bluuebunny/crossref_metadata_2025 huggingface dataset:
Dichotomous sized-based clinical staging of localized renal masses affects management but not clinical outcomes.
Authors: Reinstatler Lael Suzanne , Stensland Kristian D.
Published: March 2019

670

Background: Clinical staging of localized renal masses is assigned according to radiographic tumor diameter cut-offs, with T1 masses defined as 7 cm or less and T2 greater than 7cm. However, it is unknown if tumors with infinitesimal size differences exhibit oncologic behavior to warrant different surgical management. Arbitrarily dichotomizing otherwise similar tumors to different stage groups may inappropriately influence the management of renal tumors and affect patient outcomes. We evaluated differences in management and outcomes in otherwise similarly sized tumors among patients that differ only in clinical T stage. Methods: Data from the National Cancer Center Database was extracted on all patients with a diagnosis of stage T1 or T2 clear cell renal cell carcinoma (RCC). Analyses were limited to tumors on the cusp of T1/T2 staging to include: 69 mm, 70 mm, and 71 mm. Clinical data were compared and Kaplan-Meier and Cox proportional hazards survival modeling were performed. Results: A total of 2815 patients were included. There were 1882 stage T1 and 933 stage T2 tumors; there were no differences in demographics or comorbidity scores. Of 171 tumors reported to be 69 mm, 132 (77.2%) were staged as T1. Of 2339 70 mm tumors, 1686 (72%) were staged as T1. Of 305 71 mm tumors, 64 (21%) were staged as T1. For management, 11.7% of T1 masses were treated with partial nephrectomy vs 7.3% of T2 masses and 75.8% of T1 masses were treated with radical nephrectomy vs 80.7% of T2 masses (p<0.001). T2 masses were more likely to have lymph node dissection than T1 masses (15.1% vs 9.9%, p<0.001), but pathologic N and M staging was similar. On survival analyses, there was no difference in survival between T1 and T2 masses. Conclusions: In this analysis, tumors of similar size but different clinical stage exhibited similar survival, yet were managed differently according to assigned clinical T stage. Patients with large T1 or small T2 masses may be managed inappropriately if the treatment is based on dichotomized clinical staging alone. When possible, risk calculation using precise parameters such as tumor size as part of a prediction model is preferable to dichotomized rules of thumb when determining optimal treatment courses.
Analysis of toxicity and clinical outcomes (CO) in full versus reduced dose cabozantinib (cabo) in metastatic renal cell carcinoma (mRCC) patients (pts).
Authors: Martini Dylan J , Shabto Julie M. , Liu Yuan , Carthon Bradley Curtis , Speak Alexandra , Hitron Elise , Russler Greta , Caulfield Sarah , Ogan Kenneth , Harris Wayne , Master Viraj A. , Kucuk Omer , Bilen Mehmet Asim
Published: March 2019

671

Background: The full dose of cabo is 60 mg, but some pts are treated with a reduced dose with the clinical anticipation of adverse events (AEs). We compared AEs and CO in mRCC pts treated with full versus reduced dose cabo. Methods: We performed a retrospective analysis of 65 mRCC pts treated with cabo at Winship Cancer Institute from 2016-2018. CO were measured by overall survival (OS), progression-free survival (PFS), and objective response (OR). OS and PFS were measured from first dose of cabo to date of death and clinical or radiographic progression, respectively. OR was defined as partial response (PR) or complete response (CR) per RECISTv1.1. AEs were collected from clinic notes. Univariate analysis (UVA) of association between AEs and CO was performed using logistic regression model. Results: Most pts were males (68%) and the median age was 63 years. Most (79%) had clear cell RCC (ccRCC) and the majority were IMDC intermediate (59%) or poor (39%) risk. Most pts (68%) received 60 mg and 48% of these pts underwent a dose reduction for AEs. Nearly all pts (95%) who started on a reduced dose experienced AEs, compared to 66% for pts treated with 60 mg. OR rate was similar for pts on 60 mg (18%) and pts on a reduced dose (19%). The median survival was comparable in pts treated with 60 mg and pts treated with a reduced dose (10.9 vs. 8.8 months, p=0.92 for OS and 5.6 vs. 5.1 months, p=0.23 for PFS) per Kaplan Meier estimation. AEs, particularly gastrointestinal (GI) AEs, were associated with significantly lower chance of OR (Table). Conclusions: CO may be comparable in mRCC pts treated with full versus reduced dose of cabo, but a reduced dose of cabo may not be associated with decreased AEs. GI side effects may be a poor prognostic factor in mRCC pts treated with cabo. Larger studies are warranted to validate these findings. [Table: see text]
Rates of occult brain metastases in patients (pts) with advanced renal cell carcinoma (RCC): A cohort study from patients treated across 22 clinical trials.
Authors: Kotecha Ritesh , Redzematovic Almedina , Motzer Robert J. , Voss Martin Henner
Published: March 2019

673

Background: National guidelines for RCC management only recommend brain imaging ‘if clinically indicated’; the rate of occult brain metastases is not defined. Early detection of CNS disease has major implications as it typically triggers early intervention with the aim to limit morbidity, including major complications of local progression. In an effort to define the utility of brain screening, we investigated the rate of occult brain metastasis in a large cohort of metastatic RCC pts. Methods: We performed a retrospective review of completed and actively accruing metastatic RCC clinical trials conducted at Memorial Sloan Kettering Cancer Center. Individual charts of pts screening for those studies with mandatory brain imaging at baseline were reviewed to identify subjects harboring occult brain metastases. We collected patient demographics, International Metastatic Database Consortium (IMDC) risk status, sites of metastatic disease, and tumor histology. Patients with neurologic symptoms were excluded. Descriptive statistics were applied to analyze findings across the cohort. Results: A total of 22 clinical trials for metastatic RCC conducted from 2004-2017 required brain imaging at baseline, and a total of 535 pts were screened in this context. A total of 25/535 pts were found to have occult brain metastasis (4.67%), which was multi-focal in 10/25 (40%) and sub-cm in 15/25 (60%). For these 25 pts, the mean age at diagnosis was 56 years (38-77), and IMDC risk score at enrollment was: 1/24 favorable (4%), 21/24 intermediate (88%), and 2/24 poor-risk (8%) patients. 18/25 patients presented with de novo metastatic disease; 13/25 had received prior therapies; and 24/25 patients (96%) had > 2 additional non-CNS sites of metastatic disease at time of screening. 21/23 pts and 2/23 pts were then treated with radiation and surgical resection, respectively. Conclusions: This retrospective cohort study shows a 5% rate of occult CNS disease in asymptomatic patients with advanced RCC. These findings can inform current screening guidelines for full disease assessment in metastatic RCC patients.
Positive surgical margins after radical nephrectomy for localized kidney cancer: Impact on survival.
Authors: Ryan Stephen , Sarkar Reith , Bindayi Ahmet , Eldefrawy Ahmed , Hamilton Zachary , Murphy James Don , Derweesh Ithaar
Published: March 2019

