Social Determinants of Health and the Availability of Cancer Clinical Trials in the United States.

This cohort study investigates whether county-level social determinants of health are associated with cancer clinical trial availability in the United States.

Unpacking overuse of androgen deprivation therapy for prostate cancer to inform de-implementation strategies.

BACKGROUND: Many men with prostate cancer will be exposed to androgen deprivation therapy (ADT). While evidence-based ADT use is common, ADT is also used in cases with no or limited evidence resulting in more harm than benefit, i.e., overuse. Since there are risks of ADT (e.g., diabetes, osteoporosis), it is important to understand the behaviors facilitating overuse to inform de-implementation strategies. For these reasons, we conducted a theory-informed survey study, including a discrete choice experiment (DCE), to better understand ADT overuse and provider preferences for mitigating overuse. METHODS: Our survey used the Action, Actor, Context, Target, Time (AACTT) framework, the Theoretical Domains Framework (TDF), the Capability, Opportunity, Motivation-Behavior (COM-B) Model, and a DCE to elicit provider de-implementation strategy preferences. We surveyed the Society of Government Service Urologists listserv in December 2020. We stratified respondents based on the likelihood of stopping overuse as ADT monotherapy for localized prostate cancer ("yes"/"probably yes," "probably no"/"no"), and characterized corresponding Likert scale responses to seven COM-B statements. We used multivariable regression to identify associations between stopping ADT overuse and COM-B responses. RESULTS: Our survey was completed by 84 respondents (13% response rate), with 27% indicating "probably no"/"no" to stopping ADT overuse. We found differences across respondents who said they would and would not stop ADT overuse in demographics and COM-B statements. Our model identified 2 COM-B domains (Opportunity-Social, Motivation-Reflective) significantly associated with a lower likelihood of stopping ADT overuse. Our DCE demonstrated in-person communication, multidisciplinary review, and medical record documentation may be effective in reducing ADT overuse. CONCLUSIONS: Our study used a behavioral theory-informed survey, including a DCE, to identify behaviors and context underpinning ADT overuse. Specifying behaviors supporting and gathering provider preferences in addressing ADT overuse requires a stepwise, stakeholder-engaged approach to support evidence-based cancer care. From this work, we are pursuing targeted improvement strategies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03579680.

National Long-term Survival Estimates After Radical Prostatectomy for Prostate Cancer.

OBJECTIVE: To examine survival and disease control outcomes, including metastasis-related survival outcomes, in a large contemporary cohort of patients undergoing radical prostatectomy for localized prostate cancer. METHODS: We conducted a retrospective study of men with localized prostate cancer treated with radical prostatectomy from 2005 to 2015 with follow-up through 2019 in the Veterans Health Administration. We defined biochemical recurrence (BCR) as a prostate-specific antigen ≥0.2 ng/mL. We used a validated natural language processing encoded dataset to identify incident metastatic prostate cancer. We estimated overall survival from time of surgery, time of BCR, and time of first metastasis using the Kaplan-Meier method. We then estimated time from surgery to BCR, BCR to metastatic disease, and prostate-cancer-specific survival from various time points using cumulative incidence considering competing risk of death. RESULTS: Of 21,992 men undergoing radical prostatectomy, we identified 5951 (27%) who developed BCR. Of men with BCR, 677 (11%) developed metastases. We estimated the 10-year cumulative incidence of BCR and metastases after BCR were 28% and 20%, respectively. Median overall survival after BCR was 14years, with 10-year survival of 70%. From the time of metastasis, median overall survival approached 7years, with 10-year overall survival of 34%. Prostate cancer-specific survival for the entire cohort at 10years was 94%. CONCLUSION: In this large contemporary national cohort, survival for men with biochemically recurrent prostate cancer is longer than historical cohorts. When counseling patients and designing clinical studies, these updated estimates may serve as more reliable reflections of current outcomes.

Outcomes after definitive radiation therapy for localized prostate cancer in a national health care delivery system.

