Faculty Bibliography

PURPOSE/OBJECTIVE:The following is a summary of discussion at a U.S. Food and Drug Administration (FDA) public workshop reviewing potential trial designs and endpoints for development of therapies to treat localized prostate cancer. MATERIALS AND METHODS/METHODS:The workshop focused on the challenge that drug and device development for the treatment of localized prostate cancer has been limited by the large trial sizes and lengthy timelines required to demonstrate an improvement in overall survival or metastasis-free survival and by the lack of agreed-upon alternative endpoints. Additionally, evolving treatment paradigms in the management of localized prostate cancer include the widespread use of active surveillance for patients with low- and some intermediate-risk prostate cancer and the availability of advances in imaging and genomics. RESULTS:The workshop addressed issues related to trial design in this setting and discussed several potential novel endpoints such as delay of morbidity due to radiation or prostatectomy, and pathologic endpoints such as Gleason Grade Group upgrade. CONCLUSIONS:The workshop provided an open forum for multi-stakeholder engagement to advance the development of effective treatment options in localized prostate cancer. Full workshop proceedings are available online at https://www.fda.gov/NewsEvents/MeetingsConferencesWorkshops/ucm608328.htm.

Prostate cancer screening reduces advanced disease and prostate cancer death but is controversial due to downstream harms including unnecessary biopsies and overtreatment. In 2012 the United States Preventive Services Task Force (USPSTF) recommended against screening men for prostate cancer, a practice common since the early 1990's. This dramatic policy change was opposed by many physicians and patient groups. Our group reported on the Twitter response within 24 hours of these guidelines, showing a missed opportunity for greater advocacy since the majority of tweets did not express an opinion.

PURPOSE/OBJECTIVE:The aim of this study was to determine rates of and possible reasons for guideline-discordant ordering of CT pulmonary angiography for the evaluation of suspected pulmonary embolism (PE) in the emergency department. METHODS:A retrospective review was performed of 212 consecutive encounters (January 6, 2016, to February 25, 2016) with 208 unique patients in the emergency department that resulted in CT pulmonary angiography orders. For each encounter, the revised Geneva score and two versions of the Wells criteria were calculated. Each encounter was then classified using a two-tiered risk stratification method (PE unlikely versus PE likely). Finally, the rate of and possible explanations for guideline-discordant ordering were assessed via in-depth chart review. RESULTS:The frequency of guideline-discordant studies ranged from 53 (25%) to 79 (37%), depending on the scoring system used; 46 (22%) of which were guideline discordant under all three scoring systems. Of these, 18 (39%) had at least one patient-specific factor associated with increased risk for PE but not included in the risk stratification scores (eg, travel, thrombophilia). CONCLUSIONS:Many of the guideline-discordant orders were placed for patients who presented with evidence-based risk factors for PE that are not included in the risk stratification scores. Therefore, guideline-discordant ordering may indicate that in the presence of these factors, the assessment of risk made by current scoring systems may not align with clinical suspicion.

OBJECTIVES/OBJECTIVE:To characterize bone scan use, and potential overuse, after radical prostatectomy using a large, national integrated delivery system. Overuse of imaging is well documented in the setting of newly diagnosed prostate cancer, but whether overuse persists following radical prostatectomy remains unknown. MATERIALS AND METHODS/METHODS:We identified 12,269 prostate cancer patients treated with radical prostatectomy between 2005-2008 using the Veterans Administration Central Cancer Registry. We used administrative and laboratory data to examine rates of bone scan use, including preceding PSA levels, and receipt of adjuvant or salvage therapy. We then performed multivariable logistic regression to identify factors associated with post-prostatectomy bone scan use. RESULTS:At a median follow up of 6.8 years, one in five men (22%) underwent a postoperative bone scan at a median PSA of 0.2 ng/mL. Half of bone scans (48%) were obtained in men who did not receive further treatment with androgen deprivation (ADT) or radiation therapy. After adjustment, post-prostatectomy bone scan was associated with a prior bone scan (adjusted Odds Ratio (aOR) 1.55, 95% Confidence Interval (CI) 1.32 - 1.84), positive surgical margin (aOR 1.68, 95% CI 1.40 - 2.01), preoperative PSA (aOR 1.02, 95% CI 1.01 - 1.03) as well as Hispanic ethnicity, black race, and increasing D'Amico risk category, but not with age or comorbidity. CONCLUSION/CONCLUSIONS:We found a substantial rate of bone scan utilization after radical prostatectomy. The majority was performed for PSA <1ng/mL where the likelihood of a positive test is low. More judicious use of imaging appears warranted in the post-prostatectomy setting.