676

Background: Impact of positive surgical margins (PSM) in patients undergoing radical nephrectomy (RN) in localized renal cell carcinoma (RCC) is poorly understood. We sought to understand the impact of PSM for on overall survival (OS) after RN in clinically localized RCC. Methods: Retrospective analysis of patients from the US National Cancer Database who RN for clinically localized (cT1a-cT2b cN0M0) RCC between 2003-13, were stratified into their pathological stage group [pT1a, pT1b, pT2a, pT2b, and pT3a ( = Upstaged)] and analyzed by final margin status. Cox Regression Multivariable analysis (MVA) was performed to investigate associations of PSM and covariates on OS. Kaplan-Meier analysis (KMA) of OS was performed for PSM verses NSM for the overall cohort and by stage. Results: 37,656 RN events [14312 (38%) pT1a, 13598 (36.1%) pT1b, 6551 (17.4%) pT2a, 2937 (7.8%) pT2b, and 4286 (11.3%) with pT3a upstaging]. PSM rate was 0.9% overall (0.4% pT1a, 0.4% pT1b, 0.4% pT2a, 0.4% pT2b, and 4.7% pT3a upstaged). On MVA for all-cause mortality, PSM was independently predictive for decreased OS (HR 1.51, p < 0.001), along with increasing age (HR 1.04, p < 0.001), non-Caucasian race (HR 1.199, p < 0.001), increasing charlson score (HR 2.23, p < 0.001), non-private insurance (HR 1.61, p = 0.001), high grade histology (HR 1.21, p = 0.001), and sarcomatoid histology (HR 3.61, p < 0.001). Pathologic T-stage was also predictive of decreased OS (Referent pT1a, HR 1.17, 1.47, 1.74, and 1.93, for pT1b, pT2a, pT2b, pT3a, respectively; all p < 0.001). KMA revealed worsened 5-year OS for PSM vs. NSM for the overall cohort (62.4% vs. 81%, p < 0.001), pT2a (61% vs. 79.4%, p = 0.013), and pT3a (50% vs. 68.3%, p < 0.001) groups. Conclusions: PSM is a rare event after RN, but is associated with worsened OS, particularly in pT2 and pT3a upstaged patients. Mechanism of decreased OS cannot be clarified given limitations of the NCDB, these suggest that PSM may pose increased oncologic risks in higher pathological stage. Consideration of further definitive strategies (ex: preemptive wide field resection) may be warranted in select circumstances. Furthermore, our findings call for re-consideration of exclusion of PSM patients from adjuvant therapy trials.
Is there a correlation between Gleason score and maximum standardized uptake value in locally advanced prostate cancer patients?
Authors: Cem Onal , Torun Nese , Guler Ozan Cem , Reyhan Mehmet , Akkus Yildrim Berna , Yapar Ali Fuat
Published: March 2019

68

Background: The aim was to assess the intensity of 68Ga-PSMA uptake in the primary tumour in patients locally advanced prostate cancer treated with definitive radiotherapy. Also correlation between the maximum standardized uptake value (SUVmax) of primary tumour and the Gleason score (GS) or prostate-specific antigen (PSA) level was assessed. Methods: The data of 201 biopsy-proven prostated cancer patients were retrospectively analysed. Median age of entire cohort was 68 years (range; 45 – 85 years). PET/CT images were analysed visually and semiquantitatively by measuring the SUVmax. The SUVmax of the primary tumour was assessed in relation to both PSA level and GS. Results: Median age of entire cohort was 68 years (ranged 45 – 85 years). Median PSA value at diagnosis was 20.3 ng/mL (ranged 2.1 – 301.0 ng/mL). Forty-two patients (23.9%) was in intermediate risk group, and 159 patients (79.1%) had high risk disease. Seventy two patients (36.8%) had regional lymph node metastasis. Median SUVmax of primary tumor and metastatic lymph nodes were 13.0 (ranged 1.3 - 84.3) and 12.6 (ranged 3.6 – 64.5), respectively. Patients with GS 7 or lower had significantly lower SUVmax compared to patients with GS > 7 (12.1±8.4 vs. 20.9±16.4; p < 0.001). However, there was no significant difference in SUVmax of tumors with GS of 3+4 and 4+3 (14.8±8.6 vs. 16.3±12.7; p = 0.6). Patients with PSA ≥10.0 ng/mL exhibited significantly higher uptake than those with PSA levels < 10.0 ng/mL (12.1±8.4 vs. 20.9±16.4; p < 0.001). SUVmax of intermediate risk patients was significantly lower than that of high risk patients (12.7±11.1 vs. 19.8±16.8; p = 0.01). In 72 patients with lymph node metastasis SUVmax was significantly higher compared to 129 patients without lymph node metastasis (24.9±21.3 vs. 14.7±10.6; p < 0.001). Conclusions: Tumours with GS 7 or lower, patients with PSAvalues ≤10 ng/mL, intermediate risk patients and patients without regional lymph node metastasis showed significantly lower 68Ga-PSMA uptake. 68Ga-PSMA-PET/CT should be preferentially applied for primary staging of prostate cancer in patients with GS > 7, PSA levels ≥10 ng/ml, high risk patients and patients with regional lymph node metastasis.
Hypofractionated, accelerated radiotherapy to the prostate bed: Five-year outcomes of a prospective phase I/II study.
Authors: Martell Kevin , Cheung Patrick , Morton Gerard , Chung Hans T. , Deabreu Andrea , Zhang Liying , Pang Geordi , Alayed Yasir , Mamedov Alexandre , Gladwish Adam , Loblaw Andrew
Published: March 2019

