PSA-PFS2 was significantly improved, and other efficacy parameters were numerically improved in the combination over the enzalutamide arm. CONCLUSION: The combination of enzalutamide and radium-223 was found to be safe and associated with promising efficacy in men with mCRPC. These hypothesis-generating results portend well for the ongoing phase III PEACE III trial in this setting.

Endocrine therapy and radiotherapy use among older women with hormone receptor-positive, clinically node-negative breast cancer.

PURPOSE: To examine patterns of radiotherapy (RT) and endocrine therapy (ET) use, associations between RT omission and ET adherence, and associations among ET and RT use and disease recurrence in older women with early-stage, estrogen receptor-positive breast cancer. METHODS: Women age 65 and older diagnosed with hormone receptor-positive, clinically node-negative breast cancer between 2005 and 2018 and who did not undergo mastectomy were included. Multinomial logistic regression was used to examine the trends in practice patterns over time and by age. Kaplan-Meier estimates were used to estimate the probability of ET discontinuation. Cox proportional hazards models were constructed to assess associations between recurrence and ET/RT. RESULTS: Of the 484 enrolled patients, 47.9% patients underwent RT and initiated ET, 27.4% received ET alone, 10.2% received RT alone, and 13.8% patients received neither. Older patients had a higher probability of receiving ET alone or neither ET nor RT (both p < 0.001). The probability of initiating ET was greater among patients who underwent RT than those who omitted RT (p < 0.001). Regardless of RT status (RT or no RT), initiation and continuation of ET may be associated with reduced risk of recurrence. CONCLUSION: Patients who opt for no adjuvant therapy, or who do not tolerate ET, are at increased risk of disease recurrence if they omit RT. Clinicians should consider the likelihood a patient will adhere to ET prior to recommending omission of RT.

Comparative Effectiveness of Immune Checkpoint Inhibitors in Patients with Platinum Refractory Advanced Urothelial Carcinoma.

PURPOSE: Five programmed cell death protein 1 or its ligand (L1) inhibitors are approved for treatment of platinum refractory, locally advanced/unresectable or metastatic urothelial carcinoma. However, their comparative effectiveness is unknown. We compared time to initiation of third therapy or death, and overall survival with different programmed cell death protein 1/L1 inhibitors in patients with platinum refractory metastatic urothelial carcinoma. MATERIALS AND METHODS: Patient-level data were extracted from a real-world de-identified database. Comparative effectiveness was inferred via Cox proportional hazards model, weighted by matching weights. Each patient's propensity for each treatment was modeled via random forest, based on potential drivers of treatment selection. A propensity score for each therapy was used to calculate a matching weight, targeting the same estimand as 1:1 matching of treatment groups with balance among potential confounders. Eligibility criteria included diagnosis of metastatic urothelial carcinoma, receipt of first line treatment with a platinum based chemotherapy, followed by initiation of single agent programmed cell death protein 1/L1 inhibitor after disease progression from August 1, 2016 through May 1, 2019. RESULTS: Overall, 609 patients were eligible for analysis. Median time to initiation of third therapy or death with atezolizumab, nivolumab and pembrolizumab was 4.2, 5.3 and 4.5 months, respectively, and median overall survival was 6.4, 8.0 and 8.3 months, respectively. Matching weighted analyses did not show strong evidence of differences among programmed cell death protein 1/L1 inhibitors in terms of time to initiation of third therapy or death and overall survival. CONCLUSIONS: In this large real-world cohort, effectiveness in terms of time to initiation of third therapy or death and overall survival with programmed cell death protein 1/L1 inhibitors in patients with platinum refractory locally advanced/unresectable or metastatic urothelial carcinoma was similar.

Understanding the Prevalence of Prediabetes and Diabetes in Patients With Cancer in Clinical Practice: A Real-World Cohort Study.

BACKGROUND: This study aimed to understand the prevalence of prediabetes (preDM) and diabetes mellitus (DM) in patients with cancer overall and by tumor site, cancer treatment, and time point in the cancer continuum. METHODS: This cohort study was conducted at Huntsman Cancer Institute at the University of Utah. Patients with a first primary invasive cancer enrolled in the Total Cancer Care protocol between July 2016 and July 2018 were eligible. Prevalence of preDM and DM was based on ICD code, laboratory tests for hemoglobin A1c, fasting plasma glucose, nonfasting blood glucose, or insulin prescription. RESULTS: The final cohort comprised 3,512 patients with cancer, with a mean age of 57.8 years at cancer diagnosis. Of all patients, 49.1% (n=1,724) were female. At cancer diagnosis, the prevalence of preDM and DM was 6.0% (95% CI, 5.3%-6.8%) and 12.2% (95% CI, 11.2%-13.3%), respectively. One year after diagnosis the prevalence was 16.6% (95% CI, 15.4%-17.9%) and 25.0% (95% CI, 23.6%-26.4%), respectively. At the end of the observation period, the prevalence of preDM and DM was 21.2% (95% CI, 19.9%-22.6%) and 32.6% (95% CI, 31.1%-34.2%), respectively. Patients with myeloma (39.2%; 95% CI, 32.6%-46.2%) had the highest prevalence of preDM, and those with pancreatic cancer had the highest prevalence of DM (65.1%; 95% CI, 57.0%-72.3%). Patients who underwent chemotherapy, radiotherapy, or immunotherapy had a higher prevalence of preDM and DM compared with those who did not undergo these therapies. CONCLUSIONS: Every second patient with cancer experiences preDM or DM. It is essential to foster interprofessional collaboration and to develop evidence-based practice guidelines. A better understanding of the impact of cancer treatment on the development of preDM and DM remains critical.

Higher Ultraviolet Radiation Exposure Among Rural-Dwelling Versus Urban-Dwelling Adults and Children: Implications for Skin Cancer Prevention.

Ultraviolet radiation (UVR) exposure is a primary risk factor for the development of melanoma. However, adults and adolescents often do not engage in preventive behaviors to reduce UVR exposure. Rural residents may be at higher risk for melanoma due to lower use of sun protection strategies, which increases their overall UVR exposure compared to those who live in urban areas. The purpose of this study was to evaluate differences in UVR exposure between rural and urban residents in a geographic area with high incidence of melanoma. Children (aged 8-17 years) and adults (≥ 18 years) from rural and urban areas of Utah were asked to wear a UVR monitoring device for 14 days. The sample included 97 children and 97 adults. Data was collected from June to October 2018. Non-parametric Mann-Whitney tests and quantile regression were used to compare UVR exposure levels between urban and rural participants, separately for adults and children. For adults, rural residence significantly increased total UVR dose ( ß: 24.6; 95% CI 3.75, 42.74) and the UVR dose during peak UVR hours among participants with the highest UVR doses (ß: 16.3; 95% CI 17.4, 24.63). Rural children exhibited significantly higher UVR doses for peak UVR hours for the entire study period (ß: 4.14; 95% CI 0.83, 7.46) and on weekdays (ß: 0.39; 95% CI 0.05, 0.73). The findings from this study indicate that rural residents may receive higher levels of UVR exposure than urban residents, and that prevention efforts could be tailored to address these geographical differences.