PURPOSE: Accurate information regarding real-world outcomes after contemporary radiation therapy for localized prostate cancer is important for shared decision-making. Clinically relevant end points at 10 years among men treated within a national health care delivery system were examined. METHODS: National administrative, cancer registry, and electronic health record data were used for patients undergoing definitive radiation therapy with or without concurrent androgen deprivation therapy within the Veterans Health Administration from 2005 to 2015. National Death Index data were used through 2019 for overall and prostate cancer-specific survival and identified date of incident metastatic prostate cancer using a validated natural language processing algorithm. Metastasis-free, prostate cancer-specific, and overall survival using Kaplan-Meier methods were estimated. RESULTS: Among 41,735 men treated with definitive radiation therapy, the median age at diagnosis was 65 years and median follow-up was 8.7 years. Most had intermediate (42%) and high-risk (33%) disease, with 40% receiving androgen deprivation therapy as part of initial therapy. Unadjusted 10-year metastasis-free survival was 96%, 92%, and 80% for low-, intermediate-, and high-risk disease. Similarly, unadjusted 10-year prostate cancer-specific survival was 98%, 97%, and 90% for low-, intermediate-, and high-risk disease. The unadjusted overall survival was lower across increasing disease risk categories at 77%, 71%, and 62% for low-, intermediate-, and high-risk disease (p < .001). CONCLUSIONS: These data provide population-based 10-year benchmarks for clinically relevant end points, including metastasis-free survival, among patients with localized prostate cancer undergoing radiation therapy using contemporary techniques. The survival rates for high-risk disease in particular suggest that outcomes have recently improved.

Out-of-Pocket Costs for Prostate Cancer Medications Substantially Vary by Medicare Part D Plan: An Online Tool Presents an Opportunity to Mitigate Financial Toxicity.

INTRODUCTION: Patients with advanced prostate cancer are frequently prescribed enzalutamide or abiraterone, often requiring high out-of-pocket costs. Many of these patients are insured through Medicare and have an option to select among 54 different Part D drug plans. However, less than 30% of patients report comparing costs before selecting a plan. An online Part D plan navigator is publicly available and allows patients to compare estimated out-of-pocket prescriptions costs. In this study, we examine the variability of out-of-pocket costs based on available Part D drug plans for patients with prostate cancer and demonstrate how an online tool could save patients thousands of dollars. METHODS: We identified drug plans available for selection in 2023 using the online Medicare Part D Plan Finder. We sampled plan options for 12 different zip codes within the United States. A university-sponsored specialty cancer pharmacy and online mail-order pharmacy were included for comparison. We identified out-of-pocket costs for enzalutamide and abiraterone based on all Part D plans available for selection. RESULTS: On average, 24 Part D drug plans were available for each zip code. Median annual out-of-pocket costs were $11,626 for enzalutamide and $9,275 for abiraterone. The range of annual out-of-pocket costs were $9,854 to $13,061 for enzalutamide and $1,379 to $13,274 for abiraterone. Within certain zip codes, potential out-of-pocket cost savings were $2,512 for enzalutamide and $9,321 for abiraterone. Median difference of out-of-pocket cost between enzalutamide and abiraterone was $8,758. CONCLUSIONS: Out-of-pocket costs vary considerably across Part D drug plans. The Medicare Part D Plan Finder is a simple and effective tool to identify affordable drug plans. Guidance on plan selection could save patients thousands of dollars and help mitigate the financial toxicity of treatment. Comprehensive cancer centers could include plan navigators as an essential component of treatment.

Evolving a national clinical trials learning health system.

Clinical trials generate key evidence to inform decision making, and also benefit participants directly. However, clinical trials frequently fail, often struggle to enroll participants, and are expensive. Part of the problem with trial conduct may be the disconnected nature of clinical trials, preventing rapid data sharing, generation of insights and targeted improvement interventions, and identification of knowledge gaps. In other areas of healthcare, a learning health system (LHS) has been proposed as a model to facilitate continuous learning and improvement. We propose that an LHS approach could greatly benefit clinical trials, allowing for continuous improvements to trial conduct and efficiency. A robust trial data sharing system, continuous analysis of trial enrollment and other success metrics, and development of targeted trial improvement interventions are potentially key components of a Trials LHS reflecting the learning cycle and allowing for continuous trial improvement. Through the development and use of a Trials LHS, clinical trials could be treated as a system, producing benefits to patients, advancing care, and decreasing costs for stakeholders.

Exploring implementation outcomes in the clinical trial context: a qualitative study of physician trial stakeholders.

INTRODUCTION: Cancer clinical trials can be considered evidence-based interventions with substantial benefits, but suffer from poor implementation leading to low enrollment and frequent failure. Applying implementation science approaches such as outcomes frameworks to the trial context could aid in contextualizing and evaluating trial improvement strategies. However, the acceptability and appropriateness of these adapted outcomes to trial stakeholders are unclear. For these reasons, we interviewed cancer clinical trial physician stakeholders to explore how they perceive and address clinical trial implementation outcomes. METHODS: We purposively selected 15 cancer clinical trial physician stakeholders from our institution representing different specialties, trial roles, and trial sponsor types. We performed semi-structured interviews to explore a previous adaptation of Proctor's Implementation Outcomes Framework to the clinical trial context. Emergent themes from each outcome were developed. RESULTS: The implementation outcomes were well understood and applicable (i.e., appropriate and acceptable) to clinical trial stakeholders. We describe cancer clinical trial physician stakeholder understanding of these outcomes and current application of these concepts. Trial feasibility and implementation cost were felt to be most critical to trial design and implementation. Trial penetration was most difficult to measure, primarily due to eligible patient identification. In general, we found that formal methods for trial improvement and trial implementation evaluation were poorly developed. Cancer clinical trial physician stakeholders referred to some design and implementation techniques used to improve trials, but these were infrequently formally evaluated or theory-based. CONCLUSION: Implementation outcomes adapted to the trial context were acceptable and appropriate to cancer clinical trial physician stakeholders. Use of these outcomes could facilitate the evaluation and design of clinical trial improvement interventions. Additionally, these outcomes highlight potential areas for the development of new tools, for example informatics solutions, to improve the evaluation and implementation of clinical trials.