7

Background: There have been few studies to date that examine the role of hypofractionated radiotherapy for prostate cancer in the post-operative setting. This study reports on the 5-year outcomes from a single institution, prospective, phase I/II study on hypofractionated prostate bed radiotherapy. Methods: Patients enrolled in this study were all eligible for post-operative radiotherapy and received a prescribed dose of 51Gy in 17 fractions to the prostate bed. On subsequent follow-up, GI/GU toxicity was assessed using the NCI CTCAE v3.0, PSA was evaluated and quality-of-life was assessed using the EPIC questionnaire. Results: A total of 30 patients were enrolled between 2008 and 2011. Median age was 65 [52-75] years. Median pre-treatment PSA was 0.12 ng/ml [0.01-1.42]. Twenty-four (86%) patients had Gleason 7 disease, 13 (43%) had pT3 disease and 20 (67%) had positive margins. Twenty-six (87%) patients underwent radiotherapy as salvage treatment. No patient experienced CTCAE grade 3/4 toxicity. Two (7%) patients experienced at least one CTCAE grade 2 late GI toxicity and 11 (37%) had at least one late grade 2 GU toxicity. At baseline and 5 years post radiotherapy, mean EPIC urinary domain score were 80 (SD: 18) and 82 (17). Mean EPIC bowel domain score were 93 (13) and 93 (15). One (4%) patient had a minimally clinically important change (MCIC) in urinary domain score and 1 (4%) patient had a MCIC in bowel domain score. Nelson-Aalen estimated cumulative incidence of biochemical failure were 31% (nadir+0.2) and 18% (nadir+2.0) at 5 years. Four-year PSA ≥0.4 was highly predictive of subsequent rise to nadir+2.0 at 5 years (Nelson-Aalen cumulative hazard: 1.45; standard error: 0.701; p < 0.0001). Five (17%) patients received hormonal therapy for biochemical failure. Nelson-Aalen estimated cumulative incidence of hormone therapy use was 14% at 5 years. Conclusions: In this phase I/II study, hypofractionated post-operative radiotherapy appears to have good clinical efficacy without significant late toxicity. Phase III studies are warranted. Clinical trial information: 042-2009.
MiR-34a to enhance the radiosensitivity of 22RV1 and 22RV1-radiation resistance prostate cancer cell lines.
Authors: Thoms John , Aoki Satoko , Belbin Thomas
Published: March 2019

74

Background: Radiation therapy (RT) is a standard treatment option for men with prostate cancer (PCa), yet men still fail RT at a rate of up to 50%. MicroRNAs (miRNAs) can influence the tumor RT response, and the abundance or lack of specific miRNAs can alter radiosensitivity through alteration of survival pathway signals. We show that altered expression of miR-34a plays an important role in radiosensitivity. Methods: Both clinical and molecular data from TCGA-PRAD cohort were analyzed. MiR-34a expression was also determined in an independent cohort of 30 patients with PCa treated with RT. An RT resistant subline (22RV1-IRR) from the parental 22RV1 line was generated. MiR-34a expression level was determined in 22RV1, 22RV1-IRR and PrEC cells. 22RV1 and 22RV1-IRR cells were transfected with miR-34a mimics. Stable clones overexpressing miR-34a were generated. The influence of miR-34a on cellular proliferation, migration, clonogenic survival and response to RT was measured using standard assays. Results: Analysis of TCGA-PRAD data showed that low levels of miR-34a was associated with biochemical recurrence (BCR). In our cohort of 30 PCa patients treated with RT, miR-34a was consistently under expressed and associated with BCR. MiR-34a was down regulated in 22RV1 cells compared to PrEC cells and further down regulated in 22RV1-IRR cells. 22RV1 - IRR cells expressed lower levels of TP53, but overexpressed cMYC, BIRC5 (survivin) and E2F3. MiR-34a mimics resulted in a decreased expression of survivin at the mRNA and protein level in 22RV1 and 22RV1-IRR cells. MiR-34a expression was unregulated in response to RT in both cell lines. Survivin and E2F3 expression were down regulated in response to RT in both cell lines. MiR-34a mimics suppressed cell proliferation in 22RV1 and 22RV1-IRR cells. MiR-34a mimics also suppressed cellular migration, by the wound healing assay, in both 22RV1 and 22RV1-IRR cells. Stable clones overexpressing miR-34a were associated with increased radiosensitivity via clonogenic survival assay. Conclusions: Together, these data suggest that low expression of miR-34a is associated with BCR and overexpression of miR-34a enhances radiosensitivity by the downregulation of survivin and E2F3.
Bowel and bladder reproducibility in image-guided SBRT prostate: Results of a patterns of practice survey.
Authors: Mandia Jeremy , Escorcia Freddy , Ning Holly , Salerno Kilian Elizabeth , Citrin Deborah E. , Rowe Lindsay S.
Published: March 2019

