Faculty Bibliography

BACKGROUND:Genetic counseling and germline testing have an increasingly important role for patients with prostate cancer (PCa); however, recent data suggests they are underutilized. Our objective was to perform a qualitative study of the barriers and facilitators of germline genetic evaluation among physicians who manage PCa. METHODS:We conducted semi-structured interviews with medical oncologists, radiation oncologists, and urologists from different U.S. practice settings until thematic saturation was achieved at n = 14. The interview guide was based on the Tailored Implementation in Chronic Diseases Framework to identify key determinants of practice. Interview transcripts were independently coded by ≥2 investigators using a constant comparative method. RESULTS:The decision to perform or refer for germline genetic evaluation is affected by factors at multiple levels. Although patient factors sometimes play a role, the dominant themes in the decision to conduct germline genetic evaluation were at the physician and organizational level. Physician knowledge, coordination of care, perceptions of the guidelines, and concerns about cost were most frequently discussed as the main factors affecting utilization of germline genetic evaluation. CONCLUSIONS:There are currently numerous barriers to implementation of germline genetic evaluation for PCa. Efforts to expand physician education, to develop tools to enhance genetics in practice, and to facilitate coordination of care surrounding genetic evaluation are important to promote guideline-concordant care.

BACKGROUND:In 2012, the United States Preventative Services Task Force (USPSTF) formally recommended against all Prostate Specific Antigen (PSA) screening for prostate cancer. Our goal was to characterize PSA screening trends in the Veterans Health Administration (VA) before and after the USPSTF recommendation, and to determine if PSA screening was more likely to be ordered based on a Veteran's race or age. METHODS:Using the VA Corporate Data Warehouse, we created 10 annual groups of PSA-eligible men covering 2009-2018. We identified all PSA tests performed in the VA to determine yearly rates of PSA screening. All statistical tests were two-sided. RESULTS:The overall rate of PSA testing in the VA decreased from 63.3% in 2009 to 51.2% in 2018 (p<.001). PSA screening rates varied markedly by age group during our study period, with men aged 70-80 having the highest initial rate and greatest decline (70.6% in 2009 to 48.4% in 2018, p<.001). Men aged 55-69 saw a smaller decline (65.2% in 2009 to 58.9% in 2018, p<.001) while the youngest men, aged 40-54, had an increase in PSA screening (26.2% in 2009 to 37.8 in 2018, p<.001). CONCLUSIONS:In this analysis of PSA screening rates among veterans before and after the 2012 USPSTF recommendation against screening, we found that overall PSA screening decreased only modestly, continuing for more than half of the men in our study. Veterans of different races had similar screening rates, suggesting that VA care may minimize racial disparities. Veterans of varying age experienced significantly different trends in PSA screening.

BACKGROUND:Germline testing is recommended for all men with metastatic prostate cancer (PCa), and for some with localized PCa meeting specific histologic or family history criteria. Germline genetic evaluation has important implications for PCa prognosis and management, as well as implications for family members and cancer screening. Despite the importance of germline evaluation, its utilization in urologic practice is unknown. MATERIALS AND METHODS/METHODS:We conducted a 32-item survey of U.S. urologists to examine knowledge of germline testing guidelines and practice patterns. It was shared through email to 6 American Urological Association sections, the Veterans Affairs Urology Mailgroup, and social media. RESULTS:Among 132 total respondents from diverse practice settings across the U.S., 12% perform germline testing, 44% refer to a genetic counselor, 11% do both, and 33% do not test/refer. Only 4% had formal education in genetics. While 98% ask about PCa family history, only 76% and 52% ask about breast and ovarian cancer. When presented with hypothetical case scenarios where germline testing is indicated, many respondents indicated they would not offer genetic counseling or testing. Younger age (p = 0,03), academic practice (p = 0.04), and specializing in PCa/oncology (p = 0.007) were significantly associated with performing or referring for germline testing. Specializing in PCa/oncology was significantly associated with recommending germline testing for all case scenarios involving metastatic PCa (p = 0.0009) CONCLUSION: Our results suggest significant gaps in knowledge of germline testing and alignment of practice with national guidelines among urologists. Germline testing education and facilitation of genetic evaluation in urologic practice is warranted.