BACKGROUND/AIM/OBJECTIVE:National guidelines offer little guidance on the use of PSA progression (PSA increase as defined below) as a clinical endpoint in metastatic castration-resistant prostate cancer (mCRPC). The aim of the study was to examine treatment patterns/outcomes with abiraterone (abi)/enzalutamide (enza) throughout PSA progression and near the end of life (EOL). PATIENTS AND METHODS/METHODS:Cases of mCRPC treated with abi or enza from the New York Veterans Affairs (VA) from 6/2011-8/2017 were reviewed. Regression analyses were conducted to identify factors associated with continuation of abi/enza treatment up to the EOL, and survival. RESULTS:Of 184 patients, 72 received abi alone, 28 received enza alone, and 84 received both. Treatment was changed for PSA progression alone in 39.1% (abi) and 25.7% (enza) of patients. A total of 37 patients (20%) received abi/enza within 1 month before death, 30% of whom were receiving hospice services. Older patients and black patients were less likely to receive abi/enza up to the EOL. CONCLUSION/CONCLUSIONS:Abi/enza are frequently discontinued for PSA progression alone and continued at EOL. The clinical benefit of these practices warrants additional study.

INTRODUCTION/BACKGROUND:Disparities in survival for bladder and kidney cancer among the genders and patients with varying insurance coverage have been identified. Microhematuria (MH), a potential early clinical sign of genitourinary malignancy, should prompt a standardized diagnostic evaluation. However, many patients do not complete a full evaluation and may be at risk of a missed or delayed identification of genitourinary pathology. METHODS:Patients 35 and older with a new diagnosis of MH between 2007 and 2015 were retrospectively identified at a large health system. Our primary outcome of interest was completion of cystoscopy and imaging. Regression modeling was used to assess associations between gender and insurance status with completion of a MH evaluation, adjusted for clinical factors, urinalysis data, and patient demographics. RESULTS:Of 15,161 patients with MH, only 1,273 patients (8.4%) completed upper tract imaging and a cystoscopy; 899 (5.9%) within 1 year. Median time to imaging was 75 days and 68.5 days for cystoscopy. Of those with an incomplete evaluation, 23.7% underwent cystoscopy and 76.3% underwent imaging. Male gender, private insurance, and increased MH severity on UA were associated with a complete evaluation. More patients who completed an evaluation were diagnosed with bladder (4.8% vs. 0.3%) and kidney cancer (3.1% vs. 0.4%) when compared to those who did not. CONCLUSION/CONCLUSIONS:Few patients complete a timely evaluation of MH. Women and underinsured patients are disproportionately less likely to complete a work-up for microhematuria and this may have downstream implications for diagnosis.

BACKGROUND:Accurate assessment of life expectancy (LE) is critical to treatment decision making for men with prostate cancer. We sought to externally validate the Prostate Cancer Comorbidity Index (PCCI) for prediction of long-term mortality in men with prostate cancer and operationalize it using claims data. METHODS:We conducted an observational study of 181,009 men with prostate cancer from the Veterans Affairs Health System diagnosed from 2000-2013. Overall mortality across PCCI scores was analyzed using Kaplan-Meier and Cox proportional hazards analysis. Discrimination and calibration were measured using c-index and mean prediction error, respectively. RESULTS:Among men with PCCI scores of 0, 1-2, 3-4, 5-6, 7-9, and 10+, 10-year overall mortality was 15%, 26%, 36%, 41%, 52%, and 69%, respectively. Multivariable Cox analysis showed an increasing hazard of mortality (95%CI) with higher PCCI scores: 1.22 (1.18-1.27), 1.69 (1.61-1.76), 2.08 (2.00-2.17), 2.88 (2.76-3.00), 4.50 (4.32-4.69) for scores of 1-2, 3-4, 5-6, 7-9, and 10+, respectively. C-index for prediction of overall mortality was 0.773. Mean absolute error for prediction of 10-year overall mortality was 0.032. Among men with clinically localized, Gleason ≤6 disease with LE<10 years and Gleason ≤7 disease with LE<5 years as defined by the PCCI, 3,999/12,185 (33%) and 1,038/3,930 (26%) men were treated with definitive local treatment, respectively. CONCLUSIONS:The PCCI is a claims-based, externally validated tool that predicts mortality in men with prostate cancer. Integration of the PCCI into clinical pathways may improve prostate cancer management through more accurate LE assessment.