76

Background: Use of prostate stereotactic body radiotherapy (SBRT) as treatment for localized prostate cancer (PCa) is increasing. Given the high dose (>5Gy) per fraction (Fx) being delivered, SBRT requires careful preparation and delivery to ensure accuracy and precision. Guidelines and data on best practice for bowel and bladder preparation are lacking. Therefore, we surveyed practicing radiation oncologists (RO) to document practice patterns for prostate SBRT. Methods: From June to October 2018 we completed a nationwide survey of 1395 American Society for Therapeutic Radiology and Oncology (ASTRO) members who self-identified as managing PCa. A SurveyMonkey link was sent via email, and analysis included practicing RO who treat PCa with SBRT. Results: 204 responses were received with 32% (64/204) using SBRT. 80% (51/64) provided the fractionation used: 33% (17/51) use 35Gy to 36.25Gy, and 17.6% (9/51) use >40Gy in 5 Fx, and 1 used >9Gy Fx. 94% use implantable devices for localization (83% fiducial markers, 17% radiofrequency transponders). 65% (42/64) use a hydrogel spacer. 75% (48/64) use daily cone beam CT (CBCT) for image guidance. The majority use a 5 mm PTV, with 3 mm posteriorly. For bladder and bowel preparation 97% (62/64) provided preferences. For bladder, 90.3% (56/62) required a comfortably full bladder for both simulation and treatment. For simulation, 92% (57/62) have a bowel protocol (BP) to optimize rectal reproducibility. 51.6% (31/62) have patients empty their bowels prior, and 51.6% (31/62) prescribe a BP. Diet alteration was recommended by 77% (48/62). 86% (53/62) used a BP during SBRT treatment. Of those using a BP, 67% (43/64) continued it throughout SBRT with 30% (19/64) continuing BP unless symptoms change management. Only 3% (2/64) stop BP after simulation. Conclusions: The variability of data in the literature on effective BP for treatment reproducibility for PCa is reflected in the varied patterns of practice seen in our survey. Consensus on bladder preparation is seen for a majority of practitioners. A variety of BP regimens are employed.
Providers’ inability to estimate health literacy among African American (AA) patients (pts) with early prostate cancer (PCa).
Authors: Martin-Doyle William , Kilbridge Kerry L. , Regan Susan , Filson Christopher Paul , Trinh Quoc-Dien , Williams Sierra , Master Viraj A.
Published: March 2019

77

Background: Providers’ estimates of a pt’s health literacy are important for communication and shared decision making among men with early PCa. We explored differences between providers’ estimates of health literacy and measured health literacy among AA pts in a prospective cohort study at Grady Memorial Hospital and the Atlanta Veterans Administration Hospital. Methods: Providers (n=18) estimated the health literacy of 124 newly diagnosed, early-stage, AA PCa pts after discussions with each pt regarding his PCa treatment options, categorized as ≤Grade (Gr) 3; Gr 4-6; Gr 7-8; and High school. At a subsequent visit, prior to choosing his cancer treatment, each pt’s health literacy was measured using the Rapid Estimate of Adult Literacy in Medicine (REALM), using the same categories. Domains of numeracy, comprehension of common PCa terms, and anatomic knowledge were assessed using published methods. Concordance between estimated and actual health literacy was evaluated via Cohen’s Kappa coefficient (1.00 = perfect agreement). Results: Despite their discussions with the pts, providers consistently overestimated pts’ health literacy. Agreement between provider estimates and pts’ measured values was consistently low (32.0%-37.6%). These rates were approximately what would be expected by chance. Among the 75 patients with the lowest levels of health literacy, agreement was even lower (12.3%-35.6%). In this group 26.7% of provider assessments were off by ≥2 REALM categories. Conclusions: Healthcare providers are surprisingly ineffective at estimating the health literacy of their pts with early stage PCa. This poor accuracy may diminish providers’ ability to communicate successfully with pts and engage in shared decision making, especially among pts with poor health literacy. [Table: see text]
Evaluating non-hormonal therapy in a phase II trial of SM-88 for rising PSA prostate cancer.
Authors: Gartrell Benjamin Adam , Del Priore Giuseppe , Retter Avi S. , Chen Wen-Tien , Sokol Gerald H. , Vandell Alexander G , Roach Mack
Published: March 2019

83

Background: Absolute PSA change is an imperfect surrogate of clinical benefit; CTCs and PSA doubling time (DT) may also be used as a surrogate of progression (PD). Hormone therapy (HT) often leads to a rapid decline in PSA, however non-HT may be effective without causing a decline in absolute PSA or testosterone (T). SM-88, a non-HT novel combination Warburg effect therapy (amino acid analogue, CYP3a4 inducer, mTOR inhibitor and catalyst) does not affect T. We report outcomes leading to subsequent therapies of an ongoing PSA recurrent, non-metastatic PC trial. Methods: Prospective Phase II of rising PSA (per PCWG3), detectable CTCs, and no baseline lesions. Results: Since September 2016, 31 subjects enrolled with 17 on study for > 12 weeks. Mean age 68.9; BMI 28.7; 38% black and 62% post RT. Mean T increased 61 mg/dl from baseline 319 mg/dl (p=0.19). 82% (14/17) subjects experienced an improvement in PSA DT and 67% (10/15) experienced a decline in CTCs of >30%. Overall median PSA DT time on enrollment was 5.3 (1.4 – 37.6) and improved to 6.5 (Wilcoxon p=0.02) (see table). 3/4 subjects with PD failed to maintain a CTC drop >60% vs 2/17 without PD (p=.03); median time to nadir CTC was 3 cycles (1-7). Subjects avoiding subsequent therapy averaged a 50% CTC decline (15-100%). CTC and PSA DT effects were not correlated to T level. AEs possibly related to drug/unrelated were: No grade (G) 4 or 5; 0/1 G3; 1/7 G2; 13/19 G1. As reported elsewhere, typical HT-related side effects were not observed. Including all patients with >1 month of data, from initial diagnosis of PSA rise (median 9 months; 3-18), 96% (22/23) have remained metastases-free and 78% (18/23) remained free of additional HT (p<.05). Clinical trial information: NCT02796898. Conclusions: SM-88 may be a useful either before or as an additive to current PC treatments where normal T may be preferred. SM-88 might not worsen QOL parameters related to T level. An effect on PSA DT and CTCs were demonstrated even in an aggressive doubling time subgroup. Prospective trials are planned to confirm its utility.[Table: see text]
Cribriform pattern, Genomic Prostate Score, and adverse pathology at radical prostatectomy in a cohort of prostate cancer patients initially on active surveillance.
Authors: Zuniga Kyle Brian , Washington Samuel L. , Simko Jeffry , Greenland Nancy , Stohr Bradley A. , Cowan Janet E. , Tenggara Imelda , Maggi Martina , Chan June M. , Cooperberg Matthew R. , Carroll Peter
Published: March 2019