OBJECTIVES/OBJECTIVE:Small studies suggest that a new entity of high-grade (HG) (G3, by Ki-67 or mitotic index) well-differentiated (histologically) gastrointestinal neuroendocrine tumors (NETs) exists, but prognosis and characteristics are unknown. We further characterized demographics and prognosis of patients with colorectal G3 NETs. MATERIALS AND METHODS/METHODS:We used the Surveillance Epidemiology and End Results (SEER) database to study colorectal NETs diagnosed from 2000 to 2015. We evaluated demographic, clinical, and tumor characteristics. We compared overall survival (OS) for G1-2 NET, G3 NET, and NEC (neuroendocrine carcinoma). We used logistic regression to detect grade associations and Cox proportional hazards models to examine predictors of survival. RESULTS:We identified 5894 cases with colorectal NET (5780 [98.1%] G1-2 and 114 [1.9%] G3); the cohort was 66% white, 47% male, and had a median age of 54. Patients with G3 NET were likely to be older (odds ratio [OR]: 2.23; 95% confidence interval [CI]: 1.19-4.19 for 60 to 69 vs. <50), unmarried (OR: 1.56; 95% CI: 1.02-2.38), and less likely to be diagnosed after 2010 (OR: 0.09; 95% CI: 0.06-0.15). OS for G3 NET (median, 36 mo; 95% CI: 13-92) fell between OS for NEC (median, 7 mo; 95% CI: 6-8), and G1-2 NET (median not reached, >120 mo). Among G1-3 NETs, black patients (hazard ratio [HR]: 1.30; 95% CI: 1.03-1.62), older patients (HR: 3.63; 95% CI: 2.63-5.01 for age 60 to 69 vs. <50), unmarried patients (HR: 1.40; 95% CI: 1.17-1.68), and those with HG features (HR: 3.97; 95% CI: 3.15-4.99) had worse survival. CONCLUSIONS:We defined a subset of G3 NETs that are HG and well differentiated, more common in older, unmarried patients, with a prognosis between that of NEC and G1-2 NETs. Our analysis adds the first national registry study in support of a new classification of nonpancreatic HG and well-differentiated NETs.

OBJECTIVE:To understand how to potentially improve inappropriate prostate cancer imaging rates we used National Comprehensive Cancer Network's (NCCN) guidelines to design and implement a Clinical Reminder Order Check (CROC) that alerts ordering providers of potentially inappropriate imaging orders in real-time based on patient features of men diagnosed with low-risk prostate cancer. METHODS:We implemented the CROC at VA New York Harbor Healthcare System (VANYHHS) from April 2, 2015 to November 15, 2017. We then used VA administrative claims from the VA's Corporate Data Warehouse to analyze imaging rates among men with low-risk prostate cancer at VHANYHHS before and after CROC implementation. We also collected and cataloged provider responses in response to overriding the CROC in qualitative analysis. RESULTS:57% (117/205) of Veterans before CROC installation and 73% (61/83) of Veterans post-intervention with low-risk prostate cancer received guideline-concordant care. CONCLUSION/CONCLUSIONS:While the decrease in inappropriate imaging during our study window was almost certainly due to many factors, a CPRS-based CROC intervention is likely associated with at least moderate improvement in guideline-concordant imaging practices for Veterans with low-risk prostate cancer.

OBJECTIVES/OBJECTIVE:The impact of diabetes mellitus (DM) on colorectal cancer (CRC) outcomes remains unknown. We studied this by conducting a meta-analysis to evaluate (1) CRC outcomes with and without DM and (2) treatment patterns. METHODS:We searched PubMed, EMBASE, Google Scholar, and CINAHL for full-text English studies from 1970 to 12/31/2017. We searched keywords, subject headings, and MESH terms to locate studies of CRC outcomes/treatment and DM. Studies were evaluated by two oncologists. Of 14,332, 48 met inclusion criteria. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses method, we extracted study location, design, DM definition, covariates, comparison groups, outcomes, and relative risks and/or hazard ratios. We utilized a random-effects model to pool adjusted risk estimates. Primary outcomes were all-cause mortality (ACM), disease-free survival (DFS), relapse-free survival (RFS), and cancer-specific survival (CSS). The secondary outcome was treatment patterns. RESULTS:Forty-eight studies were included, 42 in the meta-analysis, and 6 in the descriptive analysis, totaling > 240,000 patients. ACM was 21% worse (OR 1.21, 95% CI 1.15-1.28) and DFS was 75% worse (OR 1.75, 95% CI: 1.33-2.31) in patients with DM. No differences were detected in CSS (OR 1.10, 95% CI 0.98-1.23) or RFS (OR 1.12, 95% CI 0.91-1.38). Descriptive analysis of treatment patterns in CRC and DM suggested potentially less adjuvant therapy use in cases with DM and CRC. CONCLUSIONS:Our meta-analysis suggests that patients with CRC and DM have worse ACM and DFS than patients without DM, suggesting that non-cancer causes of death in may account for worse outcomes.