INTRODUCTION/BACKGROUND:According to current National Comprehensive Cancer Network guidelines, routine imagining for staging low-risk prostate cancer is not recommended. However, extensive overuse of guideline-discordant imaging continues to persist. Incidental findings are common on imaging and little is known about the optimal management. Rates of incidental findings vs. false positive diagnosis from inappropriate imaging are poorly understood and have yet to be quantified for low- and intermediate-risk prostate cancer patients. OBJECTIVE:To determine the frequency of positive radiologic findings in patients with low- and intermediate-risk prostate cancer during initial staging at VA New York Harbor Healthcare System. METHODS:We retrospectively reviewed all low- and intermediate-risk prostate cancer patients' medical records from the VA New York Harbor Healthcare System for diagnosis from 2005 to 2015. We reviewed each individual's prebiopsy prostate specific antigen (PSA), Gleason score, and clinical stage. We also determined if imaging obtained yielded a false positive, incidental finding, or if metastatic disease occurred within the 6 months following initial diagnosis. RESULTS:There were 414 men, who were classified as low- to intermediate-risk prostate cancer and underwent inappropriate staging imaging of 4,306 men diagnosed with prostate cancer. Of these 414 men, 178 (43%) had additional follow-up imaging for positive findings. We calculated an incidental finding rate of 10% and a false positive rate of 38% for patients. Five (1%) patients had metastatic disease. CONCLUSION/CONCLUSIONS:Despite guideline recommendations, imaging overuse remains an issue for low-intermediate-risk prostate cancer patients. The false positive rate found in this analysis is alarmingly high at 38%. This use of scans is burdensome to the healthcare system and patient. This study highlights the frequency of inappropriate imaging and its negative consequences.

BACKGROUND:Men with prostate cancer are often castrated with long-acting injectable drugs termed androgen deprivation therapy (ADT). Although many benefit, ADT is also used in patients with little or nothing to gain. The best ways to stop this practice are unknown, and range from blunt pharmacy restrictions to informed decision-making. This study will refine and pilot two different de-implementation strategies for reducing ADT use among those unlikely to benefit in preparation for a comparative effectiveness trial. METHODS/DESIGN/METHODS:This innovative mixed methods research program has three aims. Aim 1: To assess preferences and barriers for de-implementation of chemical castration in prostate cancer. Guided by the theoretical domains framework (TDF), urologists and patients from facilities with the highest and lowest castration rates across the VA will be interviewed to identify key preferences and de-implementation barriers for reducing castration as prostate cancer treatment. This qualitative work will inform Aim 2 while gathering rich information for two proposed pilot intervention strategies. Aim 2: To use a discrete choice experiment (DCE), a novel barrier prioritization approach, for de-implementation strategy tailoring. The investigators will conduct national surveys of urologists to prioritize key barriers identified in Aim 1 for stopping incident castration as localized prostate cancer treatment using a DCE experiment design. These quantitative results will identify the most important barriers to be addressed through tailoring of two pilot de-implementation strategies in preparation for Aim 3 piloting. Aim 3: To pilot two tailored de-implementation strategies to reduce castration as localized prostate cancer treatment. Building on findings from Aims 1 and 2, two de-implementation strategies will be piloted. One strategy will focus on formulary restriction at the organizational level and the other on physician/patient informed decision-making at different facilities. Outcomes will include acceptability, feasibility, and scalability in preparation for an effectiveness trial comparing these two widely varying de-implementation strategies. DISCUSSION/CONCLUSIONS:Our innovative approach to de-implementation strategy development is directly aligned with state-of-the-art complex implementation intervention development and implementation science. This work will broadly advance de-implementation science for low value cancer care, and foster participation in our de-implementation evaluation trial by addressing barriers, facilitators, and concerns through pilot tailoring. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov Identifier: NCT03579680 , First Posted July 6, 2018.