88

Background: A growing body of literature suggests that the presence of cribriform pattern (CP) in prostate biopsy specimens portends worse outcomes. Furthermore, CP tumors have been found to harbor a myriad of genomic alterations associated with more aggressive disease. We sought to examine the association between CP and Genomic Prostate Score (GPS) and how this association helps predict adverse pathology (AP) at radical prostatectomy (RP) in patients initially managed with active surveillance (AS). Methods: Using the UCSF Urologic Outcomes Database (UODB), we identified 180 AS patients who underwent GPS testing and subsequently RP. Biopsy specimens were re-reviewed centrally to confirm Gleason grade. AP was defined as GS ≥ 4+3, pT3/4, or pN1 on surgical pathology. Clinical and demographic characteristics were compared by CP status using t-tests and chi-squared tests. Cox proportional hazards regression was performed to identify factors associated with AP after adjusting for age, PSA density (log), percentage of positive biopsy cores, biopsy source (UCSF versus outside), and year of diagnosis. Additional models included the base covariates plus presence of CP, GPS, and both CP and GPS. Results: For the cohort, mean age was 60.7 years (SD 7.1) with median PSA of 5.3 ng/ml (interquartile range, IQR 4.2-6.9) at diagnosis. Median PSAD was 0.14 (IQR 0.10-0.20). Among 180 patients, 27 (15%) had CP at biopsy. Mean GPS was significantly higher in CP+ compared to CP- patients (35, SD 12.7 versus 27, SD13.7, p < 0.01), and a greater proportion of CP+ patients had AP compared to CP- (59% versus 54%, p < 0.01). On multivariate analysis, CP was associated with AP (HR 1.9, 95% CI 1.1-3.4, p = 0.02), but significance was lost after adjusting for GPS (p = 0.19). Conclusions: The presence of CP at biopsy was statistically significantly associated with higher GPS. While both were associated with AP at RP, CP was not associated with AP independent of GPS, suggesting an interaction or commonality between these factors not previously explored.
Small cell carcinoma of the prostate: National patterns of care and outcomes.
Authors: Horne Zachary D. , Smith Ryan P , Beriwal Sushil , Kalash Ronny , Shinde Ashwin , Glaser Scott , Fuhrer Russell , Wegner Rodney E
Published: March 2019

9

Background: Small cell prostate cancer (SCPC) is a rare entity with treatment patterns extrapolated from small cell cancer of the lung. Outcomes have been evaluated in small series but prognostic factors are relatively poorly defined. Methods: We utilized the National Cancer Data Base to analyze men diagnosed with SCPC from 2004-2015. Only men with known clinical TNM staging, treatment modalities, and follow up were included. Overall survival (OS) was analyzed and compared with Kaplan-Meier, log-rank, and Cox proportional hazards ratios. Associations with baseline and tumor properties were performed with Chi-squared, independent t-test, and bivariate regression analyses. Results: 800 men with SCPC were identified. Median PSA was 79.0 ng/dL. 55.6% of men had cM1 disease at diagnosis, 31.4% had cN0M0 disease, and 13.0% were cN1M0. Median follow up was 12.4 months for all patients and 19.3 months for cM0 patients. Median survival for cM1, cN0M0, and cN1M0 patients was 9.8, 28.5, and 17.1 months, respectively (p<0.001). In cM0 patients, 66 (18.7%) underwent radical prostatectomy (RP), 177 (50.1%) received radiation therapy (XRT), and 195 (45.2%) received chemotherapy (CT). Median survival for men undergoing RP was not reached vs those who did not undergo RP (p<0.001). XRT also showed a trend towards improved median OS (25.2 vs. 19.1 months, p=0.139). On multivariable analysis for cM0 men, only age (HR 1.044 [95% CI 1.025-10.64] p<0.001), cN1 (HR 1.378 [95% CI 1.001-1.898] p=0.050, RP (HR 0.429 [95% CI 0.259-0.709] p=0.001), and XRT (HR 0.520 [95% CI 0.384-0.704] p<0.001) were predictive for overall survival. When examining only men who received systemic therapy, XRT was the only additional treatment modality to exhibit a survival benefit (HR 0.623 [95% CI 0.425-0.912] p=0.015). Of men with cM1 disease, 78 (17.5%) underwent definitive local therapy (RP/XRT), but no difference in OS was observed. Conclusions: Small cell prostate cancer is an aggressive disease with the majority of men presenting with metastases. In those with pelvis-confined disease who are fit for systemic therapy, radiation therapy to the primary should be considered.
Pilot study of dual imaging with 89Zr-IAB2M and 68Ga-PSMA-11 PET/CT prior to prostatectomy.
Authors: Niaz Muhammad Junaid , Jhanwar Yuliya , Flynn Thomas , Vallabhajosula Shankar , Khani Francesca , Robinson Brian D. , Tagawa Scott T. , Bander Neil Harrison , Scherr Douglas
Published: March 2019