Differential adoption of castration-resistant prostate cancer treatment across facilities in a national healthcare system.

BACKGROUND: Over the past decade, abiraterone and enzalutamide have largely replaced ketoconazole as oral treatments for castration-resistant prostate cancer (CRPC). We investigated the differential adoption of abiraterone and enzalutamide across facilities in a national healthcare system to understand the impact a facility has on the receipt of these novel therapies. METHODS: Using data from the VA Corporate Data Warehouse, we identified a cohort of men with CRPC who received the most common first-line therapies: abiraterone, enzalutamide, docetaxel, or ketoconazole between 2010 and 2017. We described variability in the adoption of abiraterone and enzalutamide across facilities by time period (2010-2013 or 2014-2017). We categorized facilities depending on the timing of adoption of abiraterone and enzalutamide relative to other facilities and described facility characteristics associated with early and late adoption. RESULTS: We identified 4998 men treated with ketoconazole, docetaxel, abiraterone, or enzalutamide as first-line CRPC therapy between 2010 and 2017 at 125 national facilities. When limiting the cohort to oral therapies, most patients treated earlier in the study period (2010-2013) received ketoconazole. A dramatic shift was seen by the second half of the study period (2014-2017) with most men treated with first-line abiraterone (61%). Despite this shift and a new standard of care, some facilities persisted in the widespread use of ketoconazole in the later period, so-called late adopting facilities. After multivariable adjustment, patients who received treatment at a late adopting facility were more likely receiving care at a lower complexity, rural facility, with less urology and hematology/oncology workforce (all p < 0.01). CONCLUSION: Many facilities persisted in their use of ketoconazole as first-line CRPC therapy, even when other facilities had adopted the new standard of care abiraterone and enzalutamide. Further work is needed to identify the effect of this late adoption on outcomes important to patients.

Evaluation of Social Determinants of Health and Prostate Cancer Outcomes Among Black and White Patients: A Systematic Review and Meta-analysis.

Importance: As the field of medicine strives for equity in care, research showing the association of social determinants of health (SDOH) with poorer health care outcomes is needed to better inform quality improvement strategies. Objective: To evaluate the association of SDOH with prostate cancer-specific mortality (PCSM) and overall survival (OS) among Black and White patients with prostate cancer. Data Sources: A MEDLINE search was performed of prostate cancer comparative effectiveness research from January 1, 1960, to June 5, 2020. Study Selection: Two authors independently selected studies conducted among patients within the United States and performed comparative outcome analysis between Black and White patients. Studies were required to report time-to-event outcomes. A total of 251 studies were identified for review. Data Extraction and Synthesis: Three authors independently screened and extracted data. End point meta-analyses were performed using both fixed-effects and random-effects models. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed, and 2 authors independently reviewed all steps. All conflicts were resolved by consensus. Main Outcomes and Measures: The primary outcome was PCSM, and the secondary outcome was OS. With the US Department of Health and Human Services Healthy People 2030 initiative, an SDOH scoring system was incorporated to evaluate the association of SDOH with the predefined end points. The covariables included in the scoring system were age, comorbidities, insurance status, income status, extent of disease, geography, standardized treatment, and equitable and harmonized insurance benefits. The scoring system was discretized into 3 categories: high (≥10 points), intermediate (5-9 points), and low (<5 points). Results: The 47 studies identified comprised 1 019 908 patients (176 028 Black men and 843 880 White men; median age, 66.4 years [IQR, 64.8-69.0 years]). The median follow-up was 66.0 months (IQR, 41.5-91.4 months). Pooled estimates found no statistically significant difference in PCSM for Black patients compared with White patients (hazard ratio [HR], 1.08 [95% CI, 0.99-1.19]; P = .08); results were similar for OS (HR, 1.01 [95% CI, 0.95-1.07]; P = .68). There was a significant race-SDOH interaction for both PCSM (regression coefficient, -0.041 [95% CI, -0.059 to 0.023]; P < .001) and OS (meta-regression coefficient, -0.017 [95% CI, -0.033 to -0.002]; P = .03). In studies with minimal accounting for SDOH (<5-point score), Black patients had significantly higher PCSM compared with White patients (HR, 1.29; 95% CI, 1.17-1.41; P < .001). In studies with greater accounting for SDOH variables (≥10-point score), PCSM was significantly lower among Black patients compared with White patients (HR, 0.86; 95% CI, 0.77-0.96; P = .02). Conclusions and Relevance: The findings of this meta-analysis suggest that there is a significant interaction between race and SDOH with respect to PCSM and OS among men with prostate cancer. Incorporating SDOH variables into data collection and analyses are vital to developing strategies for achieving equity.