Background: Tyrosine kinase inhibitors can prolong survival in advanced HCC patients, but response rates have been minimal. Recently, immune checkpoint inhibition with nivolumab (nivo) demonstrated objective response rates (ORR) of 15% (escalation phase) and 20% (expansion phase) in the Checkmate 040 study. Pre-clinical and translational studies have demonstrated that IL-8 and tumor associated macrophages (TAMs) contribute to HCC progression and recurrence following treatment. Therefore, rationale exists to evaluate combinatorial approaches to target TAM function combined with checkpoint inhibitory therapy. This phase II, randomized study will evaluate the safety and efficacy of combined anti-CSF1R (Cabiralizumab) or anti-IL-8 (BMS-986253) in combination with Nivo in advanced HCC. Method(s): Advanced HCC patients without prior systemic treatment and disease measurable by RECISTv1.1 with Childs A liver function are eligible. Patients will be enrolled (n=25 per arm) to Nivo 240 mg IV Q2 weeks monotherapy, Nivo 240 mg IV + BMS-986253 1200 mg IV Q2 weeks, or Nivo 240 mg IV + Cabiralizumab 4 mg/kg IV Q2 weeks. Primary endpoints include safety and ORR determined by RECISTv1.1. Secondary endpoints include time to response, duration of response, progression free survival, and overall survival. Exploratory endpoints include analysis of tumor microenvironment immune and tumor cell profiling of pre- and on-treatment tumor tissue

Background: Preoperative chemoRT is a standardof- care as shown in the CROSS trial (N Engl J Med 2012;366:2074-2084), Surgery is sometimes deferred in pts with clinical CR (cCR) based on lack of overall survival benefit (J Clin Oncol 2005;23:2310-2317, J Clin Oncol2007;25:1160-1168). Nivolumab has activity in advanced ESCC (Lancet Oncol 2017;18:631-639), and adding it to chemoRT may improve outcomes.
Method(s): This phase I/II study was designed to assess the safety and tolerability and efficacy of nivolumab added to chemoRT (6 weekly carboplatin AUC 2, paclitaxel 50mg/m2, RT 50.4 Gy in 1.8 Gy fractions 5/7 days) for pts with TanyN1-3 or T3-4N0M0 ESCC. The phase I primary endpoint is 'unacceptable toxicity' at 28 days after the last dose of chemotherapy. The phase II primary endpoints are cCR (endoscopy + PET/CT) and pCR rates for pts undergoing surgery. Nivolumab is given q2W x2, then concurrent chemoRT with nivolumab q2W x3. If no cCR, pt proceeds to esophagectomy, then adjuvant nivolumab q2W x3; if cCR, pt has an option of no surgery but receives nivolumab q2W x3.
Result(s):From 7/20/17 to 12/27/18, 6 pts were enrolled. No unacceptable or grade 5 toxicities were observed. The most common grade 1/2 AEs in >1 pt were anorexia, myelosuppression, elevated AST and nausea. Grade 3/4 AEs in >1 pt were lymphopenia and leukocytopenia. 2 pts required hospitalizations (dyspnea 1, colitis 1). All pts completed therapy; 1 pt had dose delay due to grade 2 esophagitis; 2 pts progressed, 4 achieved cCR. Of 4 pts with cCR, 2 pts chose surgery and both achieved pCR. None of the 4 pts recurred.
Conclusion(s): ChemoRT with nivolumab is tolerable with manageable toxicities in locally advanced ESCC. Enrollment to the phase II portion ended because of slow accrual. Adverse Events. Grade 1 &2 in > 1 pt: 4/6: Anorexia & Anemia 3/6: Leukocytopenia Neutropenia Thrombocytopenia Nausea & Elevated AST 2/6: Hypomagnesemia Hypokalemia Grade 3 & 4 in > 1 pt: 5/6: Lymphopenia, 2/6: Leukocytopenia

Current guidelines recommend conservative management as the preferred option for most low-risk prostate cancer cases, with certain possible exceptions (age <55yr, African Americans, and high-volume grade group 1). Although previous studies have documented substantial heterogeneity in the uptake of conservative management, less is known about the underlying reason for this variation and whether it is due to guideline-concordant factors (age, race, and biopsy cancer volume). We explored variation in the use of conservative management for low-risk prostate cancer among 20 597 men diagnosed in the US Veterans Affairs health care system from 2010 to 2016. Conservative management increased substantially over this time from 51% to 76% (p< 0.001). However, there was substantial variation by facility (35-100%). Multivariable analysis revealed that patient factors included in the guidelines (e.g., age and biopsy cores), other patient factors (eg, marital status and PSA) and non-patient factors (eg, geographic region, case volume, year) were associated with conservative management use. In conclusion, even within an integrated health care system, there remains significant heterogeneity in the uptake of conservative management for low-risk prostate cancer. Both guideline-concordant factors and other factors not discussed in the guidelines were associated with conservative management use. PATIENT SUMMARY: In the US Veterans Affairs health care system the vast majority of men with low-risk prostate cancer were managed conservatively by 2016, although there was significant variation by facility. Patient factors specifically mentioned in guidelines had the greatest impact on prediction of conservative management.