90

Background: Due to high expression of Prostate Specific Membrane Antigen (PSMA), it’s an excellent candidate for targeted molecular imaging. 89Zr-df-IAB2M is a J591 antibody derived minibody and 68Ga-PSMA-11 is a PSMA small molecule. Methods: Patients with clinically significant (defined as: ≥ 0.5 cm3 with Gleason pattern ≥ 4) localized prostate cancer (PCa) on conventional imaging modalities who planned to undergo surgery were imaged by PET/CT 1-3 hours after 5±2mCi of 68Ga-PSMA-11 injection and 89Zr-IAB2M PET 2-4 days after 10mg IAB2M labeled with 2.5 mCi of 89Zr injection. Image results were interpreted by a central reader without knowledge of the surgical pathology, mapped and the mapped findings later compared with surgical pathology map. Results: 9 patients having clinically localized PCa with median age 65 (46-79) and PSA 8.42 (1.6-12.2) were enrolled. All dominant PCa lesions, which had a median Gleason score 8 (6-9), were detected by both IAB2M and PSMA-11. The smallest of these dominant lesions was 8mm in size. Median SUVmax for dominant lesions was 3.3 (2.3-7.5) on IAB2M and 7.1 (1.6-23.2) on PSMA-11; median MR PIRADS was 4 (4-5). Of 9 Gleason 6 lesions identified on pathology, PSMA-11 detected 3 and IAB2M detected 2. Four extra-prostatic lesions in one patient were detected by both PET agents, 3 were confirmed by surgical pathology and 1 confirmed on bone scan 2 months post-op. A total of 8 lesions reported on scans were not reported by path: 3 were false positive on both scans, 3 were false positive on IAB2M scan only and 2 were false positive on PSMA-11 scan only. 5 Gleason 6 and 2 Gleason 3+4 lesions on pathology were missed by both PET agents and could be considered false negatives. Conclusions: In this small pilot series, performance of the both PET agents was very similar. An advantage of IAB2M is its hepatobiliary clearance rather than renal/urinary, which makes it potentially easier to visualize the PCa and/or pelvic disease; an advantage of PSMA-11 is the ability to image within 1 hour. Clinical trial information: NCT03675451.
Cost-effectiveness of a two-gene urine biomarker assay in MRI strategies for the initial detection of prostate cancer.
Authors: Govers Tim , Resnick Matthew J. , Trooskens Geert , Van Criekinge Wim , Schalken Jack A.
Published: March 2019

91

Background: MRI is increasingly used in men with a suspicion for prostate cancer (PCa) to target abnormal areas next to systematic biopsy. Although, MRI increases the detection of clinically significant PCa compared to systematic biopsy alone, overdiagnosis and overtreatment of insignificant disease still exists. The 2-gene mRNA PCR urine test combined with traditional risk factors SelectMDx (MDxhealth Irvine Ca) predicts clinically significant PCa, and can be used to reduce overdiagnosis and overtreatment. We assessed the cost-effectiveness of SelectMDx in a population of U.S. men who in the current situation undergo initial MRI and biopsies. Methods: We developed a decision-analytic model to simulate the downstream outcomes in the current MRI strategy, i.e. systematic biopsy plus targeted biopsy in case of a positive MRI. SelectMDx was assessed in two different diagnostic pathways: 1) before MRI to select patients for MRI and biopsy, 2) after a negative MRI to select patients for systematic biopsy. Outcomes were quality-adjusted life years (QALYs) and costs. Model parameters were informed by literature. Two scenarios regarding the mortality of missed PCa were used, using SPCG trial data and using data from the PIVOT trial. Results: Using SelectMDx before MRI (1) resulted in a health gain of 0.003 and 0.030 QALY per patient compared to the current MRI strategy, using the SPCG and PIVOT data, respectively. Cost savings were $1590 per patient and about $496 million for the yearly population of men at risk in the U.S. (n = 311,879). SelectMDx after negative MRI (2) resulted in a health gain of 0.008 and 0,011 QALY per patient using the SPCG and PIVOT data.. Cost savings were $436 per patient and about $136 million for the yearly population. Conclusions: The use of SelectMDx to guide prostate biopsy decision-making can improve health outcomes and lower costs. Cost savings were highest when SelectMDx was used before MRI to select patients for MRI and biopsy. With respect to health gain, the use of SelectMDx after negative MRI was most beneficial when assuming higher mortality for missed PCa (SPCG). When the mortality was assumed to be lower (PIVOT) SelectMDx should be used before MRI to result in the highest health gain.
Clinical utility study of confirms mdx for prostate cancer in a community urology practice.
Authors: Yonover Paul , Steyaert Sandra , Cohen Justin J. , Ruiz Celeste , Grafczynska Karolina , Garcia Elizabeth , DeHart Jessica , Brawer Michael , Groskopf Jack , Van Criekinge Wim
Published: March 2019

94

Background: There is an unmet need for methods to better identify patients most likely to benefit from repeat prostate biopsy after an initial negative biopsy. ConfirmMDx is a molecular test clinically validated for detection of prostate cancer (PCa) in tissue from PCa-negative biopsies. In this clinical utility study, we evaluated the impact of ConfirmMDx on the management of patients being considered for repeat prostate biopsy in a community urology practice. Methods: The study population consisted of 605 men with a prior PCa-negative prostate biopsy, who were counseled on the need to undergo repeat biopsy at a large community urology practice due to persistent elevated risk of PCa. All tissue cores from each PCa-negative patient were tested with the ConfirmMDx methylation-specific PCR test, and positive or negative ConfirmMDx results based on the presence or absence of GSTP1, APC or RASSF1 methylation in the biopsy tissue. ConfirmMDx results were provided to the physician for use in repeat biopsy decision-making. Medical record review was conducted at a minimum of nine months after ConfirmMDx results were reported. Results: Of the 605 subjects enrolled, 308 (51%) had a negative ConfirmMDx test result and 297 (49%) were positive. For the entire study population, average age was 64 (median 64, interquartile range 59 to 69), average serum PSA level 6.8 ng/mL (5.7, 4.3 to 8.1). The median follow-up for both Confirm positives and negatives was 10 months post-testing. Repeat biopsy rates for ConfirmMDx positive and negative men were 32.3% (96/297) and 5.8% (15/308), respectively (P < 0.001). For patients who received a biopsy during the follow-up period, the time between ConfirmMDx and repeat biopsy was shorter for ConfirmMDx positive men versus ConfirmMDx negatives (median 4 vs. 8 months, P = 0.007). Conclusions: In this utility study, ConfirmMDx had a significant impact on repeat prostate biopsy decision-making in a U.S. community urology setting. Repeat biopsy rates in ConfirmMDx positive men were six-fold higher than in ConfirmMDx negatives. These results reflect the clinical utility of ConfirmMDx for biopsy decision-making in real world clinical practice.
A randomized phase Ib/II study of nivolumab with or without BMS-986253 in combination with a short course of ADT in men with castration-sensitive prostate cancer (MAGIC-8).
Authors: Dallos Matthew , Aggen David Henry , Hawley Jessica , Lim Emerson A. , Stein Mark N. , Kelly William Kevin , Nanus David M. , Drake Charles G.
Published: March 2019