Holmium laser enucleation of the prostate in men on active surveillance for prostate cancer with refractory lower urinary tract symptoms secondary to enlarged prostates.

INTRODUCTION: The surgical treatment of men with lower urinary tract symptoms (LUTS) and significantly enlarged symptomatic prostates on active surveillance (AS) for low-risk prostate cancer (PCa) is not well defined. We report our single-institution initial experience with holmium laser enucleation of the prostate (HoLEP) for LUTS in men with low-risk PCa being managed with AS. MATERIALS AND METHODS: Men on AS who underwent HoLEP between 2013 and 2019 were identified. Data regarding preoperative cancer workup, prostate-specific antigen (PSA), perioperative outcomes, and voiding parameters were analyzed. Postoperative surveillance for PCa including PSA nadir, prostate magnetic resonance imaging, prostate biopsy (PBx), and PSA at last follow-up were evaluated. RESULTS: Twenty men met the inclusion criteria. Preoperative mean max flow 7.9 ml/s, median postvoid residual 101 cc, and mean transrectal ultrasound prostate size 99 cc. Patients had a median adjusted preoperative PSA of 8.5 (interquartile range [IQR]: 4.8-13.2) ng/ml. Mean resected tissue weight was 65.5 g with improved postoperative flow rate and significantly decreased residual. A total of 5/20 men had PCa in the specimen (all Gleason Grade Group 1). The median postoperative PSA nadir was 1.2 (IQR: 0.5-1.8) ng/ml at median of 5 months. At the last follow-up (median 18.5 months, IQR: 10.5-37.8), the median postoperative PSA was 1.4 (IQR: 0.63-2.48) ng/ml. Nine men underwent postoperative multiparametric magnetic resonance imaging (mpMRI) with the identification of a new prostate imaging reporting and data system 5 lesion in one patient who underwent negative fusion biopsy. Five men underwent post-HoLEP PBx with progression in two patients, who both successfully underwent radical prostatectomy. CONCLUSIONS: Men on AS for low-risk PCa can safely undergo HoLEP with significantly improved voiding parameters. Postoperative monitoring with PSA, mpMRI, and PBx can detect disease progression requiring definitive treatment. Further research is needed to optimize surveillance strategies and long-term cancer-specific outcomes.

Applying implementation frameworks to the clinical trial context.

BACKGROUND: Clinical trials advance science, benefit society, and provide optimal care to individuals with some conditions, such as cancer. However, clinical trials often fail to reach their endpoints, and low participant enrollment remains a critical problem with trial conduct. In these ways, clinical trials can be considered beneficial evidence-based practices suffering from poor implementation. Prior approaches to improving trials have had difficulties with reproducibility and limited impact, perhaps due to the lack of an underlying trial improvement framework. For these reasons, we propose adapting implementation science frameworks to the clinical trial context to improve the implementation of clinical trials. MAIN TEXT: We adapted an outcomes framework (Proctor's Implementation Outcomes Framework) and a determinants framework (the Consolidated Framework for Implementation Research) to the trial context. We linked these frameworks to ERIC-based improvement strategies and present an inferential process model for identifying and selecting trial improvement strategies based on the Implementation Research Logic Model. We describe example applications of the framework components to the trial context and present a worked example of our model applied to a trial with poor enrollment. We then consider the implications of this approach on improving existing trials, the design of future trials, and assessing trial improvement interventions. Additionally, we consider the use of implementation science in the clinical trial context, and how clinical trials can be "test cases" for implementation research. CONCLUSIONS: Clinical trials can be considered beneficial evidence-based interventions suffering from poor implementation. Adapting implementation science approaches to the clinical trial context can provide frameworks for contextual assessment, outcome measurement, targeted interventions, and a shared vocabulary for clinical trial improvement. Additionally, exploring implementation frameworks in the trial context can advance the science of implementation through both "test cases" and providing fertile ground for implementation intervention design and testing.