TPS329

Background: Androgen deprivation therapy (ADT) is highly effective in castration-sensitive prostate cancer (CSPC) but is associated with significant side effects. Novel strategies to reduce ADT exposure and prolong disease control are needed. ADT initially induces a complex immune infiltrate within prostate tumors, suggesting that immunologic intervention may be more effective at the time of castration. Emerging data suggests that the cytokine interleukin-8 (IL-8) recruits immunosuppressive polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment (TME) of many malignancies, including prostate cancer and serum IL-8 levels correlate with lack of response to anti-PD-1 therapy. We hypothesize that immunotherapy with nivolumab (a PD-1 inhibitor) with or without BMS-986253 (an IL-8 inhibitor) combined with degarelix (an LHRH antagonist) will be safe and promote an anti-tumor immune response that can prolong time to disease relapse in CSPC. Methods: This is a randomized, multicenter, two-arm, phase 1b/2 trial of patients with biochemically-recurrent or low volume metastatic CSPC and a rapidly rising PSA (≤12 months). 60 patients will receive immunotherapy with nivolumab or nivolumab plus BMS-986253 for 24 weeks. 16 weeks of ADT with degarelix will be added after 8 weeks of immunotherapy alone. The primary endpoints are safety and PSA relapse rate 10 months after the initiation of therapy. Secondary endpoints include relapse-free survival (RFS), time to testosterone recovery, rate of metastatic progression and change in PSA with immunotherapy alone. Correlative studies will quantify the systemic immune response through cytokine analysis and peripheral T cell profiling using serum and whole blood specimens collected from all enrolled patients. Pre- and on-treatment biopsies will also be obtained from the subgroup of patients with metastatic disease to further define changes in the TME using RNA-sequencing and quantitative multiplex immunofluorescence. The study is open with 1 patient currently enrolled at the time of submission. Clinical trial information: NCT03689699.
A phase II, dose finding, placebo-controlled, study of zuclomiphene citrate to amerliorate the frequency and severity of hot flashes caused by androgen deprivation in men with advanced prostate cancer.
Authors: Getzenberg Robert H. , Rodriguez Domingo , Hancock Michael L , Fisch Harry , Steiner Mitchell S.
Published: March 2019

TPS338

Background: Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT not only lowers testosterone, but also decreases estrogen levels which can cause significant side effects including hot flashes, loss of bone and bone fractures, and decreases in libido. Up to 80% of the men on ADT report hot flashes and 30-40% of men have moderate to severe hot flashes. Concern over hot flashes make patients less likely to begin ADT and can lead to early discontinuation of ADT. While the off-label use of potent steroidal estrogens has demonstrated efficacy, the appropriate dose as well as dosing route or schedule of these potent estrogens, has not been established. Furthermore, the potential for safety issues with potent steroidal estrogens remains a significant limitation to their clinical utility. Zuclomiphene citrate, is novel weak nonsteroidal estrogenic agent that should ameliorate hot flashes caused by ADT, and as one of the isomers of clomiphene, has a 50 year safety history of being well tolerated in men. Methods: The Phase 2, placebo controlled, dose finding clinical trial (V72203) evaluating zuclomiphene citrate (VERU-944) capsules, oral daily dosing, for the treatment of moderate to severe hot flashes in men with prostate cancer on ADT is in progress. Men are randomized to daily doses of placebo or zuclomiphene 10mg, 50mg or 100mg. V72203 is enrolling approximately 36 men per arm in 10 sites in the United States. The primary efficacy endpoint is the mean change in frequency of moderate and/or severe hot flashes from baseline to week 4 and maintained until week 12. Secondary endpoints include changes from baseline in bone turnover markers, free and total testosterone, SHBG, PSA, and safety. Hot flashes are being measured in real time utilizing an electronic data capture device (ePRO) provided to each subject. We anticipate completion of enrollment by the end of 2018 with study results by second quarter of 2019. Clinical trial information: NCT03646162.
PROPEL: A randomized, phase III trial evaluating the efficacy and safety of olaparib combined with abiraterone as first-line therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Clarke Noel W. , Armstrong Andrew J. , Thiery-Vuillemin Antoine , Oya Mototsugu , Ye Dingwei , Mateo Joaquin , Goessl Carsten Dietrich , Kang Jinyu , Liu Sherry , Saad Fred
Published: March 2019

TPS340

Background: A Phase II trial showed olaparib (tablets, 300 mg bid) in combination with abiraterone (1000 mg od plus prednisone/prednisolone 5 mg bid) significantly prolonged radiologic progression-free survival (rPFS) compared with abiraterone alone (median 13.8 vs 8.2 months; hazard ratio 0.65, 95% CI 0.44–0.97, P=0.034) in patients (pts) with mCRPC in the second-line metastatic setting who received prior docetaxel (Clarke et al. Lancet Oncol 2018). Treatment benefits were achieved irrespective of homologous recombination repair (HRR) mutation status, suggesting potential synergy between the two treatments that could impact a broader patient population. PROpel (EudraCT: 2018-002011-10) is the follow-on study to this, and the first Phase III trial to assess a PARP inhibitor in combination with abiraterone as first-line treatment in a genetically unselected mCRPC pt population. Methods: PROpel is a double-blind, placebo-controlled, international, multicenter study of pts randomized (1:1), as for the Phase II trial, to abiraterone (1000 mg od plus prednisone/prednisolone 5 mg bid) plus either olaparib (tablets, 300 mg bid) or placebo. Pts must not have received prior chemotherapy, new hormonal agents or other systemic treatment at mCRPC stage (except docetaxel at metastatic hormone-sensitive prostate cancer stage [mHSPC]). Randomization is stratified according to site of metastases (bone only vs visceral vs other) and docetaxel treatment at mHSPC stage (yes, no). The primary endpoint is investigator-assessed rPFS (RECIST v1.1 [soft tissue] and Prostate Working Cancer Group 3 [PCWG-3 criteria; bone]). Secondary objectives include time to first subsequent therapy or death, time to pain progression, overall survival, and health-related quality of life. Safety and tolerability will also be described. Exploratory endpoints include HRR subgroup analyses to confirm that efficacy is independent of HRR status. Screening across ~200 sites in 20 countries is being conducted to identify a target sample of ~720 pts. Enrollment is expected to begin in October 2018. (Study 8, NCT01972217). Clinical trial information: NCT03732820.
TALAPRO-1: An open-label, response rate phase II study of talazoparib (TALA) in men with DNA damage repair (DDR) defects and metastatic castration-resistant prostate cancer (mCRPC) who previously received taxane-based chemotherapy (CT) and progressed on greater than or equal to one novel hormonal therapy (NHT).
Authors: De Bono Johann S. , Higano Celestia S. , Saad Fred , Miller Kurt , Chen Hsiang-Chun , Czibere Akos , Healy Cynthia , Fizazi Karim
Published: March 2019

TPS342

Background: There are no approved therapies for mCRPC that has progressed on taxane and NHT. Preclinical studies showed that DDR-positive prostate tumors may be sensitized to PARP inhibition. TALA inhibits PARP, causing cell death in BRCA1/2-mutated cells. Methods: This study (NCT03148795) is enrolling patients (pts) (N ≈ 100) with measurable soft tissue disease per RECIST v1.1, progressive mCRPC, DDR likely to sensitize to PARP inhibition, ECOG performance status ≤ 2, and no brain metastases, who received 1-2 CT regimens (including ≥ 1 taxane-based CT) and progressed on ≥ 1 NHT (enzalutamide/abiraterone acetate). Prior use of PARP inhibitors, cyclophosphamide, mitoxantrone, or platinum-based CT ≤ 6 mos before study or progression on a platinum-based CT at any time are excluded. Pts will receive TALA 1 mg/d orally (pts with moderate renal impairment, 0.75 mg/d) until radiographic progression, unacceptable toxicity, or withdrawal of consent. TALA should not be discontinued based on increased prostate specific antigen (PSA) or circulating tumor cell (CTC) count alone. Primary endpoint is best objective response (OR) rate (complete/partial soft tissue response; exact 2-sided 95% confidence interval). Responses must be confirmed ≥ 4 wks later by computed tomography/magnetic resonance imaging with no evidence of bone progression ≥ 6 wks later per PCWG3 criteria. Secondary endpoints include time to OR, duration of response, PSA decrease ≥ 50%, CTC count conversion (to CTC = 0 and < 5 per 7.5 mL of blood), time to PSA progression, radiographic progression-free survival, overall survival, safety, pt-reported outcomes, and pharmacokinetics of TALA. Efficacy will be assessed every 8 wks for the first 24 wks, then every 12 wks thereafter. An initial safety and efficacy analysis will be performed on 20 pts after ≥ 8 wks of treatment. An interim efficacy analysis is planned when 60 pts have completed ≥ 6 mos of treatment. This study was sponsored by Pfizer Inc. Previously presented at ESMO 2018, FPN 859TiP, De Bono JS et al. Reused with permission. Clinical trial information: NCT03148795.
Genetic counseling processes and outcomes among prostate cancer patients (ProGen).
Authors: Vatnick Donna Rachel , Aktar Sandjida , Stopfer Jill E. , Kipnis Lindsay , Culver Samantha K. , Koeller Diane R. , Husband Alexander E. , Allen Kyle , Kilbridge Kerry L. , McGregor Bradley Alexander , Sweeney Christopher , Speare Virginia , Tippin Davis Brigette , Dolinsky Jill S. , Garber Judy Ellen , Rana Huma Q. , Taplin Mary-Ellen , Pomerantz Mark
Published: March 2019

TPS343

Background: Prostate cancer (PC) is among the leading causes of cancer mortality in males. Recent studies found 8-12% of advanced PC cases may be hereditary. Germline mutations have been reported in BRCA1/2, other DNA repair genes including ATM, CHEK2, PALB2 and DNA mismatch repair genes. Genetic testing can inform treatment decisions including drug targeting, such as PARP inhibitors for men with BRCA mutations, and checkpoint inhibitors for those with pathogenic mutations in mismatch repair genes2. Discovering a pathogenic mutation associated with increased cancer risk also prompts dissemination of this information to family, where subsequent testing can lead to risk stratification and impactful opportunities for cancer screening and prevention. It is critical that men with high risk and potentially lethal prostate cancer routinely be offered genetic testing as a component of their cancer care. Genetic counseling services are limited, and more efficient services are needed. Methods: We are investigating video education prior to genetic testing compared with in-person pretest counseling with a licensed genetic counselor (GC). ProGen is an ongoing randomized trial evaluating two distinct models of cancer genetics service delivery in 450 PC cases over a two-year period. The study is conducted in collaboration with Ambry Genetics utilizing a 67-gene cancer panel. The primary aim is analysis of the proportion and type of germline mutations identified. Secondary aims include testing uptake by arm, evaluation of distress, knowledge, satisfaction with testing services, family communication, and impact on cancer care. Results are communicated by telephone with a GC. Inclusion criteria are: potentially lethal PC (metastatic, localized with Gleason score ≥8, rising/persistent PSA after local therapy), early diagnosis (≤ 55 years), prior malignancy, and/or family history potentially indicating a hereditary cancer risk. Enrollment is 74% completed at a single institution. (NCT03328091). 1 Pritchard CC, et al. Inherited DNA‐repair gene mutations in men with metastatic prostate cancer. NEJM. 2016;375:443 2 Mateo J, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. NEJM . 2015;373(18):1697-1708 Clinical trial information: NCT